NEW TREATMENT AND PREVENTION OF DISEASES BASED ON IMMUNOLOGICAL MEMORY (2023)

The present disclosure relates to new therapy and disease prevention based on immunological memory. In one aspect, the present disclosure relates to mechanism-based cancer prevention/therapy. In a specific example, the present disclosure relates to a method of cancer therapy or a method of prevention using a memory response by a non-tumor antigen of a pathogen of a past infection, such asMycobacterium tuberculosisExtract as a customization marker.

The technology for disease therapy was developed from several approaches.

For example, for cancer therapy, current cancer therapy is roughly classified into the following three categories. (1) A therapeutic method for introducing a cancer-specific antigen (WT1 or cancer-specific neoantigen) with an adjuvant base and a therapeutic vaccine or a cancer antigen-dependent chimeric T cell, or a therapeutic method for introducing a cancer-presenting cell antigen (DC), which requires high medical costs , as well as a cancer antigen for each patient. Although specific immunotherapy can be given due to the use of a specific cancer antigen, the therapy can only be given to certain patients who have a cancer antigen. Since a cancer antigen is required, such a therapeutic method cannot be used for healthy persons. Therefore, the procedure cannot be used for prevention. (2) An inhibitor of a checkpoint molecule that suppresses anti-cancer immunity. An immune checkpoint molecule is a molecule that regulates a T cell response in the body. An immune checkpoint molecule inhibitor inhibits an immunosuppressive molecule expressed on a host cancer cell or regulatory T cell and promotes anti-tumor immunity. However, the problem to be solved with these agents is that they exhibit a useful effect but have strong side effects such as an increased risk of inducing an autoimmune or like disease since the effect on immune reactions to be suppressed is also deactivated. Therefore, the agents are not suitable for preventive treatment aimed at healthy people. (3) A vaccine for use in preventing oncogenesis by preventing infections. While this includes a vaccine aimed at preventing HPV infection associated with cervical cancer, the cancer target is limited.

The inventors have developed a new disease prevention and therapy based on immunological memory as a result of careful studies. As an aspect thereof, the present disclosure provides mechanism-based cancer prevention/therapy. A representative example thereof includes a method of cancer therapy or a method of prevention using a memory response by a non-tumor antigen of a pathogen of a past infection such asMycobacterium tuberculosisExtract as a customization marker.

Therefore, the present disclosure provides the following as representative aspects.

(Item 1) A composition for use in activating a regulatory T cell (Treg) having immunological memory of a non-target antigen component that is suppressed in an individual against a target, comprising the non-target antigen component.
(Item 2) The composition of any one of the above items, wherein the activation of Treg confers a target-killing ability or an immunostimulatory effect against the target.
(Item 3) A composition for use in activating a regulatory T cell (Treg) having immunological memory of a non-tumor antigen component that is suppressed in a subject, comprising the non-tumor antigen component.
(Item 4) The composition according to any one of the above items, wherein the Treg activation imparts a tumoricidal ability or an immunostimulatory effect against the tumor.
(Item 5) The composition of any of the previous items, where Treg is a memory T cell.
(Item 6) The composition of one of the previous items where the Treg is CD4 positive.
(Item 7) The composition according to any one of the above items, wherein the antigenic component comprises a protein.
(Item 8) The composition according to any one of the preceding items, wherein the antigenic component comprises an antigen selected from the group consisting of a pathogen of infection or part thereof, an antigen associated with a history, and an antigen associated with a history of vaccination.
(Item 9) The composition according to any one of the above items, wherein the antigen component comprises a humanMycobacterium tuberculosishot water extract or an influenza virus antigen.
(Item 9A) The composition of any of the preceding items, further comprising one or more features of one or more of the preceding and following items.
(Item 10) A composition characterized in that the composition is used in a method comprising checking whether the antigenic component has an immunological memory of Treg in the subject, and administering the antigenic component to the subject when the subject has an immunological memory of the antigenic component.
(Item 11) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigenic component specific in the subject for a component which is from a causative agent distinguishes the disease, disorder or condition.
(Item 12) The composition of any preceding, wherein the disease, disorder or condition comprises cancer and preferably wherein the antigenic component is a non-tumor antigenic component.
(Item 13) The composition of any of the preceding items, wherein the antigenic component is specific to a subject's memory T cell.
(Item 14) The composition according to any one of the above items, wherein the memory T cell is a memory regulatory (IL-2 producing) T cell.
(Item 15) The composition of any of the preceding items, in which the antigenic component has an immunostimulating effect.
(Item 16) The composition according to any one of the preceding, in which the antigen component acts on CD4-positive memory T cells in an antigen-dependent manner.
(Item 17) The composition according to any one of the above items, wherein the antigenic component has an activity to affect a ratio of presence between Foxp3-positive Treg cells and IFN-γ-producing T cells.
(Item 18) The composition of one of the previous items, where the bias is an increase in IFN-γ producing T cells compared to Foxp3 positive Treg cells.
(Item 19) The composition according to any one of the above items, wherein the antigenic component has an activity to affect a presence ratio between Foxp3-positive Treg cells and type 1 helper T cells.
(Item 20) The composition according to any one of the above items, wherein the IFN-γ producing T cells comprise Type 1 helper T cells.
(Item 21) The composition of any preceding item, in which the antigenic component has an activity to affect a ratio of the presence of Th1 cells.
(Item 22) The composition according to any one of the above items, wherein the IFN-γ producing T cells are Th1 positive T-bet cells.
(Item 23) The composition according to any one of the above items, wherein the antigen component which is specific has the ability to increase at least one selected from the group consisting of IFN-γ production capacity, IL-γ production capacity 2 and TNF-α Production capacity in a test sample.
(Item 24) The composition of any of the above items, wherein the antigenic component is a protein.
(Item 25) A biomarker for determining whether a non-tumor antigenic component has an anticancer effect in a subject, the biomarker comprising at least one selected from the group consisting of whether the antigenic component (i) is antigen-dependent on CD4 positive memory T affects cells, (ii) alters memory-regulating T cells, (iii) alters ability to produce IFN-γ, (iv) alters ability to produce IL-2, and (v) alters ability to produce TNF-α altered.
(Item 26) A composition or kit comprising an agent or agent for detecting a biomarker to determine whether a non-tumor antigenic component has an anticancer effect in a subject, wherein the biomarker comprises at least one selected from the group , consisting of whether the non-tumor component tumor antigen component (i) acts antigen-dependently on CD4-positive memory T cells, (ii) alters memory regulatory T cells, (iii) alters ability to produce IFN-γ, ( iv) alters IL-2 production capacity; and (v) alters TNF-α production capacity.
(Item 27) The composition of any of the preceding items, wherein the antigenic (non-tumor) component comprises an antigen associated with medical and vaccination history.
(Item 28) The composition according to any one of the above items, wherein the subject is a subject with a history of infection and the antigen component comprises an antigen for the infection.
(Item 29) The composition of any of the preceding items, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus -Infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 30) The composition of any of the preceding items when the subject is a subject with a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component comprises a humanMycobacterium tuberculosishot water extract.
(Item 31) The composition of any of the above items, wherein the subject is a subject with a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the antigenic component comprises an influenza virus.
(Item 32) The composition of any of the preceding items, wherein the disease, disorder or condition comprises melanoma.
(Item 33) The composition according to any one of the preceding items, wherein the antigenic component comprises a protein, a part thereof or a peptide.
(Item 34) The composition according to any one of the preceding items, wherein the antigenic component comprises a component capable of eliciting an immune response using CD4-positive T cells.
(Item 35) The composition according to any one of the above items, wherein the subject is verified whether the subject can elicit an anti-tumor immune response by CD4+ T cells and whether the subject can elicit an anti-tumor immune response by CD4-T -Cells capable of producing positive cells, the composition is administered.
(Item 36) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigenic component specific in the subject for a component which is from a causative agent distinguishes the disease, disorder, or condition in which

the disease, disorder or condition involves melanoma,

the antigenic component is a protein, part thereof or a peptide capable of eliciting an immune response by CD4+ T cells, and

Cancer includes cancer that is treatable and preventable with an immune response via CD4+ T cells,

wherein the subject is assessed as to whether the subject can elicit an anti-tumor immune response via CD4+ T cells and whether the subject can elicit an anti-tumor immune response via CD4+ T cells, the composition being administered.

(Item 37) A composition for use in treating or preventing a cancer or tumor in a subject, the composition comprising a non-tumor antigen component, the non-tumor antigen component comprising an immune memory regulatory T cell (Treg). non-activated -tumor antigen component which is suppressed in the patient and in which the Treg has the effect of promoting regulatory activity or antitumor immunological effect in cancer or tumor.
(Item 38) A method of making or otherwise providing a composition for use in preventing or treating cancer in a subject, the method comprising:
A) identifying a non-tumor specific antigen for the subject;
B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and
C) to produce or otherwise provide the selected non-tumor antigen.
(Item 39) The method of any of the above with one or more features in any of the above in B).
(Item 40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, the method comprising:
B) Identifying whether the subject has an immunological memory of the non-tumor antigen and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory.
(Item 41) The method of any of the above with one or more features in any of the above in B).
(Item 42) A method for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality, comprising:
a) obtaining a response profile to the antigen of a subject;
b) identify an antigenic component or combination of antigenic components from the antigenic response profile based on whether the antigenic component or combination of antigenic components has or is exhibiting an immune response to the subject; and
c) administering to the subject the antigenic component or combination of antigenic components identified in step b) in an amount sufficient to elicit an immune response in the subject.
(Item 43) The method of any of the preceding items when the disease, disorder or condition involves cancer.
(Item 44) The method of any preceding item, wherein obtaining an antigen response profile comprises verifying a subject's prior physical condition, verifying that one or more of the candidate antigens in a sample of the subject are responsive, or both .
(Item 45) The method of any preceding item, wherein obtaining an antigen response profile comprises identifying an antigenic component or combination of antigenic components that elicit an immune response via positive CD4 T cells.
(Item 46) The method according to any one of the preceding items, wherein
i) the antigen response profile includes at least one selected from the group consisting of an interview, medical history or vaccination history based on the Maternal and Child Health Handbook, its equivalent or similar and a combination thereof, and/ or
ii) testing whether one or more of the candidate antigens respond includes withdrawing a body fluid (e.g., blood) from the subject and separating the peripheral blood cells, then measuring whether the peripheral blood cells produce a cytokine in response to a so associated antigen produce antigen profile and other biomarkers.
(Item 47) The method of any preceding item, further comprising periodically testing antigen responsiveness and confirming that responsiveness is maintained.
(Item 48) The method according to any one of the preceding items, wherein a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) collecting blood from the subject and separating peripheral blood cells, and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen consistent with fitness and other biomarkers; and
iii) identifying an appropriate antigenic component or combination of antigenic components from a result of ii).
(item 49) The method of any preceding item, wherein the past physical condition includes medical history and vaccination history.
(Item 50) The method according to any one of the preceding items, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigenic component or a combination of antigenic components for the infection.
(Item 51) The method according to any one of the preceding items, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 52) The method of any preceding item, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component or combination of antigenic components comprises a humanMycobacterium tuberculosishot water extract.
(Item 53) The method according to any one of the preceding items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or antigenic responsiveness to an influenza virus, and the antigenic component or combination of antigenic components includes an influenza virus .
(Item 54) The method according to any one of the above items, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item 55) The method according to any one of the preceding items, wherein the subject is in a state before onset of cancer, after cancer treatment, in an early stage of onset of cancer, or in a precancerous state.
(Item 56) The method according to any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma where CD8 positive T cells are generally less effective.
(Item 57) The method according to any one of the preceding items, wherein the subject exhibits immunoresistance.
(Item 58) The method of any preceding item, wherein step ii) comprises measuring induction of cells simultaneously producing IFN-γ, IL-2, TNF-α or a variety of cytokines.
(Item 59) The method according to any one of the preceding items, in which the antigen response profile is obtained by performing the diagnosis of the companion in advance based on the anamnesis and the vaccination history.
(Item 60) The method according to any one of the preceding items, wherein the previous physical condition and the antigenic component or combination of antigenic components is a history of tuberculosis infection in a humanMycobacterium tuberculosishot water extract.
(Item 61) The method according to any one of the preceding items, wherein the past physical condition and the antigenic component or combination of antigenic components are a history of infection with influenza and an influenza virus.
(Item 62) The method according to any one of the preceding items, wherein the previous physical condition and the antigenic component or combination of antigenic components are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio , Mumps/Mumps Epidemic, Rotavirus Infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 63) The method according to any one of the preceding items, when the subject is a subject who has a history of BCG vaccination or a history of tuberculosis infection or has been confirmed to be antigen-responsive,

where notMycobacterium tuberculosisExtract is administered prophylactically before the onset or at an early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.

(Item 64) The method according to any of the preceding items, when the subject is a subject with a history of influenza vaccination or a history of influenza infection or has been confirmed to be responsive to antigens,

where the influenza vaccine is given prophylactically before the onset, to prevent recurrence after therapy, or at an early stage of the onset of cancer and an influenza vaccine is given subcutaneously or intradermally at an early stage of the onset of cancer or precancerous lesions.

(Item 65) A method of preventing or treating an immunity to cancer based on any of the above items, comprising revaccination of the antigenic component or combination of antigenic components.
(Article 66) A method of preventing or treating a person's cancer having a non-tumor component, the component being an antigen or extract identified through an interview and/or identified by reference to the person's history or vaccination history when the subject is a subject with a history of infection or a history of vaccination described in any of the foregoing items, wherein the component is administered to prevent recurrence after therapy, administered prophylactically before initiation, or at an early stage of initiation of therapy cancer is administered to the subject, and optionally the component is administered in an early stage of an early stage cancer or precancerous condition.
(Item 67) The method according to any one of the preceding, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, low immune system responsiveness cancer, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma , in which CD8+ T cells are generally less effective.
(Item 68) The method according to any preceding item, wherein the subject is a patient exhibiting immune resistance.
(Item 69) The method of any preceding item, wherein the identification of responsiveness is characterized by infection history, vaccination history and measurement of induction of IFN-γ, IL-2, TNF-α producing cells or a plurality of cytokines simultaneously under use of peripheral blood.
(Item 70) The method according to any of the preceding points, in which theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(Item 71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or another extract of an influenza virus (highly safe extract).
(Item 72) The method according to any one of the above items, wherein the antigenic component is a protein.
(Item 73) A vaccine formulation comprising the antigen of any one of the preceding items and an adjuvant base.
(Item 74) The vaccine formulation according to any one of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1 immune response.
(Item 75) The vaccine formulation according to any one of the preceding items, wherein the vaccine formulation is used for personalized medicine.
(Item 76) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigenic component specific in the subject for a component that is differs from a causative component agent of the disease, disorder or condition and is administered subcutaneously or intratumorally once daily (week one) and once weekly (week two and thereafter).
(Item 77) The composition according to any one of the above items, wherein the antigen component is contained at about 0.001 µg or more per unit formulation.
(Item 78) A method of treating or preventing cancer or tumor in a subject, characterized in that it comprises:
a) identifying a non-tumor specific antigen for the subject based on an antigen response profile;
b) identifying whether the subject has an immunological memory of the non-tumor antigen to identify a subject with immunological memory; and
c) administering the non-tumor antigen to the subject determined to have the immunological memory.
(Item 79) The method of any preceding item, wherein the antigen response profile comprises vaccination history and/or infection history.
(Item 80) The method of any preceding item, wherein identifying a subject having immunological memory by stimulating peripheral blood mononuclear cells (PBMC) isolated from the subject or infiltrating immune cells isolated from a tumor mass with the non-tumor antigen, measuring cytokine production and identifying a subject with a predetermined factor increased level of cytokine production compared to the level prior to stimulation as a subject with immunological memory.
(Item 81) The method according to any preceding item, wherein non-tumor antigen is administered once a day (first week) and once a week (second week and thereafter).
(Item 82) The method according to any one of the above items, wherein non-tumor antigen is administered at about 0.001 µg/dose to about 1 mg/dose.
(Item 83) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject comprising mHSP10 and/or MTB12 and/or lipoprotein LpqH.
(Item 84) The composition, kit, biomarker, vaccine formulation or method according to any one of the preceding items, comprising a plurality of agents comprising the antigen component.
(Item 85) The composition, kit, biomarker, vaccine formulation or method of any preceding item, wherein each component of the plurality of agents is provided as separate compositions.
(Item A1) A method of activating a regulatory T cell (Treg) having immunological memory of a non-target antigen component that is suppressed in a subject, comprising administering to the subject an effective amount of the non-target antigen component.
(Item A2) The method according to any one of the preceding items, wherein the activation of Treg confers a target-killing ability or an immunostimulatory effect against the target.
(Item A3) A method of activating a regulatory T cell (Treg) having immunological memory of a non-tumor antigen component that is suppressed in a subject, comprising administering to the subject an effective amount of the non-tumor antigen component.
(Item A4) The method according to any one of the above items, wherein the activation of Treg confers a tumoricidal ability or an immunostimulatory effect against the tumor.
(Item A5) The method of any preceding item, wherein Treg is a storage T-cell.
(Item A6) The method of any preceding item, wherein the Treg is CD4 positive.
(Item A7) The method according to any preceding item, wherein the antigenic component comprises a protein.
(Item A8) The method according to any one of the preceding items, wherein the antigenic component comprises an antigen selected from the group consisting of a pathogen of infection or a part thereof, an antigen associated with a history, and an antigen associated with a history of vaccination.
(Item A9) The method according to any preceding item, wherein the antigenic component comprises a humanMycobacterium tuberculosishot water extract or an influenza virus antigen.
(Item A9A) The method according to any one of the above items, further comprising one or more characteristics of one or more of the above and following items.
(Item A10) A method comprising verifying that the antigenic component has an immunological memory for Treg in the subject and administering an effective amount of the antigenic component to the subject when the subject has an immunological memory for the antigenic component.
(Item A11) A method for use in treating or preventing a disease, disorder, or condition associated with an immunological abnormality in a subject, comprising administering to the subject an effective amount of an antigenic component specific to a subject in the subject Component is distinct from a causative agent of the disease, disorder, or condition.
(Item A12) The method according to any one of the preceding items, wherein the disease, disorder or condition comprises cancer, and preferably wherein the antigenic component is a non-tumor antigenic component.
(Item A13) The method according to any one of the above items, wherein the antigen component is specific to a subject's memory T cell.
(Item A14) The method of any preceding item, wherein the memory T cell is a memory regulatory (IL-2 producing) T cell.
(Item A15) The method according to any one of the above items, wherein the antigen component has an immunostimulatory effect.
(Item A16) The method according to any one of the above items, wherein the antigen component acts on CD4-positive memory T cells in an antigen-dependent manner.
(Item A17) The method according to any one of the above items, wherein the antigenic component has an activity to shift a presence ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells.
(Item A18) The method according to any one of the preceding items, wherein the deviation is an increase in IFN-γ-producing T cells compared to Foxp3-positive Treg cells.
(Item A19) The method according to any one of the above items, wherein the antigen component has an activity to affect a presence ratio between Foxp3-positive Treg cells and type 1 helper T cells.
(Item A20) The method according to any one of the preceding items, wherein the IFN-γ producing T cells comprise type 1 helper T cells.
(Item A21) The method according to any one of the preceding items, wherein the antigen component has an activity of affecting a Th1 cell presence ratio.
(Item A22) The method according to any preceding item, wherein the IFN-γ producing T cells are Th1 positive T-bet cells.
(Item A23) The method according to any one of the preceding items, wherein the antigen component that is specific has the ability to increase at least one selected from the group consisting of IFN-γ production capacity, IL-γ production capacity 2 and TNF-α Production capacity in a test sample.
(Item A24) The method according to any preceding item, wherein the antigenic component is a protein.
(Item A25) A method for determining whether a non-tumor antigenic component has an anticancer effect in a subject, comprising determining using a biomarker comprising at least one selected from the group consisting of whether the antigenic component (i) at a cancer dependent, Weise antigen affects CD4+ memory T cells, (ii) alters memory regulating T cells, (iii) alters IFN-γ production capacity, (iv) alters IL-2 production capacity, and (v) alters the ability of TNF-α production.
(Item A26) A method of detecting a biomarker to determine whether a non-tumor antigen component has an anticancer effect in an individual, the biomarker comprising at least one selected from the group consisting of whether the non-tumor antigen Component (i) antigen- acts dependently on memory CD4+ T cells, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production capacity, (iv) alters IL-2 production capacity and ( v) alters the ability to produce TNF-α.
(Item A27) The method according to any one of the preceding items, wherein the (non-tumor) antigen component comprises an antigen associated with history and vaccination history.
(Item A28) The method according to any one of the preceding items, wherein the subject is a subject with a history of infection and the antigen component comprises an antigen for the infection.
(Item A29) The method according to any one of the preceding items, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item A30) The method according to any one of the preceding items, when the subject is a subject with a history of BCG vaccination, a history of tuberculosis infection, or an antigenic reaction theretoMycobacterium tuberculosis, and the antigenic component comprises a humanMycobacterium tuberculosishot water extract.
(Item A31) The method according to any preceding item, wherein the subject is a subject with a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the antigenic component comprises an influenza virus.
(Item A32) The method of any preceding item, wherein the disease, disorder or condition comprises melanoma.
(Item A33) The method according to any preceding item, wherein the antigenic component comprises a protein, a part thereof or a peptide.
(Item A34) The method according to any preceding item, wherein the antigenic component comprises a component capable of eliciting an immune response using CD4-positive T cells.
(Item A35) The method according to any preceding item, wherein the subject is evaluated whether the subject can elicit an anti-tumor immune response via CD4+ T cells and whether the subject can elicit an anti-tumor immune response via T cells can cause. cells CD4 positive cells, the composition is administered.
(Item A36) A method for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, comprising administering to the subject an effective amount of an antigenic component specific to a subject in the subject Component is other than a causative agent of the disease, disorder or condition in which

the disease, disorder or condition involves melanoma,

the antigenic component is a protein, part thereof or a peptide capable of eliciting an immune response by CD4+ T cells, and

Cancer includes cancer that is treatable and preventable with an immune response via CD4+ T cells,

wherein the subject is evaluated as to whether the subject can elicit an anti-tumor immune response via CD4 positive T cells and whether the subject can elicit an anti-tumor immune response via CD4 positive T cells, the antigen component is administered.

(Item A37) A method of treating or preventing cancer or tumor in a subject comprising administering an effective amount of a non-tumor antigen component, wherein the non-tumor antigen component activates a regulatory T cell (Treg) having memory immunological activity the non-tumor antigen component which is suppressed in the subject and in which the Treg has an effect of promoting regulatory activity or anti-tumor immunological effect in cancer or tumor.
(Item A38) A method of making or otherwise providing a composition for use in preventing or treating cancer in a subject, the method comprising:
A) identifying a non-tumor specific antigen for the subject;
B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and
C) to produce or otherwise provide the selected non-tumor antigen.
(Item A39) The method of any of the items above with one or more features in any of the items in B) above.
(Item A40) A method of determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising:
B) Identifying whether the subject has an immunological memory of the non-tumor antigen and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory.
(Item A41) The method of any of the items above with one or more features in any of the items in B) above.
(Item A42) A method for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality, comprising:
a) obtaining a response profile to the antigen of a subject;
b) identifying an antigenic component or combination of antigenic components from the antigen response profile, wherein the antigenic component or combination of antigenic components is identified based on whether the antigenic component or combination of antigenic components has demonstrated or is showing an immune response to the subject; and
c) administering to the subject the antigenic component or combination of antigenic components identified in step b) in an amount sufficient to elicit an immune response in the subject.
(Item A43) The method of any of the preceding items when the disease, disorder or condition involves cancer.
(Item A44) The method of any preceding item, wherein obtaining an antigen response profile comprises verifying a subject's prior physical condition, verifying that one or more of the candidate antigens in a sample of the subject are responsive, or both.
(Item A45) The method of any preceding item, wherein obtaining an antigen response profile comprises identifying an antigen component or combination of antigen components that elicits an immune response using T-CD4 positive cells.
(Item A46) The method of any of the previous items where
i) the antigen response profile includes at least one selected from the group consisting of an interview, medical history or vaccination history based on the Maternal and Child Health Handbook, its equivalent or similar and a combination thereof, and/ or
ii) testing whether one or more of the candidate antigens respond includes withdrawing a body fluid (e.g., blood) from the subject and separating the peripheral blood cells, then measuring whether the peripheral blood cells produce a cytokine in response to a so associated antigen produce antigen profile and other biomarkers.
(Item A47) The method of any preceding item, further comprising periodically testing antigen reactivity and confirming that reactivity is maintained.
(Item A48) The method according to any one of the preceding items, wherein a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) collecting blood from the subject and separating peripheral blood cells, and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen consistent with fitness and other biomarkers; and
iii) identifying a suitable antigenic component or combination of antigenic components from a result of ii).
(Item A49) The method of any preceding item, wherein the prior physical condition includes medical history and vaccination history.
(Item A50) The method according to any one of the above items, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigenic component or a combination of antigenic components for the infection.
(Item A51) The method according to any one of the preceding items, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item A52) The method of any of the preceding items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component or combination of antigenic components comprises a humanMycobacterium tuberculosishot water extract.
(Item A53) The method of any preceding item, wherein the physical condition comprises a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza vaccine, and the antigenic component or combination of antigenic components is influenza includes virus.
(Item A54) The method according to any one of the above items, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item A55) The method of any preceding item, wherein the subject is in a precancerous state, post cancer treatment, in an early stage of cancerous onset, or in a precancerous state.
(Item A56) The method of any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low susceptibility to the immune system, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma where CD8 positive T cells are generally less effective.
(Item A57) The method according to any one of the preceding items when the subject exhibits immunoresistance.
(Item A58) The method of any preceding item, wherein step ii) comprises measuring induction of cells simultaneously producing IFN-γ, IL-2, TNF-α or a variety of cytokines.
(Item A59) The method according to any one of the preceding items, in which the antigen response profile is obtained by performing the diagnosis of the companion in advance based on the anamnesis and the vaccination history.
(Item A60) The method of any preceding item, wherein the previous physical condition and the antigenic component or combination of antigenic components is a history of tuberculosis infection in a humanMycobacterium tuberculosishot water extract.
(Item A61) The method according to any one of the preceding items, wherein the past physical condition and the antigenic component or combination of antigenic components are a history of infection with influenza and an influenza virus.
(Item A62) The method according to any one of the preceding items, wherein the previous physical condition and the antigenic component of the combination of antigenic components is one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox, measles/rubella, polio, mumps/ Mumps epidemic, rotavirus infection, chicken pox, yellow fever, ebola, west nile fever, hib infection, pneumococcal infection, whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item A63) The method according to any preceding item, when the subject is a subject who has had a history of BCG vaccination or a history of tuberculosis infection or has been confirmed to be antigen-responsive,

where notMycobacterium tuberculosisExtract is administered prophylactically before the onset or at an early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.

(Item A64) The method of any of the preceding items, if the subject is a subject with a history of influenza vaccination or influenza infection, or has been confirmed to be antigen-responsive;

where the influenza vaccine is given prophylactically before the onset, to prevent recurrence after therapy, or at an early stage of the onset of cancer and an influenza vaccine is given subcutaneously or intradermally at an early stage of the onset of cancer or precancerous lesions.

(Item A65) A method for preventing or treating an immunity against cancer based on any of the foregoing, comprising revaccinating the antigenic component or combination of antigenic components.
(Item A66) A method of preventing or treating cancer in a subject having a non-tumor component, wherein the component is an antigen or extract identified through interview and/or identified by reference to the subject's medical history or vaccination history , wherein the subject is a subject with a history of infection or a history of vaccination described in any of the preceding items, the method comprising administering an effective amount of the component to prevent recurrence after therapy, administered prophylactically prior to onset or at an early stage stage of cancer onset to the subject and optionally comprises administering an effective amount of the component at an early stage of cancer onset or a precancerous condition.
(Item A67) The method according to any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low immune system susceptibility, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma, where CD8+ T cells are generally less effective.
(Item A68) The method of any preceding item when the subject is a patient who is immunologically resistant.
(Item A69) The method of any of the preceding items, wherein the identification of responsiveness is characterized by infection history, vaccination history and measurement of induction of IFN-γ, IL-2, TNF-α producing cells or a variety of cytokines simultaneously with peripheral Blood.
(Item A70) The method according to any one of the preceding items, in which theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(Item A71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or another extract of an influenza virus (highly safe extract).
(Item A72) The method according to any one of the preceding items, wherein the antigenic component is a protein.
(Item A73) A vaccine formulation comprising the antigen of any one of the preceding items and an adjuvant base.
(Item A74) The vaccine formulation according to any one of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1 immune response.
(Item A75) The vaccine formulation according to any one of the preceding articles, wherein the vaccine formulation is used for personalized medicine.
(Item A76) A method for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, comprising administering subcutaneously or intratumorally an effective amount of an antigenic component specific to the subject for a Component is except for a causative agent of the disease, disorder or condition once a day (first week) and once a week (second week and thereafter).
(Item A77) The method according to any one of the above items, wherein the antigen component is contained in an amount of about 0.001 µg or more per unit formulation.
(Item A78) A method of treating or preventing cancer or tumor in a subject, characterized in that it comprises:
a) identifying a non-tumor specific antigen for the subject based on an antigen response profile;
b) identifying whether the subject has an immunological memory of the non-tumor antigen to identify a subject with immunological memory; and
c) administering an effective amount of the non-tumor antigen to the subject determined to have the immunological memory.
(Item A79) The method of any preceding item, wherein the antigen response profile comprises vaccination history and/or infection history.
(Item A80) The method according to any one of the preceding items, wherein identifying a subject with immunological memory by stimulating peripheral blood mononuclear cells (PBMC) isolated from the subject or infiltrating immune cells isolated from a tumor mass with the non-tumor antigen, measuring cytokine production and identifying a subject with a predetermined factor increased level of cytokine production compared to the level prior to stimulation as a subject with immunological memory.
(Item A81) The method of any preceding item, wherein non-tumor antigen is administered once a day (first week) and once a week (second week and beyond).
(Item A82) The method according to any one of the above items, wherein non-tumor antigen is administered at about 0.001 µg/dose to about 1 mg/dose.
(Item A83) A method for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject comprising administering mHSP10 and/or MTB12 and/or LpqH lipoprotein.
(Item A84) The method according to any one of the preceding items, comprising administering a plurality of agents comprising the antigen component.
(Item A85) The method according to any one of the preceding items, wherein each component of the plurality of agents is administered as separate compositions.
(Item B1) A non-target antigen component for activating a regulatory T cell (Treg) with immunological memory of the non-target antigen component suppressed in a subject against a target.
(Item B2) The antigenic component of any of the above items, wherein the activation of Treg confers a target-killing ability or an immunostimulatory effect against the target.
(Item B3) A non-tumor antigen component to activate a regulatory T cell (Treg) with immunological memory of the non-tumor antigen component being suppressed in an individual.
(Item B4) The antigenic component of any of the above, wherein the activation of Treg confers a tumoricidal ability or an immunostimulatory effect against the tumor.
(Item B5) The antigenic component of any of the previous items, where Treg is a memory T cell.
(Item B6) The antigenic component of any of the previous items where Treg is CD4 positive.
(Item B7) The antigenic component according to any one of the preceding items, wherein the antigenic component comprises a protein.
(Item B8) The antigenic component according to any preceding item, wherein the antigenic component comprises an antigen selected from the group consisting of a pathogen of infection or a part thereof, an antigen associated with a history, and an antigen associated with a history of vaccination.
(Item B9) The antigen component according to any one of the above items, wherein the antigen component comprises a humanMycobacterium tuberculosishot water extract or an influenza virus antigen.
(Element B9A) The antigenic component of any of the preceding elements, which further comprises one or more characteristics of one or more of the preceding and following elements.
(Item B9B) An extract comprising the antigenic component of any of the preceding items.
(Item B10) An antigen component, characterized in that the antigen component is used in a method comprising checking whether the antigen component has an immunological memory of Treg in the subject, and administering the antigen component to the subject if the subject has a memory -Immune response to the component has antigen.
(Item B11) An antigenic component for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, wherein the antigenic component in the subject is specific for a component derived from a pathogen distinguishes the disease, disorder or condition.
(Item B12) The antigenic component according to any one of the preceding, wherein the disease, disorder or condition comprises cancer, and preferably wherein the antigenic component is a non-tumor antigen component.
(Item B13) The antigenic component of any of the foregoing items, wherein the antigenic component is specific to a subject's memory T cell.
(Item B14) The antigenic component of any of the above, wherein the memory T cell is a memory-regulating (IL-2-producing) T cell.
(Item B15) The antigenic component according to any one of the above items, wherein the antigenic component has an immunostimulatory effect.
(Item B16) The antigen component according to any one of the preceding items, wherein the antigen component acts on CD4-positive memory T cells in an antigen-dependent manner.
(Item B17) The antigen component according to any one of the above items, wherein the antigen component has an activity to affect a ratio of presence between Foxp3-positive Treg cells and IFN-γ-producing T cells.
(Item B18) The antigenic component of any of the previous items, the bias being an increase in IFN-γ producing T cells compared to Foxp3 positive Treg cells.
(Item B19) The antigen component according to any one of the above items, wherein the antigen component has an activity to shift a presence ratio between Foxp3-positive Treg cells and type 1 helper T cells.
(Item B20) The antigenic component according to any one of the above, wherein the IFN-γ producing T cells comprise Type 1 helper T cells.
(Item B21) The antigenic component of any of the above, wherein the antigenic component has an activity to affect the presence ratio of Th1 cells.
(Item B22) The antigen component according to any one of the preceding items, wherein the IFN-γ producing T cells are Th1 positive T-bet cells.
(Item B23) The antigen component according to any one of the above items, wherein the antigen component which is specific has the ability to increase at least one selected from the group consisting of IFN-γ production capacity, IFN-γ production capacity, IL-2 and TNF ability to produce -α in a test sample.
(Item B24) The antigenic component according to any one of the preceding items, wherein the antigenic component is a protein.
(Item B25) A biomarker for determining whether a non-tumor antigenic component has an anticancer effect in an individual, the biomarker comprising at least one selected from the group consisting of whether the antigenic component (i) is antigen-dependent on CD4 positive memory T affects cells, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production capacity, (iv) alters IL-2 production capacity, and (v) alters TNF-γ α production capacity.
(Item B26) A composition or kit comprising an agent or agent for detecting a biomarker to determine whether a non-tumor antigenic component has an anticancer effect in a subject, wherein the biomarker comprises at least one selected from the group , consisting of whether the non-tumor component of the tumor antigen (i) acts antigen-dependently on CD4-positive memory T-cells, (ii) alters memory-regulatory T-cells, (iii) alters the ability to produce IFN-γ, ( iv) alters ability to produce IL-2; and (v) alters ability to produce TNF-α.
(Item B27) The antigenic component according to any one of the preceding items, wherein the (non-tumor) antigenic component comprises an antigen associated with history and vaccination history.
(Item B28) The antigen component of any of the above items, wherein the subject is a subject with a history of infection and the antigen component comprises an antigen for the infection.
(Item B29) The composition of any of the above, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item B30) The antigenic component of any of the above items when the subject is a subject with a history of BCG vaccination, a history of tuberculosis infection, or antigen susceptibilityMycobacterium tuberculosis, and the antigenic component comprises a humanMycobacterium tuberculosishot water extract.
(Item B31) The antigenic component of any of the above items when the subject is a subject with a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus and the antigenic component comprises an influenza virus.
(Item B32) The antigenic component of any of the preceding items when the disease, disorder or condition involves melanoma.
(Item B33) The antigenic component according to any one of the preceding items, wherein the antigenic component comprises a protein, a part thereof or a peptide.
(Item B34) The antigenic component according to any preceding item, wherein the antigenic component comprises a component capable of eliciting an immune response using CD4-positive T cells.
(Item B35) The antigenic component of any of the preceding items when the subject is verified that the subject can elicit an anti-tumor immune response by CD4+ T cells and that the subject can elicit an anti-tumor immune response by cells CD4+ T cells are administered the antigen component.
(Item B36) An antigenic component for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, wherein the antigenic component is an antigenic component specific in the subject to a component that is of a causative agent of the disease, disorder or condition in which

the disease, disorder or condition involves melanoma,

the antigenic component is a protein, part thereof or a peptide capable of eliciting an immune response by CD4+ T cells, and

Cancer includes cancer that is treatable and preventable with an immune response via CD4+ T cells,

wherein the subject is evaluated as to whether the subject can elicit an anti-tumor immune response via CD4 positive T cells and whether the subject can elicit an anti-tumor immune response via CD4 positive T cells, the antigen component is administered.

(Item B37) An antigenic component for treating or preventing cancer or tumor in a subject, wherein the antigenic component comprises a non-tumor antigen component, wherein the non-tumor antigen component activates a regulatory T cell (Treg) having immunological memory of the non-tumor antigen -Component that is suppressed in a patient and in which the Treg has the effect of promoting regulatory activity or antitumor immunological effect in cancer or tumor.
(Item B38) A method of making or otherwise providing a composition for use in preventing or treating cancer in a subject, the method comprising:
A) identifying a non-tumor specific antigen for the subject;
B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and
C) to produce or otherwise provide the selected non-tumor antigen.
(Item B39) The method of any of the above with one or more features in any of the items in B) above.
(Item B40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, the method comprising:
B) Identifying whether the subject has an immunological memory of the non-tumor antigen and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory.
(Item B41) The method of any of the above with one or more features in any of the items in B) above.
(Item B42) A method for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality, comprising:
a) obtaining a response profile to the antigen of a subject;
b) identifying an antigenic component or combination of antigenic components from the antigen response profile, wherein the antigenic component or combination of antigenic components is identified based on whether the antigenic component or combination of antigenic components has demonstrated or is showing an immune response to the subject; and
c) administering to the subject the antigenic component or combination of antigenic components identified in step b) in an amount sufficient to elicit an immune response in the subject.
(Item B43) The method of any of the preceding items when the disease, disorder or condition involves cancer.
(Item B44) The method of any preceding item, wherein obtaining an antigen response profile comprises verifying a subject's prior physical condition, verifying that one or more of the candidate antigens in a sample of the subject are responsive, or both.
(Item B45) The method of any preceding item, wherein obtaining an antigen response profile comprises identifying an antigenic component or combination of antigenic components that elicit an immune response via positive CD4 T cells.
(Item B46) The method according to any one of the preceding items, wherein
i) the antigen response profile includes at least one selected from the group consisting of an interview, medical history or vaccination history based on the Maternal and Child Health Handbook, its equivalent or similar and a combination thereof, and/ or
ii) testing whether one or more of the candidate antigens respond includes withdrawing a body fluid (e.g., blood) from the subject and separating the peripheral blood cells, then measuring whether the peripheral blood cells produce a cytokine in response to a so associated antigen produce antigen profile and other biomarkers.
(Item B47) The method of any preceding item, further comprising periodically testing antigen reactivity and confirming that reactivity is maintained.
(Item B48) The method according to any one of the preceding items, wherein a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) collecting blood from the subject and separating peripheral blood cells, and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen consistent with fitness and other biomarkers; and
iii) identifying a suitable antigenic component or combination of antigenic components from a result of ii).
(Item B49) The method of any of the preceding items, where prior physical condition includes medical history and vaccination history.
(Item B50) The method of any preceding item, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigenic component or combination of antigenic components for the infection.
(Item B51) The method of any preceding item, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item B52) The method of any of the preceding items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component or combination of antigenic components comprises a humanMycobacterium tuberculosishot water extract.
(Item B53) The method of any preceding item, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the antigenic component or combination of antigenic components includes an influenza virus .
(Item B54) The method according to any one of the above items, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item B55) The method of any preceding item when the subject is in a precancerous state, post cancer treatment, in an early stage of cancerous onset, or in a precancerous state.
(Item B56) The method of any of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma where CD8 positive T cells are generally less effective.
(Item B57) The method of any preceding item when the subject exhibits immunoresistance.
(Item B58) The method of any preceding item, wherein step ii) comprises measuring induction of cells simultaneously producing IFN-γ, IL-2, TNF-α or a variety of cytokines.
(Item B59) The method according to any one of the preceding items, in which the antigen response profile is obtained by performing the diagnosis of the companion in advance based on the anamnesis and the vaccination history.
(Item B60) The method of any preceding item, wherein the prior physical condition and the antigenic component or combination of antigenic components is a history of tuberculosis infection in a humanMycobacterium tuberculosishot water extract.
(Item B61) The method of any preceding item, wherein the past physical condition and the antigenic component or combination of antigenic components is a history of infection with influenza and an influenza virus.
(Item B62) The method according to any one of the preceding items, wherein the previous physical condition and the antigenic component or combination of antigenic components are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio , Mumps/Mumps Epidemic, Rotavirus Infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item B63) The method of any of the preceding items, when the subject is a subject who has had BCG vaccination or a history of tuberculosis infection or has been confirmed to be antigen-responsive;

where notMycobacterium tuberculosisExtract is administered prophylactically before the onset or at an early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.

(Item B64) The method according to any of the preceding items, when the subject is a subject with a history of influenza vaccination or a history of influenza infection or has been confirmed to be antigen-responsive,

where the influenza vaccine is given prophylactically before the onset, to prevent recurrence after therapy, or at an early stage of the onset of cancer and an influenza vaccine is given subcutaneously or intradermally at an early stage of the onset of cancer or precancerous lesions.

(Item B65) A method for preventing or treating an immunity against cancer based on any of the above, comprising revaccination of the antigenic component or combination of antigenic components.
(Item B66) A method of preventing or treating cancer in a subject having a non-tumor component, wherein the component is an antigen or extract identified through interview and/or identified by reference to the subject's history or vaccination history when the subject is a subject with a history of infection or a history of vaccination described in any of the preceding items, wherein the component is administered to prevent recurrence after therapy, is administered prophylactically before onset, or is administered to the subject at an early stage of cancer onset, and the component is optionally administered at an early stage of cancer onset or a precancerous condition.
(Item B67) The method according to any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low immune system susceptibility, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma, where CD8+ T cells are generally less effective.
(Item B68) The method according to any one of the preceding items, wherein the subject is a patient having immune resistance.
(Item B69) The method of any preceding item, wherein the identification of responsiveness is characterized by infection history, vaccination history and measurement of induction of IFN-γ, IL-2, TNF-α producing cells or a plurality of cytokines simultaneously under use of peripheral blood.
(Item B70) The method according to any one of the preceding items, in which theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(Item B71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or another extract of an influenza virus (highly safe extract).
(Item B72) The method according to any one of the above items, wherein the antigenic component is a protein.
(Item B73) A vaccine formulation comprising the antigen of any one of the preceding items and an adjuvant base.
(Item B74) The vaccine formulation according to any one of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1 immune response.
(Item B75) The vaccine formulation according to any one of the preceding, wherein the vaccine formulation is used for personalized medicine.
(Item B76) An antigenic component for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, wherein the antigenic component in the subject is specific for a component derived from a pathogen of the disease, disorder, or condition, and is administered subcutaneously or intratumorally once daily (week one) and once weekly (week two and beyond).
(Item B77) The antigen component according to any one of the above items, wherein the antigen component is contained in an amount of about 0.001 µg or more per unit formulation.
(Item B78) A non-tumor antigen component for use in a method of treating or preventing a cancer or tumor in a patient, the method comprising:
a) identifying a non-tumor specific antigen for the subject based on an antigen response profile;
b) identifying whether the subject has an immunological memory of the non-tumor antigen to identify a subject with immunological memory; and
c) administering the non-tumor antigen to the subject determined to have the immunological memory.
(Item B79) The antigenic component of any of the above substances, wherein the antigenic response profile comprises a history of vaccination and/or a history of infection.
(Item B80) The antigenic component of any of the preceding items, wherein identification of a subject with immunological memory stimulates peripheral blood mononuclear cells (PBMC) isolated from the subject or infiltrating immune cells derived from a tumor mass with the non-tumor antigen have been isolated. measuring cytokine production and identifying an individual with an increased level of cytokine production by a predetermined factor compared to the level before stimulation as an individual with immunological memory.
(position B81) The antigen component of any of the above, wherein non-tumor antigen is administered once daily (week one) and once weekly (week two and thereafter).
(Item B82) The antigen component according to any one of the preceding items, wherein the non-tumor antigen is administered at about 0.001 µg/dose to about 1 mg/dose.
(Item B83) mHSP10 and/or MTB12 and/or LpqH lipoprotein for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject.
(Item B84) A composition, antigen component, kit, biomarker, vaccine formulation or method according to any one of the preceding items characterized by administering a plurality of agents comprising the antigen component.
(Item B85) The composition, antigenic component, kit, biomarker, vaccine formulation or method according to any one of the preceding items, characterized in that each component of the plurality of agents is administered as separate compositions.
(Item C1) Use of a non-target antigen component in the manufacture of a composition for use in activating a regulatory T cell (Treg) having immunological memory of the non-target antigen component that is repressed in a subject against a target.
(Item C2) The use of any of the foregoing items, wherein activation of Treg confers a target killing ability or an immunostimulatory effect against the target.
(Item C3) Use of a non-tumor antigen component in the manufacture of a composition for use in activating a regulatory T cell (Treg) having immunological memory of the non-tumor antigen component which is suppressed in a subject.
(Item C4) The use of any of the above, wherein the activation of Treg confers a tumoricidal ability or an immunostimulatory effect against the tumor.
(Item C5) Using any of the previous items, where Treg is a memory T cell.
(Item C6) Use of any of the previous items when the Treg is CD4 positive.
(Item C7) The use of any of the above items, wherein the antigenic component comprises a protein.
(Item C8) The use of any of the preceding items, wherein the antigenic component comprises an antigen selected from the group consisting of a pathogen of infection or part thereof, an antigen associated with a history, and an antigen that associated with a history of vaccination.
(Item C9) Use of any of the above items, wherein the antigen component comprises a humanMycobacterium tuberculosishot water extract or an influenza virus antigen.
(Item C9A) The use of any of the above items, further comprising one or more features of one or more of the above and following items.
(Item C10) Use of an antigen component in the manufacture of a composition used in a method comprising checking whether the antigen component has an immunological memory of Treg in the subject, and administering the antigen component to the subject if the subject has an immunological Memory component has antigenic.
(Item C11) Use of an antigenic component in the manufacture of a composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, wherein the antigenic component is an antigenic component specific to the subject is specific to a component distinct from the causative agent of the disease, disorder or condition.
(Item C12) The use of any of the foregoing when the disease, disorder or condition comprises cancer and preferably when the antigenic component is a non-tumor antigenic component.
(Item C13) The use of any of the above items when the antigenic component is specific to a subject's memory T cell.
(Item C14) The use of any of the above, wherein the memory T cell is a memory regulatory (IL-2 producing) T cell.
(Item C15) The use of any of the above items in which the antigenic component has an immunostimulating effect.
(Item C16) The use of any of the above items, wherein the antigen component acts on CD4-positive memory T cells in an antigen-dependent manner.
(Item C17) The use of any of the above items, wherein the antigenic component has an activity to affect the ratio of presence between Foxp3-positive Treg cells and IFN-γ-producing T cells.
(Item C18) Using any of the previous items, the bias being an increase in IFN-γ producing T cells compared to Foxp3 positive Treg cells.
(Item C19) The use of any of the above items, wherein the antigenic component has an activity to affect the ratio of presence between Foxp3-positive Treg cells and Type 1 helper T cells.
(Item C20) The use according to any one of the preceding, wherein the IFN-γ producing T cells comprise type 1 helper T cells.
(Item C21) The use of any of the above items, wherein the antigenic component has an activity to affect a proportion of the presence of Th1 cells.
(Item C22) The use according to any one of the preceding, wherein the IFN-γ producing T cells are Th1 positive T-bet cells.
(Item C23) The use according to any one of the above, wherein the antigen component which is specific has the ability to produce at least one selected from the group consisting of IFN-γ production capacity, IL-γ production capacity 2 and TNF-α production increase capacity in a subject sample.
(Item C24) The use of any of the preceding items, wherein the antigenic component is a protein.
(Item C25) A biomarker for determining whether a non-tumor antigenic component has an anticancer effect in a subject, the biomarker comprising at least one selected from the group consisting of whether the antigenic component (i) affects memory in an antigen-dependent manner affects CD4+ T cells, (ii) alters memory-regulating T cells, (iii) alters ability to produce IFN-γ, (iv) alters ability to produce IL-2, and (v) alters ability to Production of TNF-α .
(Item C26) A composition or kit comprising an agent or agent for detecting a biomarker to determine whether a non-tumor antigenic component has an anticancer effect in an individual, wherein the biomarker comprises at least one selected from the group , consisting of whether the non-tumor component of the tumor antigen (i) acts antigen-dependently on CD4-positive memory T-cells, (ii) alters memory-regulatory T-cells, (iii) alters the ability to produce IFN-γ, ( iv) alters ability to produce IL-2; and (v) alters ability to produce TNF-α.
(Item C27) The use of any of the foregoing items in which the antigen (non-tumor) component comprises an antigen associated with medical and vaccination history.
(Item C28) The use of any of the above when the subject is a subject with a history of infection and the antigen component comprises an antigen for the infection.
(Item C29) The use of any of the above articles, wherein the infection comprises at least one infection selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps , rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item C30) Use of any of the previous items when the subject is a subject with a history of BCG vaccination, a history of tuberculosis infection, or antigen reactivityMycobacterium tuberculosis, and the antigenic component comprises a humanMycobacterium tuberculosishot water extract.
(Item C31) The use of any of the foregoing items when the subject is a subject with a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus and the antigenic component comprises an influenza virus.
(Item C32) Use any of the above items when the disease, disorder or condition involves melanoma.
(Item C33) The use of any of the preceding items, wherein the antigenic component comprises a protein, part thereof or a peptide.
(Item C34) The use according to any preceding item, wherein the antigenic component comprises a component capable of eliciting an immune response using CD4+ T cells.
(Item C35) Use of any of the previous items when the subject is verified that the subject is capable of eliciting an anti-tumor immune response by CD4+ T cells and that the subject is capable of eliciting an anti-tumor immune response by T cells CD4 capable of eliciting positive cells, the composition is administered.
(Item C36) Use of an antigenic component in the manufacture of a composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, wherein the antigenic component is an antigenic component specific to the subject is specific to a component distinct from a causative agent of the disease, disorder, or condition in which

the disease, disorder or condition involves melanoma,

the antigenic component is a protein, part thereof or a peptide capable of eliciting an immune response by CD4+ T cells, and

Cancer includes cancer that is treatable and preventable with an immune response via CD4+ T cells,

wherein the subject is assessed as to whether the subject can elicit an anti-tumor immune response via CD4+ T cells and whether the subject can elicit an anti-tumor immune response via CD4+ T cells, the composition being administered.

(Item C37) Use of a non-tumor antigen component in the manufacture of a composition for use in treating or preventing a cancer or tumor in a patient, wherein the non-tumor antigen component is a regulatory T cell (Treg) with immunological memory activates the non-tumor antigen component which is suppressed in an individual and in which the Treg has an effect of promoting regulatory activity or anti-tumor immune action in cancer or tumor.
(Item C38) A method of making or otherwise providing a composition for use in preventing or treating cancer in a subject, the method comprising:
A) identifying a non-tumor specific antigen for the subject;
B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and
C) to produce or otherwise provide the selected non-tumor antigen.
(Item C39) The method of any of the above with one or more features in any of the items in B) above.
(Item C40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, the method comprising:
B) Identifying whether the subject has an immunological memory of the non-tumor antigen and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory.
(Item C41) The method of any of the above with one or more characteristics in any of the items in B) above.
(Item C42) A method for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality, comprising:
a) obtaining a response profile to the antigen of a subject;
b) identifying an antigenic component or combination of antigenic components from the antigen response profile, wherein the antigenic component or combination of antigenic components is identified based on whether the antigenic component or combination of antigenic components has demonstrated or is showing an immune response to the subject; and
c) administering to the subject the antigenic component or combination of antigenic components identified in step b) in an amount sufficient to elicit an immune response in the subject.
(Item C43) The method of any of the preceding items when the disease, disorder or condition involves cancer.
(Item C44) The method of any preceding item, wherein obtaining an antigen response profile comprises verifying a subject's prior physical condition, verifying that one or more of the candidate antigens in a sample of the subject are responsive, or both .
(Item C45) The method of any preceding item, wherein obtaining an antigen response profile comprises identifying an antigen component or combination of antigen components that elicits an immune response using T CD4 positive cells.
(Point C46) The method of any of the previous points where
i) the antigen response profile includes at least one selected from the group consisting of an interview, medical history or vaccination history based on the Maternal and Child Health Handbook, its equivalent or similar and a combination thereof, and/ or
ii) testing whether one or more of the candidate antigens respond includes withdrawing a body fluid (e.g., blood) from the subject and separating the peripheral blood cells, then measuring whether the peripheral blood cells produce a cytokine in response to a so associated antigen produce antigen profile and other biomarkers.
(Item C47) The method of any preceding item, further comprising periodically testing antigen responsiveness and confirming that responsiveness is maintained.
(Item C48) The method according to any one of the preceding items, wherein a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) collecting blood from the subject and separating peripheral blood cells, and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen consistent with fitness and other biomarkers; and
iii) identifying a suitable antigenic component or combination of antigenic components from a result of ii).
(Item C49) The method of any preceding item, wherein the prior physical condition includes medical history and vaccination history.
(Item C50) The method of any preceding item, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigenic component or combination of antigenic components for the infection.
(Item C51) The method of any preceding item, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, poliomyelitis, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item C52) The method of any of the preceding items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component or combination of antigenic components comprises a humanMycobacterium tuberculosishot water extract.
(Item C53) The method of any preceding item, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the antigenic component or combination of antigenic components includes an influenza virus .
(Item C54) The method according to any one of the above items, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item C55) The method of any preceding item, wherein the subject is in a pre-cancer state, post-cancer treatment, in an early stage of cancer onset, or in a precancerous state.
(Item C56) The method of any preceding, wherein the cancer is selected from the group consisting of normal cancer, relatively slowly progressive cancer, cancer with low immune system susceptibility, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma, where CD8+ T cells are generally less effective.
(Item C57) The method of any preceding item, wherein the subject has immunological resistance.
(Item C58) The method of any preceding item, wherein step ii) comprises measuring induction of cells simultaneously producing IFN-γ, IL-2, TNF-α or a variety of cytokines.
(Item C59) The method according to any one of the preceding items, in which the antigen response profile is obtained by performing the diagnosis of the companion in advance based on the anamnesis and the vaccination history.
(Item C60) The method of any preceding item, wherein the prior physical condition and the antigenic component or combination of antigenic components is a history of tuberculosis infection and a humanMycobacterium tuberculosishot water extract.
(Item C61) The method of any preceding item, wherein the prior physical condition and the antigenic component or combination of antigenic components is a history of infection with influenza and an influenza virus.
(Item C62) The method of any preceding item, wherein the previous physical condition and the antigenic component or combination of antigenic components is one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio , Mumps/Mumps Epidemic, Rotavirus Infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item C63) The method according to any one of the preceding items, when the subject is a subject with a history of BCG vaccination or a history of tuberculosis infection or has been confirmed to be antigen-responsive,

where notMycobacterium tuberculosisExtract is administered prophylactically before the onset or at an early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.

(Item C64) The method of any of the preceding items, if the subject is a subject with a history of influenza vaccination or influenza infection, or has been confirmed to be antigen-responsive;

where the influenza vaccine is given prophylactically before the onset, to prevent recurrence after therapy, or at an early stage of the onset of cancer and an influenza vaccine is given subcutaneously or intradermally at an early stage of the onset of cancer or precancerous lesions.

(Item C65) A method of preventing or treating an immunity to cancer based on any of the above items, comprising revaccination of the antigenic component or combination of antigenic components.
(Item C66) A method of preventing or treating cancer in an individual having a non-tumor component, wherein the component is an antigen or extract identified through interview and/or identified by reference to the individual's medical history or vaccination history, if the subject is a subject with a history of infection or a history of vaccination described in any of the preceding items, wherein the component is administered to prevent recurrence after therapy, is administered prophylactically before the onset, or the subject is at an early stage of the cancer onset, and the component is optionally administered at an early stage of cancer or precancerous onset.
(Item C67) The method of any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, low immune system susceptibility cancer, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma, where CD8+ T cells are generally less effective.
(Item C68) The method of any preceding item when the subject is a patient exhibiting immunological resistance.
(Item C69) The method of any preceding item, wherein the identification of responsiveness is characterized by infection history, vaccination history and measurement of induction of IFN-γ, IL-2, TNF-α producing cells or a plurality of cytokines simultaneously under use of peripheral blood.
(Point C70) The method according to any of the preceding points, in which theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(Item C71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or another extract of an influenza virus (highly safe extract).
(Item C72) The method according to any one of the preceding items, wherein the antigenic component is a protein.
(Item C73) A vaccine formulation comprising the antigen from any of the preceding items and an adjuvant base.
(Item C74) The vaccine formulation according to any one of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1 immune response.
(Item C75) The vaccine formulation according to any one of the preceding, wherein the vaccine formulation is used for personalized medicine.
(Item C76) Use of an antigenic component specific to a component in a subject other than a causative agent of a disease, disorder or condition in the manufacture of a composition for use in treating or preventing the disease, disorder, or Condition associated with an immunological abnormality in the subject, wherein the composition is administered subcutaneously or intratumorally once daily (week one) and once weekly (week two and thereafter).
(Item C77) The use of any of the foregoing items, wherein the antigen component is contained in an amount of about 0.001 µg or more per unit formulation.
(Item C78) Use of a non-tumor antigen component in the manufacture of a composition for use in a method of treating or preventing a cancer or tumor in a patient, the method comprising:
a) identifying a non-tumor specific antigen for the subject based on an antigen response profile;
b) identifying whether the subject has an immunological memory of the non-tumor antigen to identify a subject with immunological memory; and
c) administering the non-tumor antigen to the subject determined to have the immunological memory.
(Item C79) The use of any of the above items when the antigen response profile includes vaccination and/or infection history.
(Item C80) The use of any of the foregoing items, wherein the identification of a subject with immunological memory stimulates peripheral blood mononuclear cells (PBMC) isolated from the subject or immune cells isolated from a tumor mass with the non-tumor antigen infiltrating the measuring cytokine production and identifying a subject with an amount of cytokine production that is increased by a predetermined factor compared to the pre-stimulation level as a subject with immunological memory.
(Item C81) The use of any of the above items, wherein non-tumor antigen is administered once daily (week one) and once weekly (week two and thereafter).
(Item C82) The use of any of the foregoing means, wherein non-tumor antigen is administered at about 0.001 µg/dose to about 1 mg/dose.
(Item C83) Use of mHSP10 and/or MTB12 and/or LpqH lipoprotein in the manufacture of a composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject.
(Item C84) The use or method of any preceding wherein the antigen component is administered by a variety of means.
(Item C85) The use or method of any preceding item, wherein each component of the plurality of agents is provided as separate compositions.
(Item X1) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigen component specific to the subject (or to which the subject has an immunological memory). a component distinct from a causative agent of the disease, disorder, or condition.
(Item X2) The composition of any of the preceding items when the disease, disorder or condition involves cancer.
(Item X3) The composition according to any one of the preceding items, wherein the non-tumor antigen component is specific for a memory T cell of the subject.
(Item X4) The composition according to any one of the above items, wherein the memory T cell is a memory regulatory (IL-2 producing) T cell.
(Item X5) The composition of any of the preceding items, in which the non-tumor antigen component has an immunostimulatory effect.
(Item X6) The composition according to any one of the preceding items, wherein the non-tumor antigen component acts on CD4-positive memory T cells in an antigen-dependent manner.
(Item X7) The composition according to any preceding item, wherein the non-tumor antigenic component has an activity to affect a presence ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells.
(Item X8) The composition of any of the previous items, where the bias is an increase in IFN-γ-producing T cells compared to Foxp3-positive Treg cells.
(Item X9) The composition according to any one of the above, wherein the non-tumor antigenic component has an activity to affect a presence ratio between Foxp3-positive Treg cells and type 1 helper T cells.
(Item X10) The composition according to any one of the preceding items, wherein the IFN-γ producing T cells comprise type 1 helper T cells.
(Item X11) The composition according to any one of the above, wherein the non-tumor antigen component has an activity to affect a Th1 cell presence ratio.
(Item X12) The composition according to any one of the above items, wherein the IFN-γ producing T cells are Th1 positive T-bet cells.
(Item X13) The composition of any of the preceding items, wherein the non-tumor antigen component that is subject-specific (or for which the subject has an immunological memory) has the ability to produce at least one selected from the group consisting of IFN-γ production capacity, IL-2 production capacity and TNF-α production capacity in a test sample.
(Item X14) A biomarker for determining whether a non-tumor antigen component has an anticancer effect in a subject, the biomarker comprising at least one selected from the group consisting of whether the non-tumor antigen component (i) in an antigen-dependent Condition acts mode in memory CD4+ T cells, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production capacity, (iv) alters IL-2 production capacity and (v) alters ability for TNF-α production.
(Item X15) A composition or kit comprising an agent or means for detecting a biomarker to determine whether a non-tumor antigen component has an anticancer effect in a subject, wherein the biomarker comprises at least one selected from the group, consisting of whether the non-tumor component tumor antigen component (i) acts antigen-dependently on memory CD4+ T cells, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production capacity, and (iv ) changes IL-2 production capacity.
(Item X16) The method, biomarker, composition or kit according to any one of the preceding items, wherein the antigen (non-tumor) component comprises an antigen associated with history and vaccination history.
(Item X17) The method, biomarker, composition or kit according to any one of the preceding, wherein the subject is a subject with a history of infection and the antigen component comprises an antigen for the infection.
(Item X18) The method, biomarker, composition or kit according to any one of the preceding, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, Consists of polio, epidemic mumps/mumps, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Position X19) The method, biomarker, composition or kit of any preceding, wherein the subject is a subject with a history of BCG vaccination, a history of tuberculosis infection or an antigenic responseMycobacterium tuberculosis, and the antigenic component comprises a humanMycobacterium tuberculosishot water extract.
(Item X20) A method of making a composition for use in preventing or treating cancer in a subject, the method comprising:
A) identifying a non-tumor specific antigen for the subject;
B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and
C) Preparation of the selected non-tumor antigen.
(Position X21) The method of position X20 with one or more characteristics in one of positions X2 to X20 in B).
(Item X22) A method of determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising:
B) Identifying whether the subject has an immunological memory of the non-tumor antigen and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory.
(Position X23) The method of position X22, with one or more characteristics in one of positions X2 to X21 in B).
(Item X23A) A method of treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject comprising administering an effective amount of an antigenic component specific to the subject (or for which the subject has a has immunological memory). to a component distinct from a causative agent of the subject's disease, disorder or condition.
(Item X23AA) The method of item X23A that has one or more features in any one of items X2 through X23.
(Item X23B) An antigenic component for use in the treatment or prevention of a disease, disorder or condition associated with an immunological abnormality in a subject, wherein the antigenic component is an antigenic component specific to the subject (or to which the subject suffers immunological memory) to a component distinct from a causative agent of the disease, disorder or condition.
(Item X23BB) The antigenic component of item X23B with one or more characteristics in any one of items X2 to X23.
(Item X23C) Use of an antigen component that is specific in a subject (or for which the subject has an immunological memory) for a component that is different from a causative agent of the disease, disorder or condition in a method for producing a A medicament for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in the subject.
(Item X23CC) Use of item X23C with one or more characteristics in any of items X2 to X23.
(position X24) A method for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality, comprising:
a) obtaining a response profile to the antigen of a subject;
b) identify a subject-responsive antigen or combination of antigens based on the antigen response profile; and
c) administering the component to the subject in an amount sufficient to elicit an immune response in the subject.
(Item X25) The method of any of the preceding items when the disease, disorder or condition involves cancer.
(Item X26) The method of item X24 or X25, wherein obtaining an antigen reactivity profile comprises verifying a subject's prior physical condition, verifying that one or more of the candidate antigens in a sample from the subject are responsive, or both.
(Item X27) The method of any preceding item, wherein i) the antigen response profile comprises at least one selected from the group consisting of interview, medical history, or vaccination history based on a Maternal and Child Health Handbook, an equivalent thereof, or the like and a combination thereof and/or
ii) checking whether one or more of the candidate antigens are responsive involves withdrawing a body fluid (e.g. blood) from the subject and separating the peripheral blood cells, then measuring whether the peripheral blood cells express a cytokine (IL-2, produce IFN-γ) , TNF-α or similar) in response to an antigen associated with the antigenic profile and other biomarkers.
(Item X28) The method of any preceding item, further comprising periodically testing antigen reactivity and confirming that reactivity is maintained.
(Item X29) The method according to any one of the preceding items, wherein a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) Taking blood from the subject and separating the peripheral blood cells and then measuring whether the peripheral blood cells produce a cytokine (IL-2, IFN-γ, TNF-α or the like) in response to a corresponding antigen, physical condition and other biomarkers ; and
iii) identifying a suitable antigen or combination thereof from a result of ii).
(Item X30) The method of any of the previous items, where the previous physical condition includes anamnesis and vaccination history.
(Item X31) The method of any preceding item, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigen for the infection.
(Item X32) The method according to any one of the preceding items, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item X33) The method of any of the preceding items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or an antigen responseMycobacterium tuberculosis, and the antigen or combination thereof comprises a humanMycobacterium tuberculosishot water extract.
(Item X34) The method according to any one of the above items, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item X35) The method of any preceding item, wherein the subject is in a precancerous onset condition, an early stage of cancer onset condition, after cancer treatment, or in a precancerous condition.
(Item X36) The method of any of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low susceptibility to the immune system, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma where CD8 positive T cells are generally less effective.
(Item X37) The method of any preceding item when the subject exhibits immunoresistance.
(Item X38) The method of any preceding item, wherein step ii) comprises measuring the induction of cells simultaneously producing IFN-γ, IL-2, TNF-α or a variety of cytokines.
(Item X39) The method according to any one of the preceding items, in which the antigen response profile is obtained by performing the diagnosis of the companion in advance based on the anamnesis and the vaccination history.
(Item X40) The method of any of the previous items, wherein the past physical condition and component is a history of tuberculosis infection and a humanMycobacterium tuberculosishot water extract.
(Item X41) The method according to any one of the preceding items, wherein the prior physical condition and component is one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/mumps, rotavirus infection, chicken pox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item X42) The method of any preceding item, wherein the subject is a patient with a history of BCG vaccination or a history of tuberculosis infection, a person with a history of vaccination or a history of infection with a personalized therapeutic method in a healthy person with antigen-confirmed responsiveness, a person withMycobacterium tuberculosishistory of infection or a person with a history of BCG vaccination,

where notMycobacterium tuberculosisExtract is administered prophylactically before the onset or at an early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.

(Item X43) A method for preventing or treating an immunity against cancer based on any of the above, comprising an antigen revaccination.
(position X44) A method of preventing or treating cancer in a subject having a non-tumor component, wherein the component is an antigen or extract associated with medical history and vaccination history, wherein the subject is a subject with a history of infection or vaccination such as described in any of the preceding items, wherein the component is administered prophylactically prior to onset, is administered to prevent recurrence after therapy, or is administered to the patient at an early stage of cancer onset, and the component is optionally administered at an early stage of Cancer is administered onset or precancerous.
(Item X45) The method of any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low susceptibility to the immune system, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma where CD8 positive T cells are generally less effective.
(Item X46) The method of any preceding item, wherein the subject is a patient exhibiting immune resistance.
(Item X47) The method according to any one of the preceding items, wherein the identification of responsiveness is characterized by infection history, vaccination history and measurement of induction of IFN-γ, IL-2, TNF-α producing cells or a variety of the cytokines simultaneous use of peripheral Blood.
(Item X48) The method of one of the previous items where theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(position X49) A vaccine formulation comprising the antigen from any of the preceding positions and an adjuvant base.
(position X49A) A vaccine formulation comprising an antigen to at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, epidemic mumps/mumps, infectious rotavirus, varicella, yellow fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria and an adjuvant base.
(Item X49B) The vaccine formulation according to Item X49A, wherein a physical condition of a subject of the vaccine formulation comprises a history of BCG vaccination, a history of tuberculosis infection, or an antigen responseMycobacterium tuberculosis, and the antigen includes a humanMycobacterium tuberculosishot water extract.
(Item X50) The vaccine formulation according to any one of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1 immune response (e.g. a nucleic acid-based base such as CpG).
(Item X50A) A composition for use in preventing or treating a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising a component identified by a) obtaining an antigen response profile of a subject and b) identifying, based on the antigen response profile, a subject-responsive antigen or combination of antigens in an amount sufficient to elicit an immune response in the subject.
(Item X50A1) A composition for use in preventing or treating cancer in a subject, comprising a non-tumor component, wherein the component is an antigen or extract associated with medical history and vaccination history, wherein the subject is a subject with a history of infection is or vaccination history described in any of the preceding items, wherein the component is administered prophylactically to the subject prior to onset, is administered to prevent recurrence after therapy, or is administered at an early stage of cancer onset, and the Component optionally administered at an early stage of onset of cancer or precancerous lesions.
(Item X50AA) The component of item X50A or X50A1 that has one or more characteristics of one of items X1 through X50.
(Item X50B) A component for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality in a subject, the component being identified by a) obtaining an antigen response profile of a subject and b) Identification of a subject-responsive antigen or combination of antigens based on the antigen responsiveness profile.
(Item X50B1) A non-tumor component for use in preventing or treating cancer in a subject, wherein the component is an antigen or extract associated with medical history and vaccination history, wherein the subject is a subject with a history of infection or vaccination is as described in any of the preceding items, wherein the component is administered to the patient prophylactically prior to onset, is administered to prevent recurrence after therapy, or is administered at an early stage of cancer onset, and the component is optionally administered at an early Stage of the cancer administered is onset or precancerous.
(Item X50BB) The component of item X50B or X50B1 that has one or more characteristics of one of items X1 through X50AA.
(Position X50C) Use of a component in the manufacture of a medicament for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality in a subject, the component being identified by a) obtaining a response profile for identify a subject antigen and b) a subject-responsive antigen or combination of antigens based on the antigen response profile.
(Item X50C1) Use of a non-tumor component in the manufacture of a medicament for use in the prevention or treatment of cancer in a subject, wherein the component is an antigen or extract associated with medical and vaccination history, wherein the subject is a Subject is a history of infection or a history of vaccination described in any of the preceding items, wherein the component is administered to the patient prophylactically before the onset, to prevent recurrence after therapy, or at an early stage of the onset of cancer, and optionally the component is administered in an early stage of cancer or a precancerous condition.
(Item X50CC) The use of item X50C or X50C1 with one or more characteristics of one of items X1 to X50BB.

The present disclosure also provides the following.

(Item 1) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigenic component specific in the subject for a component which is from a causative agent distinguishes the disease, disorder or condition.
(Item 2) The composition of the preceding item, wherein the disease, disorder or condition includes cancer, and preferably wherein the antigenic component is an antigenic component other than a tumor.
(Item 3) The composition of any of the preceding items, wherein the antigenic component is specific to a subject's memory T cell.
(Item 4) The composition according to any one of the above items, wherein the memory T cell is a memory regulatory (IL-2 producing) T cell.
(Item 5) The composition of any one of the preceding items, in which the antigenic component has an immunostimulating effect.
(Item 6) The composition according to any one of the above, in which the antigen component acts on CD4-positive memory T cells in an antigen-dependent manner.
(Item 7) The composition according to any one of the preceding items, wherein the antigenic component has an activity to affect a presence ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells.
(Item 8) The composition of one of the previous items, where the bias is an increase in IFN-γ producing T cells compared to Foxp3 positive Treg cells.
(Item 9) The composition according to any one of the above items, wherein the antigenic component has an activity to affect a presence ratio between Foxp3-positive Treg cells and type 1 helper T cells.
(Item 10) The composition according to any one of the above items, wherein the IFN-γ producing T cells comprise type 1 helper T cells.
(Item 11) The composition of any one of the above items, in which the antigenic component has an activity to affect a ratio of the presence of Th1 cells.
(Item 12) The composition according to any one of the above items, wherein the IFN-γ producing T cells are Th1 positive T-bet cells.
(Item 13) The composition according to any one of the preceding items, wherein the antigen component which is specific has the ability to increase at least one selected from the group consisting of IFN-γ production capacity, IL-γ production capacity 2 and TNF-α Production capacity in a test sample.
(Item 14) A biomarker for determining whether a non-tumor antigenic component has an anticancer effect in a patient, the biomarker comprising at least one selected from the group consisting of whether the antigenic component is (i) antigen-dependent affects CD4+ memory T cells, (ii) alters memory regulating T cells, (iii) alters ability to produce IFN-γ, (iv) alters ability to produce IL-2, and (v) ability altered to produce TNF-α.
(Item 14A) A method of determining whether a non-tumor antigenic component has an anticancer effect in a subject, the method comprising the step of determining at least one of (i) whether the antigenic component acts on T cells in an antigen-dependent manner CD4-positive memory, (ii) whether the antigen component alters memory-regulating T cells, (iii) whether the antigen component alters the ability to produce IFN-γ, (iv) whether the antigen component alters the ability to produce IL-2, and ( v) whether the antigenic component alters the ability to produce TNF-α.
(Item 15) A composition or kit comprising an agent or agent for detecting a biomarker to determine whether a non-tumor antigenic component has an anticancer effect in a subject, wherein the biomarker comprises at least one selected from the group , consisting of whether the non-tumor component of the tumor antigen (i) acts antigen-dependently on CD4-positive memory T-cells, (ii) alters memory-regulatory T-cells, (iii) alters the ability to produce IFN-γ, ( iv) alters ability to produce IL-2; and (v) alters ability to produce TNF-α.
(Item 15A) A composition or kit for determining whether a non-tumor antigen component has an anticancer effect in a subject, the composition or kit comprising an agent or device that determines at least one selected from the group consisting from (i.e.) whether the non-tumor antigen component acts in an antigen-dependent manner on CD4-positive memory T cells, (ii) whether the non-tumor antigen component alters memory regulatory T cells, (iii) whether the non-tumor antigen component alters the Ability alters production of IFN-γ, (iv) whether the non-tumor antigen component alters the ability to produce IL-2, and (v) whether the non-tumor antigen component alters the ability to produce TNF-α.
(Item 16) The composition of any of the preceding items, wherein the antigenic (non-tumor) component comprises an antigen associated with medical and vaccination history.
(Item 17) The composition according to any one of the above items, wherein the subject is a subject with a history of infection and the antigen component comprises an antigen for the infection.
(Item 18) The composition of any of the foregoing, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 19) The composition of any of the preceding items when the subject is a subject with a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component comprises a humanMycobacterium tuberculosishot water extract.
(Item 20) The composition of any of the above items, wherein the subject is a subject with a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the antigenic component comprises an influenza virus.
(Item 21) A method of making or otherwise providing a composition for use in preventing or treating cancer in a subject, the method comprising:
A) identifying a non-tumor specific antigen for the subject;
B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and
C) to produce or otherwise provide the selected non-tumor antigen.
(Item 22) The method of any of the above with one or more features in any of the above in B).
(Item 23) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, the method comprising:
B) Identifying whether the subject has an immunological memory of the non-tumor antigen and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory.
(Item 24) The method of any of the above with one or more features in any of the above in B).
(Item 25) A method for use in the prevention or treatment of a disease, disorder or condition associated with an immunological abnormality, comprising:
a) obtaining a response profile to the antigen of a subject;
b) identifying an antigenic component or combination of antigenic components from the antigen response profile, wherein the antigenic component or combination of antigenic components is identified based on whether the antigenic component or combination of antigenic components has demonstrated or is showing an immune response to the subject; and
c) administering to the subject the antigenic component or combination of antigenic components identified in step b) in an amount sufficient to elicit an immune response in the subject.
(Item 26) The method of any of the preceding items when the disease, disorder or condition involves cancer.
(Item 27) The method of any preceding item, wherein obtaining an antigen response profile comprises examining a subject's prior physical condition, verifying that one or more of the candidate antigens in a sample of the subject responds, or both .
(Item 28) The method of any preceding item, wherein i) the antigen response profile includes at least one selected from the group consisting of interview, medical history, or vaccination history based on a Maternal and Child Health Handbook, a equivalent thereof, or the like and a combination thereof, and/or ii) checking whether one or more of the candidate antigens are responsive comprises withdrawing a body fluid (e.g. blood) from the subject and separating the cells of peripheral blood cells and then measuring whether the blood cells produce a cytokine in response to an antigen associated with the antigenic profile and other biomarkers.
(Item 29) The method of any preceding item, further comprising periodically testing antigen responsiveness and confirming that responsiveness is maintained.
(Item 30) The method according to any of the preceding items, wherein a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) collecting blood from the subject and separating peripheral blood cells, and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen consistent with fitness and other biomarkers; and
iii) identifying a suitable antigenic component or combination of antigenic components from a result of ii).
(Item 31) The method of any preceding item, wherein the prior physical condition includes medical history and vaccination history.
(Item 32) The method according to any one of the preceding items, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigenic component or a combination of antigenic components for the infection.
(Item 33) The method according to any one of the above items, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/epidemic mumps, rotavirus infection , Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 34) The method according to any preceding item, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigenic component or combination of antigenic components comprises a humanMycobacterium tuberculosishot water extract.
(Item 35) The method of any preceding item, wherein the physical condition comprises a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the antigenic component or combination of antigenic components comprises an influenza virus .
(Item 36) The method according to any one of the above items, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item 37) The method according to any one of the preceding items, wherein the subject is in a state before onset of cancer, after cancer treatment, in an early stage of onset of cancer, or in a precancerous state.
(Item 38) The method according to any one of the preceding, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressive carcinoma, low immune system responsiveness cancer, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma, where CD8+ T cells are generally less effective.
(Item 39) The method according to any one of the preceding items, wherein the subject exhibits immunoresistance.
(Item 40) The method of any preceding item, wherein step ii) comprises measuring induction of cells simultaneously producing IFN-γ, IL-2, TNF-α or a variety of cytokines.
(Item 41) The method according to any one of the preceding items, in which the antigen response profile is obtained by performing the diagnosis of the companion in advance based on the anamnesis and the vaccination history.
(Item 42) The method according to any one of the preceding items, wherein the previous physical condition and the antigenic component or combination of antigenic components is a history of tuberculosis infection in a humanMycobacterium tuberculosishot water extract.
(Item 43) The method according to any one of the preceding items, wherein the previous physical condition and the antigenic component or combination of antigenic components are a history of infection with influenza and an influenza virus.
(Item 44) The method according to any one of the preceding items, wherein the prior physical condition and component is one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/mumps, rotavirus infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 45) The method according to any one of the preceding items, wherein the subject is a patient with a history of BCG vaccination or a history of tuberculosis infection, or a subject confirmed to be responsive to an antigen, where thatMycobacterium tuberculosisExtract is administered prophylactically before onset, to prevent recurrence after therapy, or in the early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.
(Item 46) The method according to any one of the preceding items, wherein the subject is a subject with a history of influenza vaccination or influenza infection or has been confirmed to be responsive to an antigen, wherein the influenza vaccine administered prophylactically before onset, administered to prevent recurrence after therapy or administered at an early stage of cancer onset, and an influenza vaccine is administered subcutaneously or intradermally at an early stage of cancer onset or precancerous lesion.
(Item 47) A method for preventing or treating an immunity to cancer based on any of the above items, comprising revaccination of the antigenic component or combination of antigenic components.
(Item 48) A method of preventing or treating a subject's cancer with a non-tumor component, the component being an antigen or extract identified through interview and/or identified by reference to the subject's history or vaccination history, if the subject is a person with a history of infection or a history of vaccination as described in any of the foregoing items, wherein the component is administered to prevent recurrence after therapy, is administered prophylactically prior to initiation, or is administered early in the initiation of therapy for cancer to the subject, and the component is optionally administered at an early stage of an early stage cancer or precancerous condition.
(Item 49) The method according to any one of the above, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, low immune system responsive cancer, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma , in which CD8+ T cells are generally less effective.
(Item 50) The method according to any one of the preceding items, wherein the subject is a patient exhibiting immune resistance.
(Item 51) The method according to any preceding item, wherein the identification of responsiveness is characterized by history of infection, history of vaccination and measurement of induction of cells producing IFN-γ, IL-2, TNF-α or is a variety of cytokines simultaneously using peripheral blood.
(Item 52) ​​The method according to any of the preceding points, in which theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(Item 53) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or another extract of an influenza virus (highly safe extract).
(Item 54) A vaccine formulation comprising the antigen of any one of the preceding items and an adjuvant base.
(Article 54A) A vaccine formulation containing an antigen to at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, epidemic mumps/mumps, infectious rotavirus, varicella, yellow fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, Zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria and an adjuvant base.
(Item 54B) The vaccine formulation according to any preceding item, wherein a physical condition of a subject of the vaccine formulation comprises a history of BCG vaccination, a history of tuberculosis infection, or a response to antigensMycobacterium tuberculosis, and the antigen includes a humanMycobacterium tuberculosishot water extract.
(Item 55) The vaccine formulation according to any one of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1 immune response.
(Item 56) The vaccine formulation according to any one of the preceding items, wherein the vaccine formulation is used for personalized medicine.
(Item 25A) A composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality, comprising an antigenic component or combination of antigenic components for use in a method of preventing or treating a disease , disorder or condition associated with an immune abnormality comprising:
a) obtaining a response profile to the antigen of a subject;
b) identifying an antigenic component or combination of antigenic components from the antigen response profile, wherein the antigenic component or combination of antigenic components is identified based on whether the antigenic component or combination of antigenic components has demonstrated or is showing an immune response to the subject; and
c) administering to the subject the antigenic component or combination of antigenic components identified in step b) in an amount sufficient to elicit an immune response in the subject.
(Item 26A) The antigenic component or combination of antigenic components, or the composition of any of the foregoing, when the disease, disorder or condition involves cancer.
(Item 27A) The antigenic component or combination of antigenic ingredients or composition of any of the preceding items, wherein obtaining an antigenic response profile comprises verifying a subject's prior physical condition, verifying that one or more of the candidate antigens at a Address subject Sample or both.
(Item 28A) The antigenic component or combination of antigenic ingredients or composition of any of the preceding items, wherein i) the antigenic responsiveness profile comprises at least one selected from the group consisting of interview, medical history, or vaccination history based on at a Mother History and Child Health Handbook, an equivalent or similar, and a combination thereof, and/or (ii) testing whether one or more of the candidate antigens are responsive includes collecting a body fluid (e.g., blood) from the subject and separating it of peripheral blood cells and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen associated with the antigenic profile and other biomarkers.
(Item 29A) The antigenic component or combination of antigenic components, or the composition of any of the foregoing, further comprising periodically testing antigenic reactivity and confirming that reactivity is maintained.
(Item 30A) The antigenic component or combination of antigenic components or composition of any of the foregoing items, in which a) and b) are carried out with the following steps:
i) obtaining a prior physical condition of a subject;
ii) collecting blood from the subject and separating peripheral blood cells, and then measuring whether the peripheral blood cells produce a cytokine in response to an antigen consistent with fitness and other biomarkers; and
iii) identifying a suitable antigenic component or combination of antigenic components from a result of ii).
(Item 31A) The antigenic component or combination of antigenic components or composition of any of the foregoing, wherein the prior physical condition includes medical history and vaccination history.
(Item 32A) The antigenic component or combination of antigenic components, or the composition of any one of the preceding items, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigenic component or combination of antigenic components for the infection.
(Item 33A) The antigenic component or combination of antigenic components or composition of any of the foregoing, wherein the infection comprises at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, Polio, Mumps/Mumps Epidemic, Rotavirus Infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Item 34A) The antigenic component or combination of antigenic components, or the composition of any of the foregoing, wherein the physical condition comprises a history of BCG vaccination, a history of tuberculosis infection, or antigen susceptibilityMycobacterium tuberculosis, and the antigenic component or combination of antigenic components comprises a humanMycobacterium tuberculosishot water extract.
(Item 35A) The antigenic component or combination of antigenic components, or composition of any of the foregoing, wherein the physical condition comprises a history of influenza vaccination, a history of influenza infection, or an antigenic response to an influenza virus, and the Component or antigenic combination of antigenic components includes an influenza virus.
(Item 36A) The antigenic component or combination of antigenic components or composition according to any one of the foregoing, wherein the administration comprises subcutaneous administration or intradermal administration.
(Item 37A) The antigenic component or combination of antigenic components, or the composition of any of the foregoing, wherein the subject is in a precancerous onset, postcancer treatment, early stage onset of cancer, or precancerous condition.
(Item 38A) The antigenic component or combination of antigenic components or composition of any of the foregoing, wherein the cancer is selected from the group consisting of normal carcinoma, relatively slowly progressing carcinoma, cancer with low sensitivity to the oral immune system, oral squamous cell carcinoma, cervical cancer and MHC class I negative carcinoma, in which CD8-positive T cells are generally less effective.
(Item 39A) The antigenic component or combination of antigenic ingredients or composition of any of the preceding items to which the subject exhibits immunological resistance.
(Item 40A) The antigenic component or combination of antigenic ingredients or composition of any of the preceding items, wherein step ii) comprises measuring induction of cells co-expressing IFN-γ, IL-2, TNF-α or a plurality of produce cytokines.
(Item 41A) The antigenic component or combination of antigenic constituents or composition of any of the preceding items, in which the profile of antigenic susceptibility is obtained by performing the diagnosis of the companion based on medical history and vaccination history.
(Item 42A) The antigenic component or combination of antigenic components or the composition of any of the foregoing, wherein the prior physical condition and the antigenic component or combination of antigenic components are a history of tuberculosis infection and a humanMycobacterium tuberculosishot water extract.
(Item 43A) The antigenic component or combination of antigenic components or the composition of any of the foregoing, wherein the prior physical condition and the antigenic component or combination of antigenic components is a history of infection with influenza and an influenza virus.
(Item 44A) The antigenic component or combination of antigenic components or the composition of any of the foregoing, wherein the foregoing physical condition and the component is one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio , Mumps/Mumps Epidemic, Rotavirus Infection, Chickenpox, Yellow Fever, Ebola, West Nile Fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, Toxoplasma, Zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.
(Article 45A) The antigenic component or combination of antigenic components, or the composition of any of the foregoing items, when the subject is a subject with a history of BCG vaccination or a history of tuberculosis infection or has been confirmed to be responsive to the antigen ,

where notMycobacterium tuberculosisExtract is administered prophylactically before the onset or at an early stage of onset of cancer, and an extract fromMycobacterium tuberculosisit is administered subcutaneously or intradermally by a conventional method at an early stage of the onset of cancer or a precancerous condition.

(Item 46A) The antigenic component or combination of antigenic components, or the composition of any of the foregoing, when the subject is a subject with a history of influenza vaccination or a history of influenza infection or has been confirmed to be responsive to the antigen,

where the influenza vaccine is given prophylactically before the onset, to prevent recurrence after therapy, or at an early stage of the onset of cancer and an influenza vaccine is given subcutaneously or intradermally at an early stage of the onset of cancer or precancerous lesions.

(Item 47A) An antigenic component or combination of antigenic components or a composition for use in a method of preventing or treating immunity to cancer based on any of the preceding items, the method comprising revaccination of the antigenic component or combination of antigenic components includes .
(Article 48A) A non-tumor component for use in a method of preventing or treating cancer in a subject, wherein the component is an antigen or extract identified through interview and/or by reference to the subject's medical or vaccination history has been identified, wherein the person is an individual with a history of infection or a history of vaccination described in any of the preceding items, wherein the component is administered to prevent recurrence after therapy, is administered prophylactically before the start or in an early stage of cancer onset is administered to the subject, and the component is optionally administered at an early stage of early stage cancer or a precancerous condition.
(Item 49A) The non-tumor component of any of the above items, wherein the cancer is selected from the group consisting of normal cancer, relatively slowly progressing cancer, cancer with low immune system susceptibility, oral squamous cell carcinoma, oral cervical cancer and MHC class I cancer -negative carcinoma, in which CD8-positive T-cells are generally less effective.
(Item 50A) The non-tumor component of any of the preceding items when the subject is a patient exhibiting immune resistance.
(Item 51A) The antigen or combination of antigens or the non-tumor component of any of the above items, identifying susceptibility by history of infection, history of vaccination and measurement of induction of IFN-producing cells γ, IL is labeled -2, TNF-α or a variety of cytokines with the simultaneous use of peripheral blood.
(Article 52A) The antigen or combination of antigens from any of the preceding articles in which theMycobacterium tuberculosisExtract is a hot water extract from humansMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract).
(Item 53A) The antigen or combination of antigens of any one of the preceding items, wherein the influenza virus is human influenza virus or other influenza virus (highly safe extract).

The present disclosure intends that one or more of the foregoing devices may be provided not only as the explicitly disclosed combinations, but also as other combinations thereof. Additional embodiments and advantages of the present disclosure will be appreciated by those skilled in the art upon reading and understanding the following detailed description as needed.

The present disclosure provides technology that can effectively prevent or treat refractory diseases such as host immune memory cancer.

For cancer immunotherapy, an immunotherapy using a tumor antigen is actively studied, but a clear therapeutic effect has not been obtained. However, the present disclosure was able to counteract this. The present disclosure has also unexpectedly found such an aspect as "specific" immunotherapy of a humanMycobacterium tuberculosisHot water extract considered a “non-specific” immunotherapy using a non-tumor component and designed to be delivered as a specific immunotherapy. This not only enabled targeted therapy, but also preventive use. By elucidating the mechanism of action of specific immunotherapy, it could be shown that a suitable patient is selected and a suitable therapy is provided as personalized medicine that can be used in various applications.

Regulatory T cells (Treg cells) are involved in many forms of immune regulation, particularly immunosuppression. Some checkpoint molecule inhibitors turn off regulatory T cell immunosuppression to boost immunity. Although these agents show useful effects, the problem to be solved is that they have strong side effects. The effect is limited to some of the patients and no clear diagnostic drug is available that can differentiate the patients. Because side effects are strong when proper distinction is not possible, a distinction is needed. Although it was almost impossible in the past, the present disclosure was able to provide an appropriate therapeutic and preventive method to discriminate patients using the immunological memory mechanism and to discriminate and administer an appropriate agent to a patient. This was confirmed by the demonstration of a new method of immunotherapy and cancer prevention and therapy that uses memory responses of a non-tumor antigen as a personalized marker that relies on the regulatory action of a non-tumor antigen-dependent regulatory T cell (Treg- cell) based. due to a previous vaccination with a humanMycobacterium tuberculosisHot water extract or similar (confirmed to be safe in humans) used as a representative example. Therefore, the present disclosure provides a new immunotherapy.

FIGO.1is a diagram examining the correlation betweenMycobacterium tuberculosisInfection and memory T cells showing the results of conducting an experiment under the conditions described in Example 1. The graphs to the left of the top row are graphs showing the correlation between PPD-induced producer cells and PPD-induced producer cells. Extract A for IFN-γ, IL-2 and TNF-α. The middle row graphs are, from left, graphs showing the correlation between CMV-induced cells and Extract A-induced cells expressing IFN-γ, IL-2 and TNF-α. to produce. Graphs in the bottom row are, from left, graphs showing the correlation between MHSP10-induced cells and Extract A-induced cells producing IFN-γ, IL-2 and TNF-α.

FIGO.2Fig. 12 is a graph of examining the antitumor effect of Extract A depending on the difference in immune status. Example 2 describes its details. COWARD.2A shows the schedule of administration for BCG or Extract A + Freund's incomplete adjuvant (E + FIA), tumor cells and Extract A. The top row of FIG.2B shows the results of engraftment of B16BL6 in (B) naïve mice, (C) BCG-infected mice and (D) mice immunized with Extract A emulsion, and the bottom row shows results of B16F10 engraftments from the left, (E ) naïve mouse, (F) BCG-infected mouse, and (G) mouse immunized with emulsion of Extract A. The horizontal axis indicates the number of days elapsed after tumor transplantation and the vertical axis indicates the change in tumor volume on. * indicates that there is a statistically significant difference.

FIG.3-1e3-2show experimental results on tumor growth suppression effect when a model antigen was administered to an animal with model antigen-specific memory cells. COWARD.3-1Figure 12 shows the change in B16BL6 tumor growth when ovalbumin was administered from the left to naïve mice (A) and mice immunized with ovalbumin + FIA + extract A (B).

FIGO.3-2Figure 12 shows changes in B16BL6 tumor volume when ovalbumin-specific Th1-differentiated CD4T cells were introduced and ovalbumin was administered from the left to Rag2-deficient mice (left) and IL2Rγ-Rag2 double chain-deficient mice (right).

FIGO.4Figure 12 shows B16BL6 tumor weight when Extract A was administered to mice immunized with a vaccine formulation comprising different adjuvant bases. Example 4 provides a detailed explanation. Shown from left are vaccines used for immunization four weeks prior and two weeks prior. Results are from mice administered phosphate buffered saline (PBS), FIA, K3-SPG adjuvant (see Kouji Kobiyama, et al., Proceedings of the National Academy of Sciences Feb. 2014, 111(8) 3086-3091; DOI: 10.1073/pnas .1319268111), K3+cyclic GMP-AMP (cGAMP), intradermal administration of Extract A (id), Extract A+FIA, Extract A+K3-SPG, Extract A+K3+cGAMP and Extract A+ K3+ Alum. Black dots show results in animals given saline and red dots show results in animals given Extract A.

FIGO.5Figure 12 shows the results of evaluating the effect of Extract A on tumor infiltrating lymphocytes (TIL) in the transplanted tumor by flow cytometry, the details of which are described in Example 5. The left panels show from left T-bet positive, Foxp3 negative, T-bet positive Foxp3 positive and T-bet negative Foxp3 positive TIL. The right panel shows the results of a typical flow cytometry.

FIGO.6Figure 12 shows the results of evaluating the effect of Extract A on tumor infiltrating lymphocytes (TIL) in the transplanted tumor by flow cytometry, details of which are described in Example 6. The figure shows positive T-bet Foxp3 negative from the left. T-bet positive Foxp3 positive, T-bet negative Foxp3 positive and T-bet negative Foxp3 negative TIL producing IFN-γ by Extract A stimulation.

FIGO.7Figure 12 shows results of related experiments to identify cells essential for antitumor activity due to Extract A. Their details are described in Example 8.7A is a diagram showing the administration schedule of BCG, tumor cells, Extract A, anti-CD4 antibody and anti-IFN-γ antibody to mice. FIG.7B for7D shows the volume change of subcutaneously transplanted B16BL6 when saline (S) or Extract A (E) was administered to mice in which CD4-positive cells were depleted using an anti-CD4 antibody after BCG infection (FIG.7B) oder CD4-Knockout-Camundongos (FIG.7C) or class II MHC knockout mice (FIG.7D) each infected with BCG. COWARD.7E shows the results of administering saline or Extract A to BCG-infected mice and collecting spleen cells, then stimulating with Extract A, staining for intracellular cytokines, and performing FACS analysis. COWARD.7F shows tumor volume when saline (S) or Extract A (E) was administered to IFN-γ-depleted mice using anti-IFN-γ antibodies after BCG infection. COWARD.7G is a graph showing the amount of IFN-γ produced when splenocytes from BCG-infected wild-type (WT) mice, CD4 knockout mice (CD4 KO), and MHC class II knockout mice (MHCII KO ) were stimulated with extract A. COWARD.7H is a graph showing the amount of IFN-γ produced when splenocytes from BCG-infected wild-type (WT) mice and CD1d1 knockout mice (CD1d1) were stimulated with Extract A.7I is a graph showing the amount of IFN-γ produced when spleen cells from CD4- or CD8-depleted mice were stimulated with Extract A.

FIGO.8Figure 12 shows the change in tumor volume of B16BL6 when Extract A was administered to BCG-infected mice. Its details are described in Example 9.8A is a diagram showing the experimental schedule. FIG.8B to G show tumor volume when saline (S) or Extract A (E) was administered after infecting Rag2-deficient mice (FIG.8B), CD8-positive, cell-depleted mice (FIG.8C), CD1d1-deficient and FcR-deficient mice (FIG.8D), NK1.1-positive mice with cell depletion (FIG.8E), IL12p40-deficient mice (FIG.8F) and Batf3-deficient mice (FIG.8G) mit BCG.

FIGO.9Figure 12 shows the results of an antitumor effect when a non-tumor antigen was administered to a BCG-infected mouse. Its details are described in Example 10.9A shows the amount of IFN-γ secreted when splenocytes isolated from a BCG-infected mouse were treated with subtilisin-treated extract A (Sub), heat-inactivated subtilisin-treated extract A (HI-Sub), trypsin-treated extract A (Trp) or heat-treated Extract A with inactivated trypsin (HI-Trp) as a relative value where the amount of IFN-γ production from Extract A stimulation is 100%. COWARD.9B shows the amount of IFN-γ produced when splenocytes isolated from a BCG-infected mouse were stimulated with Extract A or LpqH. COWARD.9C shows tumor volume when saline or LpqH was administered to naïve mice and BCG-infected mice.

FIGO.10Fig. 12 is a diagram showing the result of analysis of tumor microenvironment after Extract A administration. Details thereof are described in Example 11.10A shows the TIL cell count per 1 mg tumor of a naïve mouse administered with saline or Extract A, and the right panel shows the TIL cell count per 1 mg tumor of a BCG-infected mouse administered with saline or Extract A. Extract A. FIG.10B shows the correlation between tumor weight and TIL cell count per 1 mg tumor. COWARD.10C shows TIL-CD3 positive cell count, TIL-CD3 positive CD8 positive cell count and TIL-CD3 positive CD4 positive cell count per 1 mg tumor from a BCG-infected mouse given saline or Extract A.10D shows a typical T-bet and Foxp3 expression result for TIL from a naïve mouse administered saline or Extract A analyzed by flow cytometry. FIG.10and G show the correlation between tumor weight and T-bet positive TIL-Foxp3 negative cells (FIG.10E), TIL-positive Foxp3-positive T-bet-Zellen (ABB.10F) and TIL-positive Foxp3 T-bet negative cells (FIG.10G).

FIGO.11Fig. 12 is a graph showing the correlation between an antitumor effect due to Extract A and IFN-γ producing TIL. Its details are described in Example 12.11A shows the experimental protocol and the right panel shows the results of a typical flow cytometry for the expression of T-bet and IFN-γ in TIL in BCG-infected mice administered saline or Extract A.11B shows the IFN-γ positive TIL cell count per 1 mg tumor under non-stimulatory conditions. COWARD.11C shows the number of IFN-γ positive TIL cells per 1 mg tumor under Extract A or LpqH stimulation conditions. FIG.11D to F show the correlation between tumor weight and IFN-γ-positive TIL cell count under non-stimulatory conditions (Fig.11D), IFN-γ-positive TIL cell count under stimulation conditions of extract A (FIG.11E) and IFN-γ positive TIL cell count under LpqH stimulation conditions.

FIGO.12Fig. 14 is a test chart of an antitumor effect of an influenza vaccine due to a difference in immune status. Its details are described in Example 13.12A shows the dosing schedule for PR8 influenza virus, tumor cells and influenza vaccine. COWARD.12B shows the results of implantation of B16BL6 into a naïve mouse and FIG.12C shows its results in a PR8 infected mouse. The horizontal axis indicates days after tumor implantation and the vertical axis indicates change in tumor volume. * indicates a statistically significant difference.

FIGO.13A is an exemplary schematic diagram of a clinical protocol.

FIGO.13B is another example of a schematic diagram of a clinical protocol.

The present disclosure is explained below while showing some of its best modes. Throughout the specification, a singular term shall be understood to include the plural form thereof unless expressly stated otherwise. Therefore, articles in the singular (e.g., “a,” “an,” “the,” and similar in the case of English) are also understood to include their term in the plural form, unless expressly stated otherwise. In addition, terms used in this document should be understood to have the meaning commonly used in the art unless expressly stated otherwise. Therefore, unless otherwise defined, all scientific and technical terms used in this document have the same meaning as commonly understood by those skilled in the art to which the present disclosure pertains. In the event of a conflict, this specification (including definitions) takes precedence.

The terms used here are explained below.

As used herein, the term "specific" in relation to any type of substance or component refers to the substance or component having the property of eliciting a response in a subject that is unique to the subject. In a typical example, “specific” here means that the subject has an immunological memory, in particular in the area of ​​therapy or prevention. In particular, this term can mean specific to a subject's memory T cell.

As used herein, whether a subject "has an immunological memory" for a particular component or substance can be assessed by measuring whether the component or substance resides in the subject or the subject's biological component (e.g., cell or the like) (i) enhances antigen-dependent form of cytokine production or has a growth-promoting effect on CD4-positive memory T-cells, (ii) alters the expression of a surface antigen of a memory-regulatory T-cell, (iii) alters the ratio of Treg to Th1, (iv) induces IFN-γ production from Th1-positive T-bet cells, (v) alters IFN-γ production capacity, (vi) alters IL-2 production capacity, (vii) ability to produce TNF-α altered and (viii) has a specific antibody against a component or substance in the blood and confirms that at least one of them is positive.

As used herein, an "antigenic component" refers to a component capable of eliciting an antigen-antibody reaction in a subject and is also referred to herein as an "antigen". "Antigenic component" can be a single component (substance) or a complex. An antigen component can be provided as a variety of different combinations, which is then referred to as an "antigen component combination". An antigen component herein may be provided as an isolated antigen component, a complex thereof, or an extract comprising the same.

As used herein, "non-tumor antigen component" refers to an antigenic component that is not a cancer antigen. Whether a component or substance here is a “non-tumor antigenic component” can be verified by comprehensively identifying and comparing, for example, proteins or mRNA at a tumor site and other sites. Next-generation mass spectrometry, microarray or sequencers are mainly used for identification. This can be verified by studying sequence information or the like. An "antibody" refers to a protein that serves to recognize and eliminate a foreign body. In this case, the foreign body is called an "antigen". In general, a component such as a protein that is specific or excessive in cancer is referred to as a "cancer antigen." Therefore, a non-tumor antigen (component) can be considered to be any component that is not a cancer antigen. As used herein, a non-tumor antigen component can have an immunostimulatory effect (or adjuvant activity).

As used herein, an antigenic component used in the present disclosure may be an antigen associated with history and vaccination history, or an antigen for infection.

As used herein, "antigen associated with history and vaccination history" refers to an antigenic component contained in a vaccine or history. This can be checked using an approach called ELISA to see if there is a specific antibody, or an approach called FACS or ELISPOT to see if there is an antigen-specific T cell.

(Video) Liwu Li at Online Immunometabolism Seminars - Innate immune memory in acute and chronic diseases

As used herein, an "antigen to an infection" refers to a component capable of eliciting an immune response from an organism or virus capable of causing an infection. This can be verified by an approach known as ELISA to examine whether a specific antibody or antigen-specific T cell is present.

As used herein, an "infection" can be any infection such as tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, epidemic mumps/mumps, rotavirus infection, varicella, yellow fever, Ebola, Nile fever, Hib infection , pneumococcal infection, whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenicEscherichia coliB. toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies, diphtheria or the like. The infection is preferably tuberculosis. When tuberculosis is used as the infection, an individual preferably has a history of BCG vaccination, a history of tuberculosis infection, or an antigenic responseMycobacterium tuberculosis.

As used herein, "antigen responsiveness" is defined to have the same meaning as is known in the art and refers to a subject that elicits an antigen-antibody response in response to a substance known for the subject is specific or similar.

As used herein, an "antigen susceptibility profile" in the context of a given subject is the collective term (profile) for the subject's antigenic susceptibility to various substances or the like. An antigen response profile can be obtained by various approaches such as B. looking at previous physical conditions such as medical history (e.g. history of infection) and vaccination history, or looking at antigen responsiveness using an antigen panel. For example, they may be materialized through questioning, medical history, or vaccination history based on the Maternal and Child Health Handbook, its equivalent or a similar one, and their combinations. In addition, responsiveness can be checked by taking body fluids (e.g. blood) from the subject and sorting out peripheral blood cells, and then measuring whether the peripheral blood cells have a cytokine (IL-2, IFN-γ, TNF-α, a Combination of two or more thereof or the like) in response to an antigen-associated antigenic profile and other biomarkers.

As used herein, a "memory T cell" refers to a cell that serves to maintain immunological memory by being present in the body for an extended period of time. 90% of effector T cells die after 1 to 2 weeks in the body if not continuously exposed to the same antigen. Some of the remaining T-cells subsequently differentiate into approximately two cell populations, which function as a "memory cell" due to their function of maintaining immunological memory by being present in the body for a long period of time. Roughly classified, memory cells include central memory T cells (TCM) and effector memory T cells (TEM). The long-term survival of these two types of memory T cells can quickly trigger an immune response if the same pathogen invades again. It is understood that not only does the memory T cell produced upon the first encounter with an antigen survive, but also a pool of memory T cells is regenerated when the same antigen is encountered again.

TCMthe cells resemble naïve T cells with respect to their cell surface markers; and express CCR7 which is a chemokine receptor, CD62L which is a cell adhesion factor, and the like. The cells are mainly present in the T-cell region of the secondary lymphoid tissue. It is understood that when re-exposed to the same antigen, cells produce IL-2 and grow rapidly, and some differentiate into TEMcells.

It is now understood that TEMCells have reduced expression of cell adhesion factors such as CD62L and CCR7, are not present in secondary lymphoid tissues, but mainly locally in inflammation (e.g. lung, liver, intestinal tract or the like), and produce a large amount of cytokines such as IL-4, IFN-γ or IL-5 by the same antigenic stimulation.

In a preferred embodiment, the memory T cell targeted by the component of the present disclosure may be a memory regulatory (IL-2 producing) T cell. Regulatory T cells (Treg) are a type of T cell that block excessive immune responses. Treg cells are roughly classified into endogenous Treg cells (natural Treg; nTreg) naturally produced in the thymus gland and induced Treg cells (iTreg) resulting from stimulation of a cytokine or the like in peripheral tissue. A "memory regulatory (IL-2 producing) T cell" is a cell with properties of both a "memory T cell" and a "regulatory T cell".

As used herein, "immunostimulatory effect" refers to an effect of non-specifically activating an immune biological function to augment a decreased defense. Whether a certain substance has an "immunostimulating effect" can be checked by a reporter gene assay of a natural immune receptor, a test evaluating activation of immune cells using lymphocytes or the like having cytokine production or the like as an indicator.

As used herein, "activated" refers to a condition in which a function of a cell (e.g., T cell), protein, polypeptide, gene, or the like is increased. "Activated" includes a state in which a change or increase in a function of a cell is detected, a state in which cell growth is increased, a state in which expression of a protein, polypeptide, gene or the like is increased, a state in which the expression pattern has changed, a state in which cells with suppression ability are suppressed, a state in which a suppressed function is unlocked, and the like. Activation as used herein specifically refers to T(Treg) cell regulatory activation. Regulatory T cell (Treg) activation is also known as and is synonymous with regulatory T cell (Treg) turnover. As used herein, activation of Treg is also mentioned in relation to a goal. In this case, it refers to exerting a prophylactic or therapeutic effect on a disease that involves Treg activation towards a target. Examples of the target in such a case include, but are not limited to, cancer and a cancer-derived agent.

Whether an immune cell is "activated" can be checked by a test or similar described under "Immune-stimulating effect". "Turning on" a gene can be quantified by real-time PCR, RNA-Seq, Northern hybridization, hybridization using a DNA template, or the like. The expression level of a polypeptide can be quantified using an antibody that recognizes the polypeptide, a coloring compound that has a binding affinity for the polypeptide, or the like. In addition to the quantification methods described above, conventional methods used in the art can also be used.

As used herein, when predicting a given target (e.g., cancer), "non-target antigenic component" refers to components other than the target (e.g., non-tumor component when the target is cancer).

As used herein, "adjuvant" refers to a substance used to enhance an effect (immunogenicity) of an agent, such as a vaccine (antigen), by co-administration with the agent. The term derives from the Latin word "adjuvare" which means "to help". It is possible to check whether a particular substance is acting as an 'adjuvant' in another substance (e.g. an antigen) by testing the administration of the substance with an antigen in a mouse to monitor the production of antigen-specific antibodies evaluate.

As used herein, an "antigen-dependent" "effect" on a given component associated with a target, such as a T cell, refers to the component that has an effect on the target as a result of an antigen-antibody. This can be demonstrated by the loss of effect when an antigen-antibody reaction is blocked or the like.

As used herein, a "CD4+ memory T cell" refers to a CD4+ memory T cell. In this regard, CD4-positive, as used herein, is positive in terms of a higher degree of staining by immunostaining or the like using a CD4-specific antibody labeled with a fluorescent dye or the like compared to the staining level with a non-specific antibody used as a negative control.

As used herein, a "Foxp3-positive Treg cell" refers to a Foxp3-positive Treg cell. In this regard, Foxp3-positive, as used herein, is considered positive in view of a higher degree of staining by immunostaining or the like using a Foxp3-specific antibody labeled with a fluorescent dye or the like compared to the staining level with a non-specific antibody used as a negative control .

As used herein, an "IFN-γ producing T cell" refers to a T cell capable of producing interferon-γ (IFN-γ). In this regard, an IFN-γ-producing T cell as used herein can be screened for a higher degree of staining by immunostaining or the like using an IFN-γ-specific antibody labeled with a fluorescent dye or the like compared to a Staining level can be identified with a non-specific antibody that is used as a negative control.

As used herein, a “type 1 helper T cell” is also referred to as a “Th1 cell” and is a subset of a CD4+ T cell (called helper T cells), such as the thymus gland . This is a cell type that quickly enters the bloodstream, migrates to an infected site, and secretes cytokines such as IFN-γ or IL-2 to trigger macrophage activation or an inflammatory response. Th1 cells are also responsible for cellular immunity, which is a locally occurring immune response in which CTL or macrophages directly attack cells. Subsets of CD4+ T cells also include type 2 helper T cells (Th2 cells) that secrete cytokines such as IL-4 or IL-5 and activate naïve B cells that express the same antigen in secondary lymphoid tissues detect. Th2 cells are responsible for humoral immunity, which is an immune response that focuses on B cells and antibodies.

As used herein, a "T-bet positive Th1 cell" refers to a T-bet positive Th1 cell. In this regard, T-bet positive as used herein means positive in terms of a higher degree of staining by immunostaining or the like using a T-bet specific antibody labeled with a fluorescent dye or the like compared to the staining degree with a non-specific antibody used as a negative control. The T-bet transcription factor encoded in the Tbx21 gene in a Th1 cell controls and promotes the production of interferon γ as a transcription factor that directly and positively determines lineage. Interferon γ is classified as Type II interferon as one of the interferon family with antipathogenic and antitumor effects. It is known to induce expression of T-bet, which is a transcription factor that defines a Th1 cell, and maintains interferon-γ production through feed-forward control.

As used herein, "enhancement(s)" in capacity, such as IFN-γ production capacity, IL-2 production capacity, and TNF-α production capacity, is determined in terms of a significant increase in the number of cells produced as increased or amount of Production of IFN-γ and IL-2 by stimulating an antigen or the like compared to a negative control by immunostaining using an antibody specific for IFN-γ, IL-2 or TNF-α labeled with a marker (substance or the like), like a fluorescent dye. The amount of cytokine produced can be measured by ELISA and the number of cytokine producing cells can be measured by FACS.

As used herein, a "biomarker" refers to a substance, such as a protein, or an event measured in a biological sample, such as blood, where the presence or degree of progression of a specific physical condition, such as a disease , is reflected by their presence/absence, concentration or level. Therefore, as used herein, a biomarker is understood to include events such as whether the biomarker antigen acts memory CD4+ T cell dependent, alters a memory regulatory T cell, Treg to Th1 ratio altered, IFN-γ production induces Th1 T-bet positive cells, altered IFN-γ producing ability, altered IL-2 producing ability and altered TNF-α producing ability .

Whether a biomarker antigen is dependent on memory CD4-positive T cells can be determined by means of a statistically significant increase in the positive cell count of an antibody used in the staining using FACS analysis.

Whether a biomarker alters a memory-regulating T cell can be determined by a statistically significant increase in the positive cell count of an antibody used in staining by FACS analysis.

Whether a biomarker alters the Treg-to-Th1 ratio or induces IFN-γ production of Th1-positive T-bet cells can be determined using FACS measurement after intracellular cytokine staining and transcription factor staining or measurement of the cytokines produced be determined by ELISA.

Whether a biomarker alters IFN-γ production capacity, IL-2 production capacity, and TNF-α production capacity can be determined using FACS measurement after intracellular cytokine staining and transcription factor staining, or measurement of cytokines produced by ELISA.

As used herein, "bias" in the "presence ratio" of cells refers to a ratio that is statistically significantly different from a ratio of a plurality of cell types present in a normal state. Whether bias is present can be determined by reference to a cell analysis result obtained by any cell analysis approach (e.g., FACS or the like).

As used herein, a "manMycobacterium tuberculosisHot Water Extract” is typically a substance made by a humanMycobacterium tuberculosis, a mixture containing polysaccharides with arabinose, mannose and glucose as the main components. Although the anticancer effect is due to humansMycobacterium tuberculosisHot water extracts have been studied for a long time, their detailed mechanism of action is not necessarily elucidated.

In addition, the extract has not been used as a prophylactic drug. The extract can optionally also include a residual amount of ingredients such as protein, peptide, amino acid, nucleic acid or lipid (glycolipid).

The following is a representative human manufacturing processMycobacterium tuberculosishot water extracts.

HumanMycobacterium tuberculosisis cultivated for 3 to 7 weeks in a thermostatic tank at 37°C. The microbial cell film formed on a medium is then filtered. As the extracted raw material, wet microbial cells whose middle components have been removed by washing with water are used. Microbial cells are floated in distilled water in an amount 15 to 40 times their wet weight and heated at 90 to 120 °C for 80 to 180 minutes for extraction. The residue of microbial cells is removed with a sterilizing filter, and the extracted solution is concentrated to 60% or less, and then acetone, trichloroacetate, ammonium sulfate, sulfosalicylic acid or the like is added to make 0.5 to 3% (w/v) and stirred and left to stand. Subsequently, the deposited precipitate is centrifuged off and removed and the supernatant is dialyzed under running water. The inner fraction of the dialysis liquid is subjected to vacuum concentration to a volume of 1/20 to 1/4, and sodium chloride is added to the concentrate to reach 0.5 to 1% (w/v). Two to four times the volume of ethanol is added and allowed to settle, and the precipitate is then centrifuged off. After adding an additional 2 to 6-fold volume of ethanol and incubating, a precipitating polysaccharide is obtained by centrifugation or the like. Those skilled in the art will understand that any of the conditions described above can be suitably changed to obtain the same product.

As used herein, "prophylaxis" or "prevention" is an act of administering an active ingredient in the present disclosure to a person who has not developed the target disease, for example, to prevent development of the disease.

As used herein, "therapy" is, for example, an act of administering an agent of the present disclosure to a person (subject, patient) who has been diagnosed by a physician or similar professional as having a disease that determines, for example ameliorate the disease or condition, do not enlarge the cancer, or return to the state prior to the development of the disease. Even if the purpose of administration is to prevent exacerbation of the disease or condition or to prevent enlargement of the carcinoma, the administration is a therapeutic act when administered to a patient.

As used herein, an "immune abnormality" refers to any disease, disorder, or condition that results, or is suspected to result, at least in part, from an abnormality in the immune system. Examples of immune abnormalities include, but are not limited to, autoimmune diseases and the like.

Prevention and therapy of immune abnormality include prevention of immune abnormality, recovery from immune abnormality and preemptive prevention of immune abnormality.

Preferred embodiments of the present disclosure are described below. It should be understood that the embodiments provided below are provided to better facilitate understanding of the present disclosure, and therefore the scope of the present disclosure should not be limited by the following descriptions. Thus, it goes without saying that those skilled in the art can refer to the descriptions contained herein to make appropriate modifications within the scope of the present disclosure. It is also understood that the following embodiments of the present disclosure can be used alone or in combination.

The present disclosure is based on the discovery that a therapeutic and preventive effect specific and effective against neoplasms such as cancer is obtained using a non-tumor antigenic component for which a subject has an immunological memory.

<Prevention and therapy of diseases based on immune memory mechanisms>

In summary, the present disclosure provides a composition for use in preventing or treating a disease, disorder or condition in a subject based on an immunological memory mechanism or a therapeutic or preventative method using the same principle. In this regard, the composition comprises an antigenic component specific to the subject, or an antigenic component for which the subject has an immunological memory, to a component distinct from a causative agent of the disease, disorder or condition.

In a representative aspect, the present disclosure provides a composition for activating (or converting) a regulatory T cell (Treg) with immunological memory of a non-target antigenic component that is repressed in a subject against a target, comprising the non- Target Antigen Component Target Target component of the target antigen. Alternatively, the present disclosure provides a method for activating (or converting) an immunomemory regulatory T cell (Treg) of an antigenic non-target component that is repressed in a subject against a target, comprising administering an effective amount of the non-target component - antigenic targeting component for the subject.

The present disclosure has found that activation of Treg confers target killing ability or immunostimulatory effect against the target. The increase in healing power due to such a transfer of immune capacity was unexpected in normal immunological memory.

The present disclosure has found that a contained component (non-target component) has an anti-target immunity equal to or better than a target (antigen) regardless of non-specific immunological effect. By confirming this in other components, the inventors have discovered that a non-target antigenic component that is specific to a subject (or for which the subject has an immunological memory) is involved in the treatment or prevention of a target (eg .cancer) can be widespread. For example, it has been shown that a humanMycobacterium tuberculosisthe hot-water extract comprising the antigen or an influenza virus antigen has a prophylactic and therapeutic effect on the development of diseases other than tuberculosis and influenza (e.g. cancer) in a BCG-infected animal (i.e. animal from which it can be assumed). that it has an immunological memory for a component ofMycobacterium tuberculosisas antigen) or an influenza-infected animal used as a model. It was also recently discovered that for a therapeutic and/or preventive effect of a certain component (for BCG, humanMycobacterium tuberculosishot water extract) in a subject with immunological memory of the specific component, e.g. B. a BCG-infected animal or an animal infected with influenza virus, antigen reactivity of the specific component (e.g.Mycobacterium tuberculosishot water extract) is important in addition to the action of promoting infiltration at a target site (e.g. tumor) of lymphocytes or the like by immunostimulatory action, and the mechanism thereof is to retrieve an antigenic response by immunological memory due to a vaccine (antigen ) or the like vaccinated in the past and promotes an immunological action against the target through an antigenic reaction due to a non-target antigen thereof.

In one embodiment, the present disclosure provides a composition for use in activating a regulatory T cell (Treg) with immunological memory of a non-tumor antigen component that is suppressed in a subject, comprising the non-tumor antigen component. Alternatively, the present disclosure provides a method of activating a regulatory T cell (Treg) having immunological memory of a non-tumor antigen component that is suppressed in a subject, comprising administering to the subject an effective amount of the non-tumor antigen component . The activation of Treg in the present disclosure can confer a tumoricidal ability or an antitumor immunostimulatory effect.

In one embodiment, the Treg is a memory T cell and/or a CD4+ cell. Without wishing to be bound by any theory, this is because a relationship has been found with immune memory and activity via CD4 positive cells.

In another embodiment, the antigenic component comprises a protein, part thereof, or a peptide.

In one embodiment, an antigenic component comprises an antigen selected from the group consisting of a pathogen of an infection or a portion thereof, an antigen associated with a history, and an antigen associated with a vaccination history. In a specific embodiment, an antigenic component comprises a humanMycobacterium tuberculosishot water extract or an influenza virus antigen.

In another embodiment, a composition is characterized in that the composition is used in a method comprising testing whether the antigenic component has an immunological memory of Treg in the subject and administering the antigenic component to the subject if the subject has an immunological memory of the antigenic component.

It should be understood that different embodiments of the same type of components described herein can be used in the conversion technology of the present disclosure, as the various components and combinations thereof are also within the scope of the present disclosure.

In one aspect, the present disclosure provides a composition for use in preventing or treating cancer in a subject, the composition comprising a subject-specific non-tumor antigen component or a non-tumor antigen component for which the subject has an immunological memory .

Accordingly, the present disclosure identifies a subject's responsiveness to a component effective as a cancer vaccine based on the subject's prior physical condition and administers the fitness-responsive component to the subject to prevent or treat cancer.

Thus, in another aspect, the present disclosure provides a method for use in preventing or treating cancer, comprising: a) obtaining a prior physical condition of a subject; b) identify the subject's responsiveness to a component effective as a cancer vaccine based on physical condition; and c) administering the fitness-responsive component to the subject.

In one embodiment, it is preferred in the present disclosure that an active ingredient, such as a non-tumor antigenic component, is specific for a memory T cell of the subject. In particular, specific to a memory T cell means that the subject has an immunological memory of a particular specific antigen.

In one embodiment, cancer therapeutic drugs are specific examples found in the present disclosure. It is noteworthy that the antitumor effect of aMycobacterium tuberculosisHot water extract was found in the present disclosure. HumanMycobacterium tuberculosisNon-specific immunotherapy and immunostimulatory effects have been attributed to hot-water extracts as the main mechanism of action. Meanwhile, the inventors have found that a contained component has an anti-tumor immunity equal to or better than a cancer antigen, notwithstanding a non-specific immune effect, as a result of diligent studies. By confirming this in other components, the inventors have discovered that a non-tumor antigen component that is specific to a subject (or for which the subject has an immunological memory) is important in the treatment or prevention of cancer can be used. For example, it has been shown that a humanMycobacterium tuberculosisHot-water extract comprising the antigen shows a preventive and therapeutic effect on the development of cancer in a BCG-infected animal used as a model (i.e. an animal which can be assumed to have an immunological memory for a component of hasMycobacterium tuberculosisas an antigen). It was also recently discovered that for a therapeutic and/or preventive effect of a certain component (for BCG, humanMycobacterium tuberculosishot water extract) in a subject with immunological memory for the specific component, e.g. B. a BCG-infected animal, antigen reactivity of the specific component (e.g.Mycobacterium tuberculosisHot water extract) is important in addition to the action of promoting infiltration at a tumor site of lymphocytes or the like by immunostimulating action, and the mechanism thereof is to recall an antigenic response by immunological memory due to a vaccine (antigen) or the like used in the past have been vaccinated and promote an antitumor immunological effect through an antigenic reaction due to a non-tumor antigen thereof.

In one embodiment, the memory T cell associated with the immunological memory contemplated by the present disclosure is a memory-regulating T cell. The production of IL-2, for example, can be observed as an indicator of this. Examples of the indicator include, in addition to IL-2 production, IFN-γ production, TNF-α production, a combination of two or three of them, and the like. In particular, in determining that immunological memory is present, immunological memory for a target antigen can be determined by adding the antigen to an assay system comprising a T cell and then IL-2 production, IFN-γ -Production, TNF-α production or a combination of two or three of these is observed, is increased.

In one embodiment, a specific component, such as a non-tumor antigen component of the present disclosure, has an immunostimulatory effect (e.g., adjuvant activity). The immunostimulatory effect can be verified by any approach known in the art. For example, evaluation of the effect on a natural immune receptor, the ability to induce production of a specific antibody, or the like can be used.

In one embodiment, a specific component, such as a non-tumor antigen component of the present disclosure, acts antigen-dependently on CD4-positive memory T cells. Whether the antigen-dependent component acts on memory CD4+ T cells can be verified by any approach known in the art. For example, flow cytometric analysis using an MHC-II tetramer and a specific antigen peptide or flow cytometric analysis on IFN-γ producing cells after stimulation with a specific antigen can be used.

In one embodiment, a specific component, such as a non-tumor antigenic component of the present disclosure, has activity to affect a ratio of presence between Foxp3-positive Treg cells and IFN-γ-producing T cells. The bias in the presence ratio between Foxp3 positive Treg cells and IFN-γ producing T cells can be checked by any cell analysis technology (e.g. FACS). A typical example involves the use of a FACS measurement approach after intracellular cytokine staining and transcription factor staining. Examples of a baseline determination in such a case include, but are not limited to, the deviation in the ratio of presence between Foxp3 positive Treg cells and IFN-γ producing T cells compared to IFN-γ producing T cells to foxp3-increase. positive Treg cells. IFN-γ-producing T cells may include type 1 helper T cells. Alternatively, in another embodiment, a specific component, such as a non-tumor antigenic component of the present disclosure, has an activity to affect a rate of presence under Treg- positive cells for Foxp3 and type 1 helper T cells.

Without wishing to be bound by any theory, the mechanism of action of bias in the ratio of presence between Foxp3-positive Treg cells and IFN-γ-producing T cells was considered an important aspect, and the inventors found out how the mechanism of action of the same , that a certain component, e.g. a humanMycobacterium tuberculosis(Component Triggering Immune Memory) acts antigen-dependently on memory CD4-positive T cells and influences the presence ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells, such as e.g. B. Type 1 helper T cells (Th1 cells) to cause a similar change in anti-tumor immunity and an increase in IFN-γ-producing T cells in the tumor. In particular, the present disclosure can be expected to increase tumor antigen-dependent antitumor immunity in the body by activating resting T cells and balancing suppressor T cells and antitumor immunity with the non-tumor antigen contained in the present agent. Component alters or alters the as well as the effect of promoting infiltration of lymphocytes into the tumor. In one embodiment of the present disclosure, an antigenic component includes a component capable of eliciting an immune response using CD4+ T cells. In one embodiment of the present disclosure, the subject is tested whether the subject can elicit an anti-tumor immune response via CD4 positive T cells, and if the subject can elicit an anti-tumor immune response via CD4 positive T cells, the composition is administered . In another embodiment, the immune response is not mediated by CD8+ T cells.

In one embodiment of the present disclosure, the targeted IFN-γ-producing T cells may include type 1 helper T cells, without wishing to be bound by any theory, this is because the anticancer effect is mediated by antigen-dependent action on the can improve CD4-positive memory T cells and causes an anti-tumor immunity-like change in type 1 helper T cells (Th1 cells) and an increase in IFN-γ-producing T cells in the tumor.

In another embodiment, the IFN-γ producing T cells in the present disclosure are Th1 positive T-bet cells. Without wishing to be bound by any theory, this is because interferon-γ is known to induce expression of a T-bet transcription factor that defines a Th1 cell and induces interferon-γ production through defense feed-forward control of a host. The novel role played by T-bet in the recognition of autocrine interferon by a Th1 cell was examined. Interferon-γ induces an abnormal type I interferon response in the absence of T-bet. T-bet preferentially suppresses the gene and pathway activated by autocrine type I interferon and suppresses abnormal amplification of the type I interferon signaling system in Th1 cells, but also to suppress abnormal autocrine type I interferon Repress interferon and its downstream signaling system in Th1 cells (see Harms Pritchard, G., Hall, A.O., Christian, D.A. et al.: "Different roles for T-bet in Th1 cell response effectors required for resistance to infection. J Immunol., 194, 1131-1140 (2015) and the like).

In one embodiment of the present disclosure, the non-tumor antigen component that is specific (or for which the subject has an immunological memory) preferably has the ability to express at least one selected from the group consisting of IFN-γ production capacity, IL - 2 production capacity and TNF-α production capacity in a test sample. Without wishing to be bound by any theory, this is because IFN-γ production capacity, IL-2 production capacity and TNF-α production capacity are beneficial in anti-cancer effect.

Since a BCG infection model that can be used here is an infection model similar to anamnesis and vaccination anamnesis, it can be understood as a fact that can be deduced based on the data it has demonstrated that T cells from dormant memories that caused by previous vaccinations are stimulated by a specific antigen and reactivated to become a tumor antigen and thus independently promote the anti-tumor immune response. This hypothesis was demonstrated by an experiment with other models of immunological memory. Therefore, it is understood that the therapy of a disease based on the immunological memory model in the present disclosure can be applied not only to the examples but also to any disease. The same effect can also be observed at the clinical study level.

Without wishing to be bound by any theory as to the mechanism of action of the present disclosure, it is understood that the bias in the proportion of Th1 cells and Treg-positive Foxp3 cells in an animal model and IFN-γ production are important in the initial response a specific component in the present disclosure is a memory-regulating (IL-2-producing) T cell based on the history and the vaccination history in peripheral blood cells (of humans or the like), and the specific component of the present disclosure, the IFN-γ -Production induced to change the ratio of Foxp3-positive regulatory T cells (Treg) and T-bet positive Th1 cells and IFN-γ production of T-bet positive Th1 cells by a chronological experiment induced also plays an important role as an operating mechanism. Findings on the involvement of IFN-γ production, IL-2 production, and TNF-α production of memory-regulating T cells based on a subject's immunological memory, such as medical history and vaccination history, were unknown, but became the result of careful studies found by the inventors. Therefore, the present disclosure has shown that IFN-γ production, IL-2 production and TNF-α production used in cells derived from human peripheral blood or the like can be a biomarker to identify a responder to select.

In particular, the present disclosure shows that the IFN-γ production capacity, IL-2 production capacity and TNF-α production capacity of the agent can be found in advance with human peripheral blood-derived cells and suggests the possibility of a complementary Diagnosis for being single subjects. Because the present biomarker is not a response to a cancer antigen, the biomarker can also be used for healthy individuals without cancer antigen, allowing for preventive treatment.

Such is the discovery of new knowledge based on scientific knowledge about the antitumor immunological effect of humansMycobacterium tuberculosisHot water extracts, which have already been confirmed as safe, have led to the invention of new preventive methods and antitumor immunotherapy, which can select and treat an appropriate person. An increase in the effectiveness of known cancer immunotherapies such as checkpoint molecule inhibitors can also be expected. Furthermore, this mechanism is not only adaptable toMycobacterium tuberculosis, but it can also be expected to increase the antitumor effect in the relevant antigenic treatment based on the vaccination history or the infection history for other infections and provide the optimal treatment for each individual.

Before transplanting cancer cells into an animal, a mixture of aMycobacterium tuberculosisHot-water extract and an adjuvant base were administered in advance as a vaccine to a normal animal and a humanMycobacterium tuberculosisthe hot water extract was further administered by a conventional method, and then the cancer cells were transplanted to evaluate an antitumor effect. As a result, it was found that a strong antitumor effect different from a conventional effect was obtained by pretreatment (vaccine-like treatment) of a mixture of aMycobacterium tuberculosisHot water extract and adjuvant base, also in conditions where peopleMycobacterium tuberculosisHot water extract alone or adjuvant base alone has no effect.

Antigenic responsiveness (triple response of IFN-γ, TNF-α and IL-2) in spleen cell-derived CD4+ CD4+ cells was increased by administration of aMycobacterium tuberculosisExtract when the effect of BCG was attenuated after inoculation of mice with BCG. In view of this result, a useful treatment method has been found which can maintain a vaccination effect against an increase in infection due to a currently problematic weakening of the vaccination effect.

The present disclosure can be expected to improve the antitumor effect in a relative antigenic treatment based on the infection history or the vaccination history not only forMycobacterium tuberculosisInfections, but also other infections. In particular, the present disclosure provides a personalized cancer immunotherapy method/preventive method/method that targets individuals with a history of infection or vaccination and can predict efficacy in advance through a memory T cell response. This is advantageous because immunotherapy with a relevant antigenic vaccine can be selected depending on the infection history or vaccination history of each individual, in contrast to conventional immunotherapy which cannot be used without identifying a cancer antigen. In addition, it can apply to healthy individuals because no cancer antigen is used, allowing for preventive treatment. In particular, the present disclosure provides a therapeutic method and a preventive method exhibiting an effect even on carcinomas, in which a preventive effect and a therapeutic effect are exhibited not only by subcutaneous administration of the present agent, using an unconventional combination and an unconventional method administration, with a humanMycobacterium tuberculosisHot water extract has proven to be a harmless active ingredient in humans.

<Biomarker>

In one aspect, the present disclosure provides a biomarker for determining whether a non-tumor antigenic component has an anticancer effect in a subject, wherein the biomarker in the present disclosure can be an event of whether the (non-tumor) antigenic component of the present disclosure (i) acts antigen-dependently on memory CD4-positive T-cells, (ii) alters memory-regulatory T-cells or (iii) induces IFN-γ production of Th1-positive T-bet cells. Therefore, the present disclosure also provides a method for determining whether a non-tumor antigen component has an anti-cancer effect in a subject, the method comprising the step of determining at least one of (i) whether the non-tumor antigen component acts antigen-dependently, comprises on CD4-positive memory T cells, (ii) whether the non-tumor antigen component alters memory regulatory T cells, (iii) whether the non-tumor antigen component alters the ability to produce IFN-γ, (iv) whether the non-tumor antigen component the tumor antigen component alters the ability to produce IL-2; and (v) whether the non-tumor antigen component alters the ability to produce TNF-α.

Thus, in another aspect, the present disclosure provides a composition or kit comprising means for detecting a biomarker to determine whether a (non-tumor) antigenic component has an anticancer effect in a subject, the means for detecting a biomarker any agent capable of verifying whether the non-tumor antigenic component acts in an antigen-dependent manner on memory CD4+ T cells, alters memory regulatory T cells, or alters the ability to produce IFN-γ, IL- 2 and TNF-α a changes Th1-positive T-bet cells. Various known and commercially available kits can be used. As such, the present disclosure also provides a composition or kit to determine whether a non-tumor antigen component has an anticancer effect in a subject, the composition or kit comprising an agent or device that determines at least one selected from the group consisting of (i) whether the non-tumor antigen component is antigen-dependent on memory CD4-positive T cells, (ii) whether the non-tumor antigen component is memory- regulatory T cells alters, (iii) whether the non-tumor antigen alters IFN-γ production capacity, (iv) whether the non-tumor antigen component alters IL-2 production capacity, and (v) whether the non-tumor antigen component altered the TNF-γ production capacity α.

A specific embodiment involves isolating peripheral mononuclear cells from an individual, stimulating the CD4+ memory cells therein with various antigens and staining for an intracellular cytokine or transcription factor to obtain an antigen response profile, and the like. In another embodiment, one or more features described in <Prevention and therapy of a disease based on an immunological memory mechanism> can be combined and applied in the implementation of the biomarker of the present disclosure.

<Method of manufacture or otherwise providing>

In another aspect, the present disclosure provides a method of making or otherwise providing a composition for use in preventing or treating a disease or disorder in a patient. The method includes: A) identifying an antigen specific to the subject but not specific to the disease or disorder; B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and C) to produce or otherwise provide the selected non-tumor antigen. As used herein, "or otherwise provide" refers to any method of delivery other than the recent manufacture of an item, and may be, for example, a method of isolating, cleaning, or obtaining the item from an appropriate source. In step C) the non-tumor antigen can be produced de novo or otherwise provided, for example by isolation from another source or the like.

In another aspect, the present disclosure provides a method of making or otherwise providing a composition for use in preventing or treating cancer in a subject. The method includes: A) identifying a subject-specific non-tumor antigen; B) identifying whether a subject has an immunological memory of the non-tumor antigen and selecting a non-tumor antigen for which the subject has an immunological memory; and C) to produce or otherwise provide the selected non-tumor antigen. In step C) the non-tumor antigen can be produced de novo or otherwise provided, for example by isolation from another source or the like.

In the manufacturing method of the present disclosure, one or more features described in <Prevention and Therapy of Disease Based on Immunological Memory Mechanism> can be suitably applied.

<Therapeutic/preventive methods, diagnostics/therapy-accompanying and medicinal treatment>

In one aspect, the present disclosure provides a method for use in preventing or treating a disease, comprising: a) obtaining an antigen response profile of a subject; b) identify a subject-responsive antigen or combination of antigens based on the antigen response profile; and c) administering the component to the subject in an amount sufficient to elicit an immune response in the subject. In one embodiment, the present disclosure provides a method for use in preventing or treating a disease, disorder or condition associated with an immunological abnormality, comprising: a) obtaining an antigen response profile of a subject; b) identify an antigen or antigen combination from the antigen response profile if the antigen or antigen combination has or has demonstrated an immune response to the subject; and c) administering to the subject the antigen or combination of antigens identified in step b) in an amount sufficient to elicit an immune response in the subject. In addition, the present disclosure also provides an antigen or combination of antigens for use in a method of preventing or treating a disease, disorder or condition associated with an immunological abnormality, comprising: a) obtaining an antigenic response profile of a subject; b) identify an antigen or antigen combination from the antigen response profile if the antigen or antigen combination has or has demonstrated an immune response to the subject; and c) administering to the subject the antigen or combination of antigens identified in step b) in an amount sufficient to elicit an immune response in the subject.

(Video) Immune Memory to COVID-19 by Dr. Rafi Ahmed

In a specific aspect, the present disclosure provides a method for use in preventing or treating cancer, comprising: a) obtaining an antigen response profile of a subject; b) identify a subject-responsive antigen or combination of antigens based on the antigen response profile; and c) administering the component to the subject in an amount sufficient to elicit an immune response in the subject.

In one aspect, the present disclosure provides a method for determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer. The method includes: B) identifying whether the subject has an immunological memory of non-tumor antigen, and identifying whether the subject's cancer can be prevented or treated if the subject has an immunological memory of non-tumor antigen. In the method of the present disclosure, one or more features described in <Prevention and Therapy of Disease Based on Immunological Memory Mechanism> can be suitably applied.

The present disclosure also provides a composition or pharmaceutical composition comprising an antigen or combination of antigens responsive to a subject obtained based on such an antigen response profile. Alternatively, the present disclosure provides a subject-responsive antigen or combination of antigens obtained based on such an antigen-responsive profile for use in treating or preventing a disease or disorder. Alternatively, the present disclosure provides use of a subject-responsive antigen or combination of antigens obtained based on such an antigen-responsive profile in a medicament for use in treating or preventing a disease or disorder.

Therefore, the present disclosure provides a composition for use in preventing or treating a disease, disorder or condition in a subject using a component identified by the method described above. The composition includes an antigenic component that is specific in the subject (or for which the subject has an immunological memory) for a component other than a causative agent of the disease, disorder or condition.

In one embodiment, the prevention or treatment method in the present disclosure may include: a) obtaining a prior physical condition of a subject; b) identify the subject's responsiveness to a component effective as a cancer vaccine based on physical condition; and c) administering the fitness-responsive component to the subject.

In a specific embodiment, obtaining an antigen response profile in the present disclosure may be confirmed by approaches including verifying a subject's prior physical condition, verifying that one or more candidate antigens in a sample derived from the subject are responsive, or both.

In another embodiment, the present disclosure provides a method of preventing or treating cancer, comprising: a) detecting a prior physical condition of a subject; b) identify the subject's responsiveness to a component effective as a cancer vaccine based on physical condition; and c) administering the fitness-responsive component to the subject.

In a specific embodiment, the past physical condition that may be used includes medical history and vaccination history. Medical history and vaccination history may be obtained, for example, by consulting a maternal and child health manual or equivalent information, medical records, other medical information (including electronically recorded information on a subject stored in the cloud, on an electronic chip or similar). A maternal and child health handbook (MCH handbook) is a book containing essential information maintained by a family to promote and maintain maternal and child health (2009 International Committee on MCH Handbook: ICMCHH).

In a specific embodiment, the useful suitability comprises a history of infection and the useful cancer vaccine comprises an antigen for the infection. Infections that can be used can be any type of infection such as tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, mumps/mumps epidemic, rotavirus infection, chicken pox, yellow fever, ebola, west nile fever, Hib infection, pneumococcal infection, whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.

The infections employed by the present disclosure can be any infection described herein. Thus, when presented as “BCG vaccination history”, “tuberculous infection history”, “antigenic susceptibility toMycobacterium tuberculosis' or similar in relation to a physical condition herein may supersede any infection described herein. As a non-limiting example of any infection, the therapeutic method, prophylactic method, and medicament of the present disclosure can also be used when there is a "history of influenza infection," as described and demonstrated in Example 13.

In a preferred embodiment, the infection used is tuberculosis. In this case, the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or an antigenic response theretoMycobacterium tuberculosis. In a preferred embodiment, when the infection is tuberculosis, it may be advantageous that a cancer antigen or vaccine component comprises a humanMycobacterium tuberculosishot water extract. The present disclosure can be used in both prevention and therapy.

The cancer antigen or vaccine of the present disclosure can be provided in a dosage form of a pharmaceutical composition. In a specific embodiment, a pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds may be converted, for example, into at least one type of compound from Extract A (see Examples) (i.e., prodrug) in an individual. In a specific embodiment, a pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are incorporated into, for example, at least one type of antigenic (non-tumor) component (or i.e., prodrug) in a subject . Multiple active ingredients, when included, may be included in a single composition (combined active ingredient) or in separate compositions. The compositions may be formulated as a single composition using modalities known in the art, including those exemplified herein. A variety of means may be provided to combine therapy (e.g., administration of an anticancer agent, radiation therapy, or the like) or with one or more other medications (e.g., surgery, chemotherapeutic agent, immune checkpoint inhibitor, or other anticancer agent) to be achieved in addition to the cancer antigen (component) or vaccine of the present disclosure. The cancer antigen (component) or vaccine of the present disclosure may be provided or administered in combination with one or more other drugs or therapeutic procedures (e.g., surgery, chemotherapeutic agent, radiation therapy, immune checkpoint inhibitor, or other anticancer agent). In one embodiment, one or more other drugs or therapeutic procedures (e.g., surgery, chemotherapy drug, radiation therapy, or other anticancer agent) may be administered after a reasonable period of time has elapsed since administration of the cancer antigen or vaccine of the present disclosure. When administered separately, two or more drugs can be administered as a kit. Non-limiting examples of anticancer agents include immune checkpoint inhibitors (PD-1 inhibitors (eg, anti-PD-1 antibodies), PD-L1 inhibitors (eg, anti-PD-L1 antibodies), CTLA-4 (e.g. anti-PD-L1 antibody), CTLA-4 antibody) and the like), chemotherapeutic agents such as antimetabolites and alkylating agents, growth inhibitors, cytotoxic agents, agents used in radiotherapy, agents anti-angiogenesis, anti-apoptotic agents, anti-tubulin agents, anti-cancer antibiotics, anti-microtubule agents, tyrosine kinase inhibitors, proteasome inhibitors, anaplastic lymphoma kinase inhibitors, Janus kinase inhibitors, CDK inhibitors, MEK inhibitors, Raf kinase -Inhibitors, PARP inhibitors, antibody drugs, other molecularly targeted drugs, platinum formulations, immunotherapy e.g. B. dendritic cell therapy, therapy, other small molecule drugs, raus agents for the treatment of cancer and the like.

The term "carrier" as used herein refers to a pharmaceutically acceptable substance, composition, or excipient, such as a liquid or solid filler, diluent, additive, solvent, or encapsulating agent, associated with or enabling transportation or Transport of a target pharmaceutical compound from one organ or body part to another organ or body part. "Pharmaceutically acceptable" refers to being compatible with other starting materials in a formulation and being harmless to patients. Non-limiting examples of pharmaceutically acceptable carriers, carriers and/or diluents may include sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, excipients such as powdered tragacanth, malt, gelatin, talc, Cocoa powder and suppository wax, oil such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean glycols such as propylene glycol, polyols such as glycerol, sorbitol, mannitol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, buffering agents such as agar, magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water , saline isotonic acid, Ringer's solution, ethyl alcohol, phosphate buffer and other compatible non-toxic substances used in a pharmaceutical formulation. A humectant, emulsifier and lubricant such as sodium lauryl sulfate, magnesium stearate or polyethylene oxide-polypropylene oxide copolymer, as well as a colorant, release agent, coating agent, sweetener, flavoring agent, perfume, preservative and antioxidant can also be included in a composition.

As used herein, "parenteral administration" refers to a dosage form for any route other than oral administration. Each mode of administration is used in a manner and amount effective for use in treating or preventing a disease, which is intended to treat or prevent cancer. Examples of parenteral means of administration include administration by transdermal absorption or transmucosal absorption, as well as injection, infusion, and combinations thereof. For example, administration by transdermal absorption or transmucosal absorption exerts an effect by contacting a transdermally absorbed formulation such as a paste, patch or spray agent with skin or mucosa so that a drug in the formulation enters the Body traverses the skin or mucous membrane. Examples of administration by injection or infusion include intravenous, intradermal, subcutaneous, intramuscular, and enteral (intestinal infusion) administration, which may also be administered as a bolus and/or sustained infusion. The injection or infusion may use a suspension, a liquid agent, an emulsion or an agent implanted in an oily or aqueous medium and comprising another formulation substance such as a suspending, stabilizing and/or dispersing agent. Enteral administration (intestinal infusion) can allow sustained drug delivery to the proximal small intestine using a percutaneous endoscopic gastrostomy tube or a portable infusion pump. More preferably, administration can be subcutaneous or intradermal. Parenteral administration (e.g. transdermal administration) can be carried out with a patch/patch or powder, spray, ointment, paste, cream, lotion, gel, solution or the like. A composition suitable for parenteral administration may comprise at least one type of pharmaceutically acceptable aseptic aqueous or non-aqueous isotonic solution, dispersant, suspension, emulsion, implanted agent or aseptic powder which is reconstituted immediately before use to form an aseptic solution for injection or a Dispersants can be reconstituted.

Compositions disclosed herein suitable for oral administration may be in a dosage form of capsule, capsule, pill, tablet, lozenge (generally using a tragacanth or acacia and sucrose based fragrance), powder, granule, aqueous or non-aqueous liquid present. aqueous solution, aqueous or non-aqueous liquid suspension, oil-in-water emulsion, water-in-oil emulsion, elixir, syrup, lozenges (using an inactive base such as gelatin, glycerin, sucrose and/or acacia) and/or or mouthwashes, each of which may comprise a predetermined amount of at least one compound in the present disclosure.

A composition disclosed herein may be administered as a bolus, electuary or paste.

The cancer antigen or vaccine in the present disclosure can be administered in any dosage form. Any pharmaceutical form, whether oral or parenteral, can be used so long as the effect can be exerted. Preferably parenteral administration is used.

A solid dosage form for oral administration (capsule, tablet, pill, dragee, powder, granule or the like) may be mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or a filling or fillers such as starch, lactose, sucrose, glucose , mannitol and/or silicic acid, binders such as carboxymethyl cellulose, alginic acid salt, gelatin, polyvinylpyrrolidone, sucrose and/or acacia, a humectant such as glycerin, a disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, special silicic acid salt, sodium carbonate and sodium starch glycolate, a dissolution retardant such as paraffin, an absorption promoter such as quaternary ammonium compound, a humectant such as cetyl alcohol, glycerol monostearate and polyethylene oxide-polypropylene oxide copolymer, an absorbent such as kaolin and bentonite clay, and a lubricant such as talc, calcium stearate, magnesium mstearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof, and a colorant. For capsule, tablet and pill, a pharmaceutical composition may also include a buffering agent. A similar type of solid composition can also be used as a filler in a soft and hard gelatin capsule using an additive such as lactose and high molecular weight polyethylene glycol.

A liquid dosage form for oral administration can include a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir. In addition to the active ingredient, a liquid dosage form can include an inactive diluent used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- Butylene glycol, oil (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, sorbitan fatty acid esters, mixtures thereof, and the like. In addition, a compound can be dissolved using cyclodextrin, such as hydroxypropyl-β-cyclodextrin.

The component of the present disclosure may include an adjuvant such as a humectant, emulsifying and suspending agent, sweetening, flavoring, coloring, perfuming or preservative. In addition to one or more compounds according to the present disclosure, a suspension may comprise a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methhydroxide, bentonite, agar, tragacanth, or a mixture thereof or the same.

The composition disclosed herein may be a suppository for rectal or vaginal administration, which may be prepared by mixing one or more compounds according to the present disclosure with one or more suitable non-stimulant additives or carriers, including cocoa butter, polyethylene glycol, wax, suppository, salicylate or the like. The composition is solid at room temperature but liquid at body temperature. Thus, the composition melts in the rectal or vaginal cavity and releases the compound of the present disclosure. A pharmaceutical composition suitable for vaginal administration may comprise a pessary, tampon, cream, gel, paste, foam or spray formulation comprising a carrier known in the art to be suitable.

The dosage form for topical or transdermal administration of the composition of the present disclosure may include powder, spray, ointment, paste, cream, lotion, gel, solution, patch and inhalant. A pharmaceutical composition or pharmaceutical tablet may be mixed with a pharmaceutically acceptable carrier and a preservative, buffering agent or high pressure gas, as may be necessary under aseptic conditions.

An ointment, paste, cream and gel can, in addition to the composition of the present disclosure, an additive such as animal or vegetable fat, oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silicic acid, talc, zinc oxide or a mix of it.

The powder or spray may comprise, in addition to the pharmaceutical composition or pharmaceutical tablet of the present disclosure, an additive such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate or polyamide powder or a mixture thereof. Additionally, the spray may include common high pressure gases such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Ophthalmic formulations, optical ointments, powders, solutions and the like are also within the scope of the present disclosure.

A composition suitable for parenteral administration may comprise at least one type of pharmaceutically acceptable aseptic aqueous or non-aqueous isotonic solution, dispersant, suspension, emulsion or aseptic powder which may be reconstituted into an aseptic injection solution or dispersant immediately before use .

The term "salt" as used herein includes acid and/or base salts formed with inorganic and/or organic acids and bases. As used herein, the term "pharmaceutically acceptable salt" refers to a salt suitable for use in contact with a patient's tissues without undue toxicity, stimulation, allergic reaction and/or similar events having an appropriate benefit/risk ratio within a reasonable balance is appropriate in the context of a final medical judgment. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19.

Pharmaceutically acceptable salts can be made with an inorganic or organic acid. Non-limiting examples of suitable inorganic salts include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic salts include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipic acid salt, alginic acid salt, ascorbic acid salt, aspartic acid salt, benzenesulfonic acid salt, besylate, benzoic acid salt, bisulfuric acid salt, boric acid salt, butyric acid salt, camphoric acid salt, camphorsulfonic acid salt, citric acid salt, cyclopentanepropionic acid salt, digluconic acid salt, dodecylsulfuric acid salt, ethanesulfonic acid salt, formic acid salt, fumaric acid salt, glucoheptonic acid salt Glycerophosphoric acid salt, Gluconic acid salt, Hemisulphuric acid salt, Heptanoic acid salt, Hexanoic acid salt, Hydroiodic acid salt, 2-Hydroxy acid salt - Ethanesulfonic acid, Lactobionic acid salt, Lactic acid salt, Lauric acid, Lauryl sulfate, Malic acid salt, Maleic acid salt, Malonic acid salt, Methanesulfonic acid salt, 2-acid salt Naphthalenesulfonic acid salt, Nicotinic acid salt, Nitric acid salt, Oleic acid salt, Oxalic acid salt, Palmitic acid salt, Palmitic acid salt , pectic acid salt, sulfuric acid salt, 3-phenylpropionic acid salt, phosphoric acidsa lz, picric acid salt, pivalic acid salt, propionic acid salt, stearic acid salt, succinic acid salt, sulfuric acid salt, tartaric acid salt, thiocyanic acid salt, p-toluenesulfonic acid salt, undecanoic acid salt and valeric acid salt. In some embodiments, examples of organic acids that can form a salt include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid , p-toluenesulfonic acid and salicylic acid.

A salt can be prepared at the time of separation and purification of a disclosed compound or separately by reacting the compound with an appropriate base or acid. Non-limiting examples of pharmaceutically acceptable salts obtained from a base include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alkyl) 4 salts. Non-limiting examples of suitable alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In addition, non-limiting examples of suitable pharmaceutically acceptable salts include optionally non-toxic ammonium, quaternary ammonium, and amine cation formed using a counterion such as a halide ion, hydroxide ion, carboxylic acid ion, sulfuric ion, phosphoric ion, nitric acid, acid ion, lower alkyl sulfonic acid ion, and aryl sulfonic acid ion. Non-limiting examples of suitable organic bases that can form a salt include primary amine, secondary amine, tertiary amine, substituted amine including naturally occurring substituted amine, cyclic amine, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and other basic resins of ion exchange. In a specific embodiment, a pharmaceutically acceptable base addition salt can be selected from ammonium, potassium, sodium, calcium and magnesium salts.

In one embodiment of the present disclosure, a target subject may be a patient in a pre-cancer state, post-cancer treatment, early stage of cancer onset, or a precancerous state. Alternatively, a target subject can be a healthy individual. If it is a healthy person, disclosure is done as a preventive method.

Examples of cancers targeted in the present disclosure include esophageal cancer, gastroesophageal junction cancer, renal cell cancer, lung cancer, digestive tract cancer, leukemia, lymphoma, myeloma, brain cancer, pancreatic cancer, endometrial cancer, prostate cancer, liver cancer, bladder cancer, gastroesophageal adenocarcinoma , chondrosarcoma, colorectal adenocarcinoma, colorectal cancer, breast cancer, renal cell cancer, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, sarcoma, urogenital cancer, gynecological cancer and adrenal cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is colorectal adenocarcinoma. In a specific embodiment, the cancer is melanoma. In a specific embodiment, cancer is breast cancer. In a specific embodiment, the cancer is bladder cancer. In a specific embodiment, the cancer is renal cell carcinoma. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, the cancer is endometrial cancer. In a specific embodiment, the cancer may be irresectable. In a specific embodiment, the cancer can be progressive. In a certain modality, the cancer can be refractory. In a specific embodiment, the cancer can be recurrent. In a specific embodiment, the cancer can be metastatic. In various embodiments of the present disclosure, the target cancer may include normal carcinoma, carcinoma with a relatively slow progression (e.g., cancer with low sensitivity to the immune system), oral squamous cell carcinoma, cervical cancer, MHC class I negative carcinoma, CD8-positive T -cells are generally less efficient, cancer resistant to immune checkpoint inhibitors and the like. A cancer patient refers to a patient suffering from a "cancer" described above. In one embodiment, the disease, disorder or condition to which the present disclosure relates includes melanoma.

A target subject in the present disclosure can be a subject demonstrating immunological resistance. The present disclosure may also be directed to a subject in whom the effect of an immune checkpoint inhibitor is weak, a subject who is resistant to therapy by cells expressing the chimeric antigen receptor, a subject who has an effect of therapy is not shown by a monoclonal antibody and the like.

The present disclosure performs a step of identifying an antigen or combination of antigens that is responsive to the subject based on the antigen responsiveness profile. In this regard, the responsiveness to a subject may be any responsiveness associated with disease therapy or prevention, particularly a responsiveness thought to be associated with immunological memory. For example, the responsiveness may include responsiveness to IFN-γ production, IL-2 production, TNF-α production, or responsiveness to any two or three thereof.

In another embodiment, the present disclosure provides a complementary diagnostic drug or diagnostic method for use in the prevention or treatment of cancer and a therapeutic or prophylactic method or medicament based thereon.

In a specific embodiment, the responsiveness check is characterized by administering the companion's diagnosis in advance based on medical history and vaccination history. In the examples contained herein it is shown that such an accompanying diagnosis is possible. One skilled in the art would recognize that based on such example or other specific descriptions, one skilled in the art could similarly make early concomitant diagnosis for other diseases or disorders.

“Make the diagnosis of the accompanying person in advance based on the anamnesis and vaccination history” can be done as follows:

Obtaining an antigenic response profile by a non-invasive method, interview, medical history, or vaccination history based on a Maternal and Child Health Handbook, its equivalent, or similar;

verify that there is indeed responsiveness using peripheral mononuclear cells isolated from a patient and an antigen panel; and

designate an antigen or a combination thereof showing the above reaction as a prophylactic drug or therapeutic drug.

Examples of such concomitant diagnosis or therapy include determining whether a human is presentMycobacterium tuberculosisThe hot water extract can be used as an antigenic component using a history of tuberculosis infection as a previous physical condition. For example, without wishing to be bound by any theory, a person whose cancer or the like is preventable can be identified using a humanMycobacterium tuberculosisHot water extraction by determination using the history of tuberculosis infection as a past physical condition, and cancer prevention can thus be realized. Alternatively, for example, a subject whose cancer or the like is preventable can be identified using a humanMycobacterium tuberculosisHot water extraction by determination using the history of tuberculosis infection as a past physical condition, and cancer therapy can thus be realized.

The prior physical condition and component may be one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, epidemic mumps/mumps, rotavirus infection, chicken pox, fever, yellow fever, Ebola, Nile fever, Hib Infection, Pneumococcal Infection, Whooping Cough, Japanese Encephalitis, Meningococcal Infection, Salmonella Infection, PathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus type 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza virus, MARS, rabies and diphtheria.

In one embodiment, a subject targeted by the present disclosure is a patient with a history of BCG vaccination or a history of tuberculosis infection, or a healthy individual whose antigen responsiveness has been confirmed and the method of the present disclosure is a personalized therapeutic procedure. In this sense, the target subject can be a person with a history of vaccinations or infections, aMycobacterium tuberculosisHistory of infection or history of BCG vaccination.

AMycobacterium tuberculosisExtract that can be used in the present disclosure is administered prophylactically before onset, administered to prevent recurrence after therapy, or administered at an early stage of onset of cancer, and an extract exemplified by the herein illustrated manufacturing process is produced, as well as an extract fromMycobacterium tuberculosisobtained by an improved manufacturing process, are administered subcutaneously or intradermally at an early stage of cancer or precancerous lesions.

In a specific embodiment, the present disclosure provides a method of preventing or treating immunity to cancer by administering in advance a concomitant diagnosis based on medical history and vaccination history that includes antigen vaccination. Example 2 describes and demonstrates that cancer immunity can be prevented or treated by administering in advance a concomitant diagnosis based on medical history and vaccination history.

In a specific embodiment, the present disclosure provides a method for preventing or treating a subject's cancer having a non-tumor component, wherein the component is an antigen or extract identified through interview and/or by reference to medical history or vaccination history the subject is identified, wherein the subject is a subject with a history of infection or a subject with a confirmed vaccination history based on history and vaccination history, wherein the component is administered prophylactically prior to initiation to prevent recurrence after therapy prevent, or is administered at an early stage of cancer onset is administered to the subject, and the component is optionally administered at an early stage of cancer onset or a precancerous condition. Examples of such methods include the methods shown in Examples 1, 2, 3, 10 and 13. Also provided in the present disclosure is a non-tumor component for use in a method of preventing or treating cancer in a subject, wherein the component is an antigen or extract identified through interview and/or by reference to history or vaccination history of the subject is identified if the subject is a person with a history of infection or vaccination as described herein, wherein the component is administered prophylactically prior to initiation, to prevent recurrence after therapy, or to the subject at an early stage of early stage cancer and optionally the component is administered in an early stage of early stage cancer or a precancerous condition.

In one aspect, the present disclosure provides a vaccine formulation comprising the antigen of any of the present disclosure and an adjuvant base. In one embodiment, the vaccine formulation is for use in personalized medicine. In this personalized medication based on the concomitant medication as provided in the present disclosure, a vaccine can be appropriately provided to the respective patient or subject. In a specific embodiment of the present disclosure, the cancer targeted by the present disclosure can be a normal carcinoma, a relatively slowly progressing carcinoma (with low sensitivity to the immune system), oral squamous cell carcinoma, cervical cancer, MHC class I negative carcinoma the CD8+ T cells are generally less effective or similar. In a specific embodiment, an object of the present disclosure is a patient exhibiting immunological resistance.

In one embodiment, a subject's susceptibility can be identified using history of infection, history of vaccination, and susceptibility to IFN-γ production, IL-2 production, TNF-α production using peripheral blood, or two or three thereof. "Response to IFN-γ production, IL-2 production, TNF-α production using peripheral blood or two or three of them" can be performed as follows:

isolating peripheral blood mononuclear cells from the blood of a subject;

culturing peripheral blood monocyte cells in the presence of the substance or PPD (purified protein derivative; purified tuberculin), a stimulant such as a tuberculosis antigen and a protein transport inhibitor such as brefeldin A or monensin;

collecting monocytic cells from peripheral blood after culturing for a period of time, staining with a cell surface marker and antibody labeled with intracellular cytokine-specific fluorescence, and analyzing the stained cells using a flow cytometer; and

determine, with an increase in various cytokine-producing cells as an indicator, with stimulation of either extract A or tuberculosis antigen on memory CD4 T cells (CD3 positive, CD4 positive, CD45RA negative). Extract A is illustrated and described in detail in Example 1 and the like.

In a certain modality, theMycobacterium tuberculosisThe extract used in the present disclosure is a hot water extractMycobacterium tuberculosisor other excerpt fromMycobacterium tuberculosis(very safe extract). Also preferred is a composition used in tuberculin or the like.

In one aspect, the present disclosure provides a vaccine formulation comprising the antigen provided in the present disclosure and an adjuvant base (e.g., a substance that promotes a Th1 immune response). In a specific embodiment, a personalized medicine vaccine formulation is used. Such personalized medicine provides an appropriate vaccine for each patient or subject based on complementary drugs such as those provided in the present disclosure. In one embodiment, the medicament or antigenic component provided in the present disclosure comprises aMycobacterium tuberculosisHot water extract or other extractMycobacterium tuberculosis(very safe extract) or an extracted component or an antigen and adjuvant base and can be provided as a vaccine formulation. Such a vaccine formulation can be prepared by mixing any material substance in any concentration. Their result is shown in Example 4. In a particular embodiment, the vaccine formulation is to be used in a method of personalized medicine.

Examples of basic adjuvants that can be used as a vaccine formulation include the following:

natural immune receptor activating adjuvant base (e.g. TLR agonist, DNA, RNA, dinucleotide, NOD1, NOD2 agonist, microbial membrane-derived substance);

aluminum-containing auxiliary base such as aluminum hydroxide;

base adjuvant capable of forming an emulsion such as ISA51 or ISA720; and

Cytokines (IL-2, IL-12, IFN-α, GM-CSF) containing an auxiliary base. Preferably, an adjuvant base includes a substance that promotes a Th1 immune response (e.g., a nucleic acid-based base such as CpG).

In a specific embodiment, the present disclosure provides a composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigenic component specific to the subject for a component is specific other than a causative agent of the disease, disorder or condition, wherein the disease, disorder or condition comprises a melanoma, the antigenic component is a protein, part thereof or a peptide and is capable of eliciting an immune response via positive CD4 T cells, and hehehe cancer includes cancer that is treatable and preventable with an immune response via CD4+ T cells,

wherein the subject is assessed as to whether the subject can elicit an anti-tumor immune response via CD4+ T cells and whether the subject can elicit an anti-tumor immune response via CD4+ T cells, the composition being administered. The present disclosure also provides a prophylactic method and a therapeutic method associated with the composition.

In another embodiment, the immune response is not mediated by CD8+ T cells.

In another embodiment, the present disclosure provides a composition for use in treating or preventing a cancer or tumor in a subject, the composition comprising a non-tumor antigen component, wherein the non-tumor antigen component is a regulatory T cell ( Treg) with memory activated non-tumor antigen component suppressed in the subject and in which the Treg has an effect of promoting regulatory activity or anti-tumor immunological effect in cancer or tumor. The present disclosure also provides a prophylactic method and a therapeutic method associated with the composition.

In another aspect, the present disclosure provides a composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject, the composition comprising an antigenic component (the antigenic component may are isolated, an extract comprising the same or different) specific for a component distinct from a causative agent of the disease, disorder or condition and administered in an appropriate dosage and administration (subcutaneous or intratumoral administration once daily (first week) and about once a week (second week and beyond)). The present disclosure also provides a prophylactic method and a therapeutic method associated with the composition. In a given embodiment, the antigenic component is contained at about 0.001 µg of Fophor plus per unit formulation.

In another aspect, the present disclosure provides a method of treating or preventing cancer or tumor in a subject, comprising: a) identifying a non-tumor antigen specific to the subject based on an antigen response profile; b) identifying whether the subject has an immunological memory of the non-tumor antigen to identify a subject with immunological memory; and c) administering the non-tumor antigen to the subject determined to have immunological memory. The present disclosure can include a prophylactic method, a therapeutic method, a pharmaceutical composition, an antigenic component, and the like associated with the method.

In one embodiment, the antigen response profile includes vaccination history and/or infection history.

In another embodiment, identifying a subject with immunological memory comprises stimulating peripheral blood mononuclear cells (PBMC) isolated from the subject, or infiltrating isolated immune cells from a tumor mass with the non-tumor antigen, measuring cytokine production and the Identifying a subject with an amount of cytokine production increased by a predetermined factor compared to the pre-stimulation level as a subject with immunological memory (also referred to as a responder).

In one embodiment, a non-tumor antigen is administered once a day, three times a week, twice a week, once a week, once every two weeks, or once a month. The dosage may be once a day initially and thereafter increased or decreased as appropriate, such as once a week from the second dosage onwards.

In another embodiment, the non-tumor antigen in the present disclosure is administered at about 0.1 µg/dose to about 1 mg/dose.

<Components>

In another aspect, the present disclosure provides a composition for use in treating or preventing a disease, disorder or condition associated with an immunological abnormality in a subject comprising mHSP10 and/or MTB12 and/or LpqH lipoprotein . The present disclosure also provides a prophylactic method and a therapeutic method associated with the composition.

As used herein, "or" is used when "at least one or more" of the subjects listed in the sentence can be employed. When specifically described herein as "within the range of two values", the range also includes the two values ​​themselves.

Referenced literature, such as scholarly literature, patents, and patent applications, cited herein are incorporated herein by reference to the same extent as the entirety of each document is specifically described.

As described above, the present disclosure has been described while showing preferred embodiments in order to facilitate understanding. The present disclosure described below is based on the examples. The foregoing descriptions and examples below are not provided to limit the present disclosure, but are for exemplary purposes only. Thus, the scope of the present disclosure is not limited to the specific embodiments and examples described herein, and is limited only by the scope of the claims.

Examples are described below. Where required, the animals used in the examples below were handled in accordance with the institutional guidelines of the National Institute for Biomedical Innovation, Health and Nutrition and other relevant ethical standards and guidelines based on the Declaration of Helsinki. While the specific products described in the examples were used, the reagents can be substituted with an equivalent product from another manufacturer (Sigma-Aldrich, Wako Pure Chemical, Nacalai Tesque, R&D Systems, USCN Life Science INC or the like).

Extract A used in this example was prepared as follows.

HumanMycobacterium tuberculosisAoyama B strain which had been lyophilized and stored (-20°C) was subjected to seed culture at 37 ± 1°C in Sauton potato medium(1). The cultured bacteria were transferred to a production medium(2)and cultured (primary culture) for 5 to 7 weeks at 37 ± 1°C. The resulting cells were washed with water for injection. Water for injection was then added to the cells in an amount equal to 20 times the weight of the wet cells. The mixture was heated at 100°C for 120 minutes to obtain an extract. The extract was filtered with a 0.45 µm membrane filter and then concentrated under reduced pressure so that the saccharide content (based on D-arabinose by the phenol-sulfuric acid method) was 4.0 to 6.0 mg/ml. to get a concentrate. Then 1% w/v sulfosalicylic acid was added to the concentrate to remove the proteins. The mixture was allowed to stand at 10°C or lower for 15 to 20 minutes. The precipitates were then removed by centrifugation (10°C or less, 1150×G, 10 minutes) to collect the supernatant. The protein concentration of the supernatant was 0.30 mg/ml or less (Lowry's method based on tyrosine). The supernatant was further processed to remove sulfosalicylic acid until the concentration was equal to or less than the detection limit (10 ppm or less, method using ferric chloride solution). The resulting solution was concentrated under reduced pressure so that the saccharide content was 1.8 to 2.2 mg/ml, and the concentrate was washed with sodium chloride (0.9% w/v) and cold ethanol in the same volume as that concentrate combined. The mixture was allowed to stand at 10°C or below for 40 hours or more, and then the precipitates (high molecular weight polysaccharide) were removed by centrifugation (10°C or below, 2040×G, 10 minutes). Then, four times the amount of cold ethanol was added to the supernatant, and the mixture was allowed to stand at 10°C or lower for 40 hours or more and centrifuged (10°C or lower, 2040×G, 10 minutes) to recover precipitates. The precipitates were dissolved in water for injection. After the saccharide content was adjusted to 1.8 to 2.2 mg/ml, the solution was filtered with a 0.45 µm membrane filter and sterilized with high-pressure steam (121°C, 20 minutes) to obtain a solution of extract ( A) to produce.

Washed potato slices were soaked in Sauton's medium, sterilized at 115°C for 15 minutes, and then used as Sauton's potato medium.

(Video) Manipulating Memories to Help Treat Brain Illness

L-Sparagin (Monohydrat) 4,0 g

Citric Acid (Monohydrate) 2.0 g

Magnesiumsulfat (Heptahydrat) 0,5 g

Potassium monohydrogen phosphate (anhydride) 0.5 g

Ammonium iron citrate 0.05 g

Glicerin 60ml

The above ingredients were dissolved in water to make a 1000 ml solution. The pH was adjusted to 7.0 to 7.3 with sodium hydroxide solution.

L-Sparagin (Monohydrat) 4,0 g

Citric Acid (Monohydrate) 2.0 g

Magnesiumsulfat (Heptahydrat) 0,5 g

Potassium monohydrogen phosphate (anhydride) 0.5 g

Ammonium iron citrate 0.05 g

Glicerin 60ml

The above ingredients were dissolved in water to prepare a 1000 ml solution and sterilized with high-pressure steam (121°C, 20 minutes). The pH was adjusted to 7.0 to 7.3 with sodium hydroxide solution.

The physicochemical properties of the resulting Extract A solution were as follows.

Light yellow clear liquid

(2) pH:

4,50-5,30

3.5% by weight (as amino acid) in a freeze-dried product

0.1% by weight in a lyophilized product

Mannose 43.4% by weight, arabinose 18.2% by weight and glucose 10.4% by weight. % (hydrolyzed with 2N trifluoroacetic acid at 100°C for 2 hours and then subjected to liquid chromatography using a fluorescent derivative of 2-cyanoacetamide (S. Honda et al., Anal. Chem., 52 , 1079 (1980)).

The Extract A prepared by the method described in the Preparation Example described above may be suitably diluted before use. In the following examples, Extract A was diluted 1 to 50,000 times and adjusted to a concentration suitable for use.

In this example, patients with a history of BCG vaccination or a history of tuberculosis infection, or a healthy individual confirmed to be antigen-responsive, were challenged with an antigen and memory T-cell Responses were analyzed to examine the effectiveness of the therapy.

(Method)

Frozen human peripheral blood mononuclear cells (PBMCs) were purchased from CTL (USA), washed using CTL anti-aggregate washing solution (CTL Europe, Germany) and suspended in RPMI 1640 (R10) containing 10% fetal bovine serum (FBS ), suspended. PBMCs were seeded at a concentration of 1×10 in a 96-well plate3Cells/well and grown overnight at 37°C, 5% CO2Conditions. Then extract A (100 μg/ml), PPD (3 μg/ml), CMV pp65 overlapping peptides (3 μg/ml) or recombinantMycobacterium tuberculosis(TB) (10 µg/ml each) was added to each culture to stimulate PBMCs and 1 µg/ml anti-CD28 (CD28.2), Golgi stop and Golgi plug (BD Biosciences ) were added at the same time. After 6 hours of stimulation, PBMCs were collected and washed with PBS. PBMCs were then stained with the Live/Dead Fixable Blue Staining Kit (Life Technologies) and blocked with Human TruStain FcX (Biolegend) and the surface was stained with fluorescently labeled antibodies, i. H. Anti-CD4 (OKT4), Anti-CD8 (RPA-T8), Anti-CD45RA (HI100), Anti-CCR7 (G043H) antibodies. PBMCs were then fixed and permeabilized with BD Cytofix/Cytoperm (BD Biosciences) and stained with anti-CD3 (SK7), anti-CD154 (24-31), anti-IL-2 (MQ1-17H12), anti-TNF-α (MAb11) and anti-IFN-γ (4SB3). Stained cells were subjected to flow cytometric analysis using LSRII and FlowJo software (BD Biosciences).

(Results)

The results are shown in the figure.1. Extract A promoted the secretion of Th1 cytokines (IFN-γ, IL-2 and TNF-α) from memory T cells of human PBMCs. IFN-γ secretion was also induced by PPD stimulation. A strong positive correlation between Extract A and PPD was observed in human PBMCs. However, no correlation was found between Extract A and CMV. Furthermore, MHSP10, one of the antigens contained in Extract A, induced IFN-γ production and showed a positive correlation with Extract A. Correlation was also found between Extract A and PPD and Extract A and MHSP10 for IL-2 and TNF- . α production.

The presence of extract A-responsive memory T cells was demonstrated in PBMCs in which memory T cells that produce Th1 cytokines in response to PPD are present.

This example examined the antitumor effects of Extract A using mice with different immune states.

(Method)

(BCG infection model)

12 mg dry BCG vaccine was suspended in 12 ml saline to make 1 mg/ml BCG vaccine solution. BCG infection models were established by infecting mice twice with subcutaneous administration of 100 µl of vaccine solution at the base of the tail, i.e. the base of the tail. H. 2 weeks before and 5 weeks before tumor cell transplantation.

(Extract an immunized emulsion model)

Extract A and Freund's incomplete adjuvant (FIA) were mixed in a 1:1 volume ratio to prepare an Extract A emulsion using a GP syringe connector (BrightPath Biotherapeutics) and a Luer-lock syringe (HENKE SASS WOLF). Models immunized with the Extract A Emulsion were immunized by administering 100 µl of the Extract A Emulsion subcutaneously to mice at the base of the tail twice, ie. H. 2 weeks before and 4 weeks before tumor cell transplantation, using a 1 ml syringe with 25 generated G-needle.

(tumor cell transplantation)

B16BL6 cells and B16F10 cells were used as tumor cells. Cells primed about 1 week before transplantation and passaged two or more times were used for these cells. B16BL6 cells were diluted to 3x10 with PBS6cells/ml and transplanted into anesthetized naïve mice, BCG-infected mice and models immunized with Extract A emulsion at a cell number of 3.0×105cells/mouse. Extract A was diluted 10-fold with saline and administered subcutaneously in the right groin at 100 µl per mouse using a 1 ml syringe with 26-G needle. The same amount of saline was administered to a control animal. Extract A was subcutaneously administered every other day from 8 days before transplantation for dissection.

The three sides (width, length and height) of the tumor were measured with an electronic caliper from day 6 after the transplantation. The tumor volume was calculated from its product. Statistical analysis was performed using Excel (Microsoft). A p-value of 0.05 or less according to a t-test when no homoscedasticity is assumed was considered a significant difference.

(Results)

When Extract A was administered to naïve mice, no antitumor effect was observed in B16BL6 cells or B16F10 cells (FIG.2Banda2AND). In contrast, an antitumor effect due to Extract A was observed in BCG-vaccinated mice (FIG.2C and F). Furthermore, an antitumor effect was observed in B16BL6 cells and B16F10 cells by administering Extract A to mice immunized in Extract A emulsion (FIG.2D and G).

It was clarified that a change in a mouse due to BCG infection plays an important role in the antitumor effect of Extract A. Furthermore, the same effect observed in an immunized model in an emulsion of Extract A strongly suggests the relationship with the acquired immune response.

This example examined the effect of suppressing tumor growth after immunization with a model antigen.

(Method)

(Effect of suppressing tumor growth after immunization with model antigen)

Mice were immunized by adding 1/50 amount of 10 mg/ml OVA protein solution (20 µg final dose) to prepare an emulsion solution after emulsion immunity. Thereafter, 2 µg of ovalbumin was administered instead of Extract A. According to the tumor cell transplantation method and the emulsion model of Extract A in Example 2, other procedures were carried out.

(Effect of tumor growth suppression by Th1 introduction)

CD4 T cells and CD11c-positive cells were transformed by AutoMACS from OT-II mice (mice expressing TCR restricted to MHC class II and specific for ovalbumin) or OT-II rag1 knockout mice ( KO) and wild-type mice using the CD4-T-Kit (Miltenyi Biotec) or CD11c-Beads (Miltenyi Biotec) according to the respective operating instructions. CD4 T cells and CD11c positive cells were prepared at a concentration of 10%7cells and 1 to 2×106Cells per 1 ml and cultured after adding 10 μg/ml anti-IL-4 antibodies, 7.5 ng/ml IL-12p70, 10 ng/ml IL-2 and 10 μg/ml OVA323-339Peptide. The medium was changed after 3 to 4 days of cultivation, and each cell was harvested after 6 to 7 days. Dead cells were removed by centrifugation using Lymphoryte (Cedarlane).

CD4 T cells from an OT-II mouse that differentiated into Th1 cells in vitro were introduced into Rag2 KO mice or Rag2, IL-2 receptor γ chain dual KO mice . Ovalbumin was administered every other day until the day of dissection, a total of 11 to 15 times. On day 8 or 16 after transplantation of OT-II mouse-derived cells, B16BL6 cells were transplanted and the change in tumor volume over time was measured.

(Results)

(Effect of suppressing tumor growth after immunization with model antigen)

A tumor growth suppressing effect was observed after administration of ovalbumin in mice immunized with an emulsion comprising ovalbumin (FIG.3-1).

(Tumour growth suppressing effect due to ovalbumin administration to ovalbumin-specific Th1-introduced mice)

When CD4 T cells separated from an OT-II mouse and differentiated into Th1 cells in vitro were transplanted into Rag2-KO mice, it was found that tumor growth was suppressed by the administration of ovalbumin (p=0.017, left side of FIG.3-2). It was also found that tumor growth was suppressed by administration of ovalbumin to Rag2, IL-2 receptor γ-chain dual KO mice (p=0.09, right side of FIG.3-2).

This example examined the antitumor effect of vaccine formulations combining different adjuvant bases.

(Method)

Mice were immunized by administering Extract A in combination with FIA adjuvants, K3-SPG, K3-cGAMP and K3-alum to mice. Saline in combination with PBS, FIA, K3-SPG and K3-cGAMP adjuvant alone was administered to a control mouse. Accordingly, each adjuvant was prepared in a dose comprising K3 at a final dose of 10 µg, K3-SPG at a final dose of 5 µg and 2.3 cGAMP at a final dose of 10 µg. An administered solution was prepared to include 50% or 25% FIA and alum (Alhydrogel, InvivoGen) in a 100 µl solution. Extract A was diluted to 1 mg/ml with PBS and 100 µl was administered intradermally (id) at the base of the tail. Tumor cells were transplanted and the tumor weight in mice on the day of dissection was measured by the same method in (Emulsion Immunized Model with Extract A) and (Tumor Cell Transplantation) of Example 2.

(Results)

The results are shown in the figure.4. It has been shown that the antitumor effect of Extract A is exerted when Extract A is administered after treatment with Extract A emulsion or Extract A in combination with an existing adjuvant.

This example evaluated the effect of Extract A on tumor infiltrating lymphocytes (TIL) in a transplanted tumor by flow cytometry.

(Method)

Mice were infected with BCG and 2×105B16BL6 cells were transplanted subcutaneously into mice after 5 weeks of BCG infection. In this regard, Extract A or saline was administered subcutaneously every other day beginning 8 days before tumor cell transplantation. Mice were sacrificed to extract tumor after 14 days of tumor cell transplantation. After dispersing the tumor using a tumor dissociation kit (Miltenyi Biotec), tumor cells and lymphocytes were separated by density gradient centrifugation. After washing the separated lymphocytes, dead cells were stained and Fc receptors were blocked. After staining the cell surface with various fluorescently labeled antibodies, the cells were fixed and permeabilized and internally stained with fluorescently labeled antibodies.

(Results)

The results are shown in the figure.5. Tumor-positive T-bet cell counts were significantly increased in mice administered Extract A after BCG infection compared to mice administered saline.

This example evaluated the effect of Extract A on tumor infiltrating lymphocytes (TIL) in a transplanted tumor by flow cytometry.

(Method)

Extract A or saline was administered to BCG-infected mice, and the tumor cells were transplanted and the tumor was extracted by the same method as in Example 5. After tumor dispersion using a tumor dissociation kit (Miltenyi Biotec), the cells, tumor cells and lymphocytes were separated by density gradient centrifugation. Each antigen and brefeldin A were added to separate lymphocyte cultures grown overnight at 37°C, 5% carbon dioxide gas. After collecting and washing the cells, dead cells were stained and Fc receptors blocked. After staining the cell surface with various fluorescently labeled antibodies, the cells were fixed and permeabilized and internally stained with fluorescently labeled antibodies.

(Results)

The results are shown in the figure.6. T-bet positive cell counts expressing IFN-γ were significantly increased in tumor tissue of mice administered Extract A after BCG infection compared to mice administered saline.

Follow-up therapy/diagnostics can be carried out as follows:

Obtaining an antigen response profile by non-invasive method, interview, medical history, or vaccination history based on a Maternal and Child Health Handbook or equivalent or similar;

verifying that there is indeed a response to the use of peripheral mononuclear cells isolated from a subject and an antigen panel; and

designate an antigen or a combination thereof showing the above reaction as a prophylactic drug or therapeutic drug.

This example identified cells essential for antitumor activity due to Extract A.

(Method)

(Administration of extract a to CD4-deficient mice)

FIGO.7A shows the administration schedule for BCG, B16BL6 cells, Extract A, anti-CD4 antibody and anti-IFN-γ antibody. Specifically, mice were injected with BCG and then 3.0 x 10 35 and 14 days prior to tumor inoculation5B16BL6 melanoma cells were inoculated. Extract A was administered subcutaneously every other day beginning 8 days prior to tumor inoculation. In a CD4-positive cell depletion experiment, 200 µg of anti-CD4 antibody was injected intraperitoneally 1 day before, 3 days after, 7 days after and 11 days after tumor inoculation. In a CD8 depletion experiment, 200 µg anti-CD8 antibodies were injected intraperitoneally 1, 2 and 3 days before and 2, 5, 8 and 11 days after tumor inoculation. In an IFN-γ depletion experiment, 200 µg anti-IFN-γ antibodies were injected intraperitoneally immediately before and 3, 6, 9 and 12 days after tumor inoculation. As mice, naive mice, CD4-deficient mice and MHC class II-deficient mice were used. A control animal was administered the same amount of saline. The tumor volume was measured by the same method as in Example 2 or similar.

(measurement of intracellular cytokine)

Mice were infected with BCG and then saline or Extract A was administered every other day starting 8 days before slaughter. The spleen was isolated from the mice and ground and centrifuged to obtain a cell pellet. After suspending the cell pellet in Pharm lysis buffer (BD) for 15 minutes, the cell suspension was centrifuged and resuspended in R10. Cell numbers were counted with a Z1 particle counter (Beckman Coulter) and adjusted to 2×107cells/ml with R10. 100 µl of the cell suspension was placed in a 96-well round bottom microplate (Asahi Techno Glass). The cells were stimulated with 100 µl R10 containing extract A. After 30 minutes, Golgi Plug (BD Biosciences) and Golgi Stop (BD Biosciences) were added. The cells were harvested after about 6 hours and washed with PBS. Cells were stained with a live/dead fixable blue staining kit and blocked with anti-mouse CD16/32 antibodies (Biolegend) and then fixed and permeabilized with BD Cytofix/Cytoperm. Antibodies against IFN-γ (XMG1.2), antibodies against IL-13 (eBio13A) and antibodies against IL-17 (TC11-18H10.1) were used for staining. Stained cells were analyzed by flow cytometry using LSRII and FlowJo software (BD Biosciences).

(Video) Immune System

(Results)

(Administration of extract a to CD4-deficient mice)

Administration of Extract A showed no antitumor effect in mice deprived of CD4+ cells using anti-CD4 antibodies (FIG.7b). The requirement of CD4 T cells for an antitumor effect of Extract A was also confirmed in an experiment using CD4-deficient mice (Fig.7C) and an experiment using MHC class II deficient mice (FIG.7D). Meanwhile, an antitumor effect due to Extract A was also observed in mice deprived of CD8 positive cells using anti-CD8 antibodies (FIG.8C) and Batf3-deficient mice lacking CD8-positive DC (FIG.8G) showing that CD8 positive cells are not essential for the antitumor effect due to Extract A.

(measurement of intracellular cytokines)

When Extract A was administered to BCG-infected mice, the percentage of IFN-γ producing cells in CD4 memory T cells increased significantly. Such a change was not observed with IL-17 or IL-13 (Fig.7AND). Furthermore, the antitumor effect due to Extract A disappeared in mice administered with IFN-γ neutralizing antibodies, suggesting that IFN-γ plays an important role in the antitumor effect due to Extract A (FIG.7F). In addition, Extract A-induced IFN-γ secretion from splenocytes of BCG-infected mice was suppressed in each of the CD4-deficient and MHC class II-deficient mice (FIG.7G). Meanwhile, IFN-γ production was maintained in CD1d1-deficient mice (FIG.7H). Furthermore, IFN-γ secretion in the spleen in response to Extract A was completely eliminated when CD4+ cells were removed from the splenocytes (Fig.7I). These results suggest that CD4 T cells switch to Th1 and these cells are the primary source of IFN-γ in BCG-infected mice induced by Extract A.

This example shows the analysis of an antitumor effect in a subcutaneous injection experimental model.

(Method)

FIGO.8A shows the schedule for an intratumoral injection experiment. Specifically, BCG was inoculated into Rag2-deficient mice, CD1d1-deficient mice, FcR-deficient mice, IL12p40-deficient mice and Batf3-deficient mice 35 and 14 days before inoculation with tumor cells. Extract A was administered subcutaneously every other day beginning 8 days prior to tumor inoculation. In the experiment according to FIG.8C, an anti-CD8 antibody was administered 3, 2 and 1 days before and 3, 7 and 11 days after tumor inoculation. In the experiment according to FIG.8And an anti-NK1.1 antibody was administered 1 day before and 3, 7 and 11 days after the tumor inoculation. The tumor volume was then measured according to the method described in Example 2.

(Results)

An antitumor effect for BCG infection due to Extract A was not observed in BCG-infected Rag2-deficient mice (Fig.8b). An antitumor effect of Extract A administration was observed in mice depleted of CD8+ cells (FIG.8C). In addition, antitumor activity was also observed in Batf3-deficient mice (Fig.8G) showing that CD8 positive cells are not essential for antitumor activity. Since the antitumor activity due to Extract A was retained in FcR-deficient mice and mice depleted of NK1.1-positive cells, it was shown that the ADCC activity is not essential for the antitumor effect due to Extract A (FIG.8D and SE). To examine the contribution of NKT cells, the effect was also evaluated in CD1d1-deficient mice, and an antitumor effect due to Extract A was also observed in these mice (FIG.8D). Therefore, it was confirmed that CD4 T cells are essential for an antitumor effect due to Extract A, but CD8 T cells, NKT cells and ADCC activity are not essential for an antitumor effect.

This example demonstrates the antitumor effect in BCG-infected mice when an unrelated tumor protein contained in Extract A was administered.

(Method)

(Extract A Protease Treatment)

A solution of EDTA-0.5% trypsin (Nacalai Tesque) and subtilisin (P5380) (Sigma-Aldrich) was used as the protease. These proteases were heat inactivated (HI) by incubation at 96°C for 15 minutes. HI-treated proteases and non-HI-treated proteases were mixed with Extract A and incubated for 16 hours. These solutions were then incubated at 96°C for 15 minutes and the active enzymes were inactivated.

(Antitumor activity and IFN-γ secretion due to Extract A subjected to protease treatment)

IFN-γ secretion from splenocytes was assayed in BCG-infected mice with saline, Extract A, subtilisin-treated Extract A (Sub), heat-inactivated subtilisin-treated Extract A (HI-Sub), trypsin-treated Extract A (Trp ) induced. or Extract A treated with heat-inactivated trypsin (HI-Trp). Each protease was used at 4 different concentrations. The amount of IFN-γ at each stimulation was divided by the amount of IFN-γ secreted by the Extract A stimulation.

(Antitumor activity of LpqH)

Extract A was administered subcutaneously to BCG-infected mice every other day beginning 8 days before tumor cell transplantation. The mice were sacrificed after 14 days of tumor cell transplantation and the tumor was extracted. A small piece of tumor was digested using a tumor dissociation kit (Miltenyi Biotec). After digestion, a tumor fragment was minced with a 70 µm sieve. Density gradient centrifugation was performed using Lympholyte-M (Cedarlane) to remove tumor cells, red blood cells and dead cells. The intermediate layer after centrifugation was collected and used as a TIL. LpqH (10 μg/mL) was then added and the Golgi Plug and Golgi Stop were added with it. After 10 hours, the cells were harvested and washed with PBS. The cells were stained with a live/dead fixable blue staining kit and blocked with anti-mouse CD16/32 antibodies (Biolegend), and then the cells were fixed and permeabilized with BD Cytofix/Cytoperm. Antibodies against IFN-γ (XMG1.2) were used for staining and stained cells were analyzed by flow cytometry using LSRII and FlowJo software (BD Biosciences).

Saline, 0.1 µg LpqH or 1 µg LpqH were administered subcutaneously to a naïve mouse and a BCG-infected mouse on alternate days beginning 8 days before tumor inoculation. The tumor volume was then measured using an electronic caliper according to the method described in Example 2 or the like.

(Results)

Protease treatment, in contrast to heat-inactivated protease treatment, tended to decrease IFN-γ secretory activity due to Extract A (FIG.9A). As a result of analyzing the treated extract A by mass spectrometry, at least two kinds of proteins MTB12 and LpqH were identified.

When BCG-infected mice were stimulated with LpqH, IFN-γ secretion was induced (Fig.9b). Injection of a recombinant LpqH protein resulted in an antitumor effect in BCG-infected mice similar to the antitumor effect due to Extract A (FIG.9C). In contrast, an antitumor effect of LpqH protein injection was not observed in a naïve mouse (Fig.9C). These results suggest that tumor growth can be suppressed by injecting an antigen into a BCG-infected mouse, and one of the active ingredients in Extract A is a protein.

This example examined the tumor microenvironment after administration of Extract A and analyzed the correlation with tumor infiltrating lymphocytes.

(Method)

(separation of TIL (tumour-infiltrating lymphocytes))

Extract A was administered subcutaneously to BCG-infected mice every other day beginning 8 days before tumor cell transplantation. The mice were sacrificed after 14 days of tumor cell transplantation and the tumor was extracted. A small tumor fragment was digested using a tumor dissociation kit (Miltenyi Biotec). After digestion, a tumor fragment was minced using a 70 µm sieve. Density gradient centrifugation was performed using Lympholyte-M (Cedarlane) to remove tumor cells, red blood cells and dead cells. The intermediate layer after centrifugation was collected and used as a TIL. TIL was detected using anti-CD45 antibodies (30-F11, BD), anti-CD62L antibodies (MEL-14, BD), anti-FOXP3 antibodies (FJK-16S, ebioscience) or anti-T-bet- Antibodies (4B10, Biolenda ). Antibodies against FOXP3 and T-bet were stained after permeabilization using BD Pharmingen Transcription Factor (BD) buffer. Stained cells were analyzed with LSRII (BD) and FlowJo software.

(Results)

Administration of Extract A to a BCG-infected mouse significantly increased the number of CD45+ CD3+ cells in the tumor microenvironment, and a significant negative correlation was found between tumor weight and CD45+ CD3+ tumor infiltrating cells (FIG.10A). A positive correlation between tumor weight and TIL count was observed in BCG-infected mice (Fig.10b). When examining cells with increased proportion in the tumor microenvironment, the ratio of CD4+ cells to CD45+ CD3 cells increased, while the ratio of CD8+ cells to CD45+ CD3 cells showed no such change (Fig.10C). When the number of T-bet positive and Foxp3 positive cells was measured, which focused on the CD4-positive T cell phenotype, it was found that the number of T-bet positive cells increased significantly. The proportion of T-bet positive Foxp3-negative and T-bet positive CD4-positive cells increased in the tumor microenvironment and a significant negative correlation was observed between tumor weight and the number of T-bet positive cells expressing infiltrate the tumor ( .10E).

This example analyzed the correlation between the antitumor effect due to Extract A and IFN-γ producing TIL.

(Method)

Intracellular IFN-γ with or without stimulation by Extract A was measured according to the experimental procedure described in FIG.11Isolated A. TIL was seeded in a culture dish and an antigen and a protein transport inhibitor were added. After overnight culture, TIL was collected and analyzed by FACS.

(Results)

It has been shown that IFN-γ-producing CD4-positive memory T cells are detected without stimulation and independently induce Extract A antigen (FIG.11Banda11D). In this experimental condition, tumor-derived cells and their fragments are preferably contained in a medium. Thus, there is a possibility that a T cell response to a tumor antigen will be detected. In addition, it was shown that CD4+ T cells capable of producing IFN-γ in response to Extract A and LpqH are present in the tumor tissue of BCG-infected mice and mice immunized with Extract A (FIG.11C,11And and11F).

This example examined an antitumor effect of influenza vaccines depending on differences in immunological conditions.

(Method)

(PR8 Infection Model)

The influenza PR8 virus was suspended in PBS so that the concentration was 10 pfu/ml to prepare a viral solution. A mouse was infected by administering 30 µl of viral solution intranasally to prepare a PR8-infected model. The mouse was infected with a virus under anesthesia.

(Administering the influenza vaccine)

An influenza vaccine was adjusted with saline so that the concentration was 1 µg/ml, and 100 µl was administered subcutaneously to the right groin of a mouse.

(Results)

When the influenza vaccine was administered to a naïve mouse, no antitumor effect was observed against a transplanted B16BL6 cell (Fig.12b). In contrast, when an influenza vaccine was administered to an influenza-infected mouse, an antitumor effect was observed (Fig.12C).

Since a vaccine which is an influenza virus antigen is administered to relieve a mouse from influenza virus infection, it is presumed that acquired immunity against an antigen other than a tumor contributes to an antitumor effect. This suggests that even when infected by a pathogenic microorganism other than tuberculosis, the acquired immunity induced by various infections, which is not limited to tuberculosis as a pathogen-associated antigen, exerts an antitumor effect upon re-exposure to the same pathogenic antigen.

This example is conducting clinical trials for prevention, prevention, or recurrence and/or cancer therapy.

(Method)

(Identification of non-tumor antigens)

Ver ABB.13A for the log of this example.

Peripheral blood mononuclear cells (PBMCs) are isolated from subjects in cancer remission and/or postoperative subjects and normal subjects. An antigen response profile is identified by reviewing the subject's vaccination history and/or infection history. Examples of vaccination and infection history include but are not limited to tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, epidemic mumps/mumps, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, Pneumococcal infection, whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza (virus), MARS, rabies, diphtheria, and the like.

The isolated PBMC (eg, 1.0 × 104for 1.0 × 106Cells) are incubated for about 6 to 24 hours with the non-tumor antigen described above (0.01 μg/ml to 1 mg/ml) or an extract containing a non-tumor antigen (0.01 μg/ml to 1 mg/ml), stimulated. ml) and cytokine production (e.g. IFN-γ, IL-2 and/or TNF-α) is measured by a detection method commonly used in the art (e.g. ELISA, qPCR and/or FACS ). Subjects with a post-stimulation cytokine production level at least twice the pre-stimulation cytokine production level are selected as responders.

(administration of non-tumor antigen)

An identified non-tumor antigen is administered according to the following dosing regimen to assess clinical efficacy.

Group composition: placebo or non-tumor antigen (about 0.001 µg/dose to about 1 mg/dose) or an extract comprising a non-tumor antigen (about 0.001 µg/dose to about 1 mg/dose based on non -Tumor antigen ): 2 doses

Number of disciplines: approx. 100

Route of administration: SC (subcutaneous administration) or IT (intratumoral administration)

Number of administrations: about once a day (first week) and about once a week (second week and beyond)

Period of administration: about 3 months to about 1 year

Primary endpoints: progression-free survival (PFS) and overall survival (OS)

Secondary endpoints: duration of response, rate of disease control, and safety

(Results)

Both the primary endpoints and the secondary endpoints were more significant in the group receiving a non-tumor antigen compared to a placebo. Examples with a response within the range of doses tested can be observed.

This example is conducting a clinical study to prevent cancer recurrence in a cancer patient.

(Method)

(Identification of non-tumor antigens)

Ver ABB.13B for log.

Tumor mass is isolated from a patient with postoperative cancer. In this example, an antigen response profile is identified by examining the vaccination history and/or infection history of the cancer patient described above for infiltration of immune cells into the tumor mass. Vaccination history and infection history may include, but are not limited to, tuberculosis, malaria, yellow fever virus, smallpox virus, smallpox vaccine, measles/rubella, polio, epidemic mumps/mumps, rotavirus infection, chickenpox, yellow fever, Ebola, Nile fever, Hib infection, pneumococcal infection , whooping cough, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenicEscherichia coli, toxoplasma, zika virus, herpesvirus 1, EBV/Epstein-Barr virus (herpesvirus 4), CMV/cytomegalovirus (herpesvirus 5), influenza (virus), MARS, rabies, diphtheria, and the like.

The tumor-infiltrating immune cell described above (eg, 1.0 × 104for 1.0 × 106cells/sample) for about 6 to 24 hours with the non-tumor antigen described above (0.01 μg/ml to 1 mg/ml) or an extract containing a non-tumor antigen (0.01 μg/ ml to 1 mg/ml). ) and cytokine production (e.g. IFN-γ, IL-2 and/or TNF-α) is measured by a detection method commonly used in the art (e.g. ELISA, qPCR and/or or FACS ). Subjects with a post-stimulation cytokine production level at least twice the pre-stimulation cytokine production level are selected as responders.

(administration of non-tumor antigen)

An identified non-tumor antigen is administered according to the following dosing regimen to assess clinical efficacy.

Group composition: placebo or non-tumor antigen (about 0.001 µg/dose to about 1 mg/dose) or extract comprising a non-tumor antigen (about 0.001 µg/dose to about 1 mg/dose based on non-tumor -Antigen tumor ): two doses

Number of disciplines: approx. 100

Route of administration: SC (subcutaneous administration) or IT (intratumoral administration)

Number of administrations: about once a day (first week) and about once a week (second week and beyond)

Period of administration: about 3 months to about 1 year

Primary endpoints: progression-free survival (PFS) and overall survival (OS)

Secondary endpoints: duration of response, rate of disease control, and safety

(Results)

Both the primary endpoints and the secondary endpoints were more significant in the group receiving a non-tumor antigen compared to a placebo. Examples with a response within the range of doses tested can be observed.

(Monitoring)

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As described above, the present disclosure is illustrated using its preferred embodiments. However, it should be understood that the scope of the present disclosure should be interpreted solely in light of the claims. It is also to be understood that all patents, patent applications and all references cited herein are incorporated by reference in the same manner as the contents are specifically described herein. The present application claims priority over Japanese Patent Application Nos. 2019-148551 filed with the Japan Patent Office on August 13, 2019, PCT/JP2019/047945 filed with the International Bureau on December 6, 2019, and 108144810 filed on June 12 , 2019 with the Taiwan Intellectual Property Office. It is to be understood that all content is incorporated herein by reference in the same manner as if the content were specifically described herein in its entirety.

The present disclosure provides a method for preventing or treating a disease such as cancer based on a mechanism not conventionally available.

FAQs

Why immunological memory is important in disease prevention? ›

The reason is that immunological memory confers a tremendous survival advantage, as it confers the ability to respond more rapidly and more effectively to a second and subsequent challenge by the same pathogen.

Is immunological memory a mechanism to protect us against reinfection? ›

Immunological memory is a mechanism to protect us against reinfection. Antibodies produced by B cells are integral to this defense strategy and underlie virtually all vaccine success.

Which part of the immune system is responsible for creating an immunological memory? ›

Furthermore, the evidence of immunological memory has been established for NK cells. NK cells can respond to haptens or viruses, which results in generation of antigen-specific memory cells. T, B and NK cells, which have a role in immunological memory, have been characterized phenotypically and functionally.

What is the concept of immunological memory and its application in vaccination? ›

Immunological memory is the ability of the immune system to respond with greater vigor upon re-encounter with the same pathogen and constitutes the basis for vaccination (Ahmed and Gray, 1996).

What is a practical application of immunological memory? ›

After the second encounter with the same antigen, they recognize the antigen and mount a faster and more robust response. Immunological memory is the basis of vaccination.

How is immunological memory achieved? ›

Immunologic memory is dependent on clonal selection. When encountering an antigen, B cells can recognize it by membrane antibody specifically binding to the antigen and can be activated to expand rapidly, with their progeny clones differentiating into plasma cells and memory B cells with the same antigen specificity.

Which of the two types of immunity has an immunological memory? ›

2.4.

Immunologic memory is another important characteristic of adaptive immunity. It means that the immune system can remember the antigens that previously activated it and launch a more intense immune reaction when encountering the same antigen a second time (Figure 2.10).

Is vaccination based on the principle of immunological memory? ›

Immunological memory, involving both B cells and T cells, is the mechanism that makes vaccination effective and explains why an individual does not become ill a second time when exposed to the same pathogens, e.g., the pathogens that cause measles or whooping cough.

Is immunological memory permanent? ›

Thus, a long life is not a key characteristic of memory T cells. Instead, immunological memory, which can last for a lifetime (Crotty and Ahmed, 2004), is maintained by relatively short-lived cells.

What is the advantage of having memory cells in specific defenses? ›

B lymphocytes are immune system cells that generate memory cells that recall the same pathogen to produce antibodies faster for subsequent infections. They operate quickly and efficiently to eradicate the pathogen that causes illness.

How do memory lymphocytes protect against disease? ›

Lymphocytes are produced in response to the specific antigens on a pathogen. After the pathogen is removed some of the lymphocytes continue to remain in the immune system. These are called memory cells. If the same pathogen enters the immune system for a second time, the response is much more rapid.

What is the advantage to the immune system to have memory cells in the specific immune response? ›

Memory immune responses

Because our memory cells are “experienced,” we will respond to a second (or subsequent) encounter more quickly. Whereas in a primary encounter, antibodies are not generated for several days, during a memory response antibodies appear in just a few days.

What is the role of memory cells in vaccination? ›

Once the body produces antibodies in its primary response to an antigen, it also creates antibody-producing memory cells, which remain alive even after the pathogen is defeated by the antibodies.

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