Novel treatment and prevention of disease based on immunological memory

Abstract

To provide a composition for preventing an immune disorder, recovering from an immune disorder, preventing an immune disorder from occurring and preventing or treating a disease, disorder or condition.SOLUTION: The present disclosure provides a composition for preventing an immune disorder, recovering from an immune disorder, preventing an immune disorder from occurring and preventing or treating a disease, disorder or condition in a subject, the composition comprising an antigen component which is specific to the subject (or immunological memory of which remains in the subject) against a component which is different from a causative factor of the disease, disorder or condition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to novel disease treatments and preventions based on immune memory, and in one aspect, to mechanism-based cancer prevention and therapy. In particular, this disclosure relates to cancer treatments and preventions that utilize memory responses induced by non-tumor antigens from pathogens of previous infections, such as Mycobacterium tuberculosis extracts, as personalized markers. [Background technology]

[0002] Various techniques have been developed to treat diseases.

[0003] For example, current cancer immunotherapy approaches can be broadly divided into three categories: (1) Therapies that involve the transfer of therapeutic vaccines or cancer antigen-dependent chimeric T cells containing cancer-specific antigens (WT1 or cancer-specific neoantigens) along with adjuvant bases, and the transfer of antigen-presenting cells (DCs). These approaches are expensive and require specific cancer antigens for each patient. While specific cancer antigens can provide specific immunotherapy, they are only applicable to patients with certain cancer antigens. Furthermore, because they require cancer antigens, they cannot be used in healthy individuals and therefore cannot be used for preventive purposes. (2) Inhibitors of checkpoint molecules that suppress cancer immunity. Immune checkpoint molecules regulate T cell responses in vivo. Checkpoint molecule inhibitors promote antitumor immunity by inhibiting immunosuppressive molecules expressed in host cancer cells and regulatory T cells. However, while these drugs demonstrate beneficial effects, they also suppress immune responses that should be suppressed, resulting in significant side effects, such as an increased risk of autoimmune diseases. Therefore, it is not suitable for preventive treatment of healthy individuals. Furthermore, although it is effective in some patients, there are no appropriate diagnostic drugs for selecting patients. (3) Vaccines that prevent cancer by preventing infection. There are vaccines aimed at preventing infection with HPV, which is associated with cervical cancer, but the target cancers are limited. Summary of the Invention [Means for solving the problem]

[0004] As a result of extensive research, the present inventors have developed novel disease treatments and preventions based on immune memory. As one aspect of this, the present disclosure provides a mechanism-based cancer prevention and therapy. A representative example of this is a cancer treatment and prevention method that uses a memory response induced by a non-tumor antigen from a pathogen of a previous infection, such as a Mycobacterium tuberculosis extract, as a personalized marker.

[0005] Thus, the present disclosure provides, as representative aspects: (Item 1) A composition for activating regulatory T cells (Tregs) that are suppressed in a subject and have immunological memory to the non-target antigen component against a target, the composition comprising a non-target antigen component. (Item 2) The composition according to any of the above items, wherein activation of the Treg confers killing ability or immunostimulatory effect on the target. (Item 3) A composition for activating regulatory T cells (Tregs) that are suppressed in a subject and have immunological memory to the non-tumor antigen component, comprising a non-tumor antigen component. (Item 4) The composition according to any of the above items, wherein activation of the Treg confers tumor-killing ability or immunostimulatory effect against tumors. (Item 5) The composition described in any of the above items, wherein the Tregs are memory T cells. (Item 6) The composition described in any of the above items, wherein the Treg is CD4 positive. (Item 7) The composition according to any of the above items, wherein the antigen component comprises a protein. (Item 8) The composition according to any of the above items, wherein the antigen component comprises an antigen selected from the group consisting of an infectious disease pathogen or a part thereof, an antigen associated with medical history, and an antigen associated with vaccination history. (Item 9) The composition according to any of the preceding items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis or an influenza virus antigen. (Item 9A) A composition according to any one of the preceding items, further comprising one or more of the features described in any one of the preceding items or any one or more of the following items. (Item 10) A composition characterized by being used in a method comprising determining whether the antigen component has Treg immune memory in the subject, and administering the antigen component to the subject if the subject has immune memory against the antigen component. (Item 11) A composition for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the composition comprising an antigen component specific in the subject to a component that is different from the causative agent of the disease, disorder, or symptom. (Item 12) The composition according to any of the preceding items, wherein the disease, disorder or condition includes cancer, and preferably the antigen component is a non-tumor antigen component. (Item 13) The composition described in any of the above items, wherein the antigen component is specific to memory T cells of the subject. (Item 14) The composition according to any of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing). (Item 15) The composition according to any of the above items, wherein the antigen component has immunostimulatory activity. (Item 16) The composition according to any of the above items, wherein the antigen component acts on memory CD4-positive T cells in an antigen-dependent manner. (Item 17) The composition according to any of the above items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to IFN-γ-producing T cells. (Item 18) The composition described in any of the above items, wherein the bias is to increase IFN-γ-producing T cells compared to Foxp3-positive Treg cells. (Item 19) The composition according to any of the above items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to type 1 helper T cells. (Item 20) The composition described in any of the above items, wherein the IFN-γ-producing T cells include type 1 helper T cells. (Item 21) The composition according to any of the above items, wherein the antigen component has the activity of shifting the proportion of Th1 cells present. (Item 22) The composition described in any of the above items, wherein the IFN-γ-producing T cells are T-bet-positive Th1 cells. (Item 23) A composition described in any of the above items, wherein the specific antigen component has the ability to enhance at least one selected from the group consisting of IFN-γ production ability, IL-2 production ability, and TNF-α production ability in a sample derived from the subject. (Item 24) The composition according to any of the above items, wherein the antigen component is a protein. (Item 25) A biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the biomarker comprising at least one selected from the group consisting of whether the antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability. (Item 26) A composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, wherein the biomarker is at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability. (Item 27) The composition described in any of the above items, wherein the (non-tumor) antigen component comprises an antigen associated with medical history or vaccination history. (Item 28) The composition according to any of the above items, wherein the subject has a history of an infectious disease, and the antigen component comprises an antigen against the infectious disease. (Item 29) The composition according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, Salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item 30) The composition according to any of the above items, wherein the subject has a history of BCG vaccination, tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component comprises a hot water extract of Mycobacterium tuberculosis. (Item 31) The composition according to any of the above items, wherein the subject has a history of influenza vaccination, influenza infection, or antigenic responsiveness to influenza virus, and the antigen component comprises influenza virus. (Item 32) The composition of any of the above items, wherein the disease, disorder, or condition includes melanoma. (Item 33) The composition according to any of the preceding items, wherein the antigen component comprises a protein, a portion thereof, or a peptide. (Item 34) The composition described in any of the above items, wherein the antigen component includes one capable of eliciting an immune response mediated by CD4-positive T cells. (Item 35) A composition described in any of the above items, characterized in that it is confirmed whether the subject is capable of initiating an anti-tumor immune response mediated by CD4-positive T cells, and the composition is administered if the subject is capable of initiating an anti-tumor immune response mediated by CD4-positive T cells. (Item 36) A composition for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the composition comprising an antigen component specific in the subject to a component different from a causative agent of the disease, disorder, or symptom, the disease, disorder, or condition comprises melanoma; the antigen component is a protein or a part thereof, or a peptide, and is capable of eliciting an immune response mediated by CD4-positive T cells; The cancer includes those that can be treated or prevented by an immune response mediated by CD4-positive T cells, and determining whether the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, and administering the composition to the subject if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells. composition. (Item 37) A composition for treating or preventing cancer or tumors in a subject, the composition comprising a non-tumor antigen component that activates regulatory T cells (Tregs) that are suppressed in the subject and have immune memory to the non-tumor antigen, and the Tregs have a regulatory activity or an effect of promoting anti-tumor immunity against cancer or tumors. (Item 38) A method for manufacturing or otherwise providing a composition for preventing or treating cancer in a subject, the method comprising: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting those with immunological memory; C) manufacturing or otherwise providing the selected non-tumor antigen; The method includes: (Item 39) A method according to any one of the preceding items, wherein B) has one or more features according to any one of the preceding items. (Item 40) A method for determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising: B) determining whether the non-tumor antigen has immunological memory in the subject, identifying said immune memory, if present, as capable of preventing or treating cancer in said subject. The method includes: (Item 41) A method according to any one of the preceding items, wherein B) has one or more features according to any one of the preceding items. (Item 42) a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigenic component or combination of antigenic components from the antigen responsiveness profile, the antigenic component or combination of antigenic components being identified based on the subject's current or past immune responsiveness to the antigenic component or antigenic components; 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; A method for preventing or treating a disease, disorder or condition associated with immune abnormalities, comprising: (Item 43) The method according to any of the above items, wherein the disease, disorder or condition comprises cancer. (Item 44) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition, and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item 45) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes identifying an antigen component or a combination of antigen components that elicits an immune response via CD4-positive T cells. (Item 46) i) the antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof; and / or ii) the confirmation of the responsiveness includes collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and measuring whether the peripheral blood cells produce cytokines in response to antigens associated with the antigenic profile, as well as other biomarkers. (Item 47) The method according to any of the above items, further comprising periodically testing the responsiveness to the antigen to confirm that the responsiveness is maintained. (Item 48) a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens corresponding to the physical condition and other biomarkers; iii) identifying an appropriate antigen component or combination of antigen components from the results of ii); The method according to any of the preceding items, wherein the method is carried out by (Item 49) A method according to any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item 50) A method according to any of the above items, wherein the physical condition includes a history of infection, and the cancer vaccine includes an antigen component or a combination of antigen components against the infection. (Item 51) The method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item 52) A method described in any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigenic component or combination of antigenic components includes a hot water extract of Mycobacterium tuberculosis. (Item 53) A method according to any of the above items, 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 antigen component or combination of antigen components includes an influenza virus. (Item 54) The method according to any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item 55) A method according to any of the above items, wherein the subject is in a state before cancer develops, after cancer treatment, in the early stages of cancer, or in a precancerous state. (Item 56) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-growing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas, which are typically not sensitive to CD8-positive T cells. (Item 57) The method described in any of the above items, wherein the subject exhibits immune resistance. (Item 58) A method according to any of the above items, wherein step ii) comprises measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item 59) The method according to any of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item 60) A method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item 61) The method described in any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of influenza infection and influenza virus. (Item 62) The method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item 63) The subject has a confirmed history of BCG vaccination, tuberculosis infection, or antigen responsiveness, The method according to any of the preceding items, characterized in that the tuberculosis Mycobacterium extract is administered prophylactically before the onset of cancer or at the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from tuberculosis Mycobacterium is administered subcutaneously or intradermally by conventional methods. (Item 64) The subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed, The method according to any one of the preceding items, wherein the influenza vaccine is administered prophylactically before the onset of cancer, administered to prevent recurrence after treatment, or administered at an early stage of cancer onset, and wherein the influenza vaccine is administered subcutaneously or intradermally at an early stage of cancer onset or in a precancerous state. (Item 65) A method for preventing or treating cancer immunity based on any of the above items, comprising revaccinating with the antigen component or combination of antigen components. (Item 66) A method for preventing or treating cancer in a subject using a non-tumor component, wherein the component is an antigen or extract identified by medical interview and / or by reference to the subject's medical history and vaccination history, the subject is an individual who has had an infection or vaccination as described in any of the above items, and the component is administered to the subject to prevent recurrence after treatment, as a prophylactic administration before onset, or at the early stage of cancer onset, and if necessary, the component is administered at the early stage of cancer onset or in a precancerous state. (Item 67) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-growing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas, which are typically not sensitive to CD8-positive T cells. (Item 68) The method described in any of the above items, wherein the subject is a patient exhibiting immune resistance. (Item 69) A method according to any of the above items, characterized in that the responsiveness is identified by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item 70) The method according to any of the above items, wherein the tuberculosis extract is a hot water extract of human tuberculosis or an extract from another tuberculosis bacterium (a highly safe extract). (Item 71) The method according to any of the above items, wherein the influenza virus is an extract (highly safe extract) from a human influenza virus or another influenza virus. (Item 72) A method according to any of the above items, wherein the antigen component is a protein. (Item 73) A vaccine formulation comprising an antigen according to any of the preceding items and an adjuvant base. (Item 74) A vaccine formulation according to any of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1-type immune response. (Item 75) The vaccine preparation according to any of the above items, wherein the vaccine preparation is used for personalized medicine. (Item 76) A composition for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the composition comprising an antigen component specific in the subject to a component different from the causative agent of the disease, disorder, or symptom, and characterized in that the composition is administered subcutaneously or intratumorally once daily (first week) and once weekly (second week and thereafter). (Item 77) The composition according to any of the above items, wherein the antigen component is contained in an amount of about 0.001 μg or more per unit formulation. (Item 78) A method for treating or preventing cancer or tumors in a subject, comprising: a) identifying non-tumor antigens specific to the subject based on the antigenic response profile; b) determining whether the subject has immune memory against the non-tumor antigen and identifying the subject with immune memory; c) administering the non-tumor antigen to the subject identified as having the immunological memory. The method includes: (Item 79) A method described in any of the above items, wherein the antigenic response profile includes vaccination history and / or infection history. (Item 80) A method according to any of the above items, wherein the step of identifying a subject with immune memory comprises stimulating peripheral blood mononuclear cells (PBMCs) 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 whose cytokine production level has increased by a predetermined fold compared to before stimulation as a subject with immune memory. (Item 81) The method according to any of the above items, wherein the 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 of the preceding items, wherein the non-tumor antigen is administered at a dose of about 0.001 μg to about 1 mg per dose. (Item 83) A composition comprising mHSP10 and / or MTB12 and / or lipoprotein LpqH for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject. (Item 84) A composition, kit, biomarker, vaccine formulation, or method described in any of the above items, characterized in that it contains multiple agents containing the antigen component. (Item 85) A composition, kit, biomarker, vaccine formulation, or method described in any of the above items, characterized in that each component of the multiple drugs is provided as a separate composition. (Item A1) A method for activating regulatory T cells (Tregs) that are suppressed in a subject and have immune memory to a non-target antigen component against a target, the method comprising the step of administering to the subject an effective amount of the non-target antigen component. (Item A2) The method according to any one of the above items, wherein activation of the Treg confers killing ability or immunostimulatory effect on the target. (Item A3) A method for activating regulatory T cells (Tregs) that are suppressed in a subject and have immune memory to a non-tumor antigen component, the method 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 Tregs confers tumor-killing ability or immunostimulatory activity against tumors. (Item A5) The method described in any of the above items, wherein the Tregs are memory T cells. (Item A6) The method described in any of the above items, wherein the Treg is CD4 positive. (Item A7) The method according to any one of the above items, wherein the antigen component comprises a protein. (Item A8) A method according to any one of the above items, wherein the antigen component comprises an antigen selected from the group consisting of an infectious disease pathogen or a part thereof, an antigen associated with medical history, and an antigen associated with vaccination history. (Item A9) The method according to any one of the above items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis or an influenza virus antigen. (Item A9A) A method according to any one of the preceding items, further comprising one or more of the features described in any one of the preceding items or one or more of the following items. (Item A10) A method comprising determining whether the antigen component has Treg immune memory in the subject, and administering an effective amount of the antigen component to the subject if the subject has immune memory against the antigen component. (Item A11) A method for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the method comprising the step of administering to the subject an effective amount of an antigen component specific in the subject to a component that is different from the causative agent of the disease, disorder, or symptom. (Item A12) The method according to any of the above items, wherein the disease, disorder or condition includes cancer, and preferably the antigen component is a non-tumor antigen component. (Item A13) A method according to any of the above items, wherein the antigen component is specific to memory T cells of the subject. (Item A14) The method according to any one of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing). (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 memory CD4-positive T cells in an antigen-dependent manner. (Item A17) The method according to any one of the above items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to IFN-γ-producing T cells. (Item A18) The method described in any of the above items, wherein the bias is to increase 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 the activity of shifting the ratio of Foxp3-positive Treg cells to type 1 helper T cells. (Item A20) A method according to any of the above items, wherein the IFN-γ-producing T cells include type 1 helper T cells. (Item A21) The method according to any one of the above items, wherein the antigen component has the activity of shifting the proportion of Th1 cells present. (Item A22) A method described in any of the above items, wherein the IFN-γ-producing T cells are T-bet-positive Th1 cells. (Item A23) A method described in any of the above items, wherein the specific antigen component has the ability to enhance at least one selected from the group consisting of IFN-γ production ability, IL-2 production ability, and TNF-α production ability in a sample derived from the subject. (Item A24) The method according to any of the above items, wherein the antigen component is a protein. (Item A25) A method for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the method comprising determining whether the antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability using at least one biomarker selected from the group consisting of: (Item A26) A method for detecting a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the biomarker including at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability. (Item A27) A method according to any of the above items, wherein the (non-tumor) antigen component comprises an antigen associated with medical history or vaccination history. (Item A28) A method according to any of the above items, wherein the subject has a history of contracting an infectious disease, and the antigen component comprises an antigen against the infectious disease. (Item A29) A method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item A30) A method according to any of the preceding items, wherein the subject has a history of BCG vaccination, tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component comprises a hot water extract of Mycobacterium tuberculosis. (Item A31) A method according to any of the above items, wherein the subject has a history of influenza vaccination, influenza infection, or antigenic responsiveness to influenza virus, and the antigen component comprises influenza virus. (Item A32) The method according to any of the above items, wherein the disease, disorder or condition comprises melanoma. (Item A33) The method according to any of the above items, wherein the antigen component comprises a protein, a part thereof, or a peptide. (Item A34) A method according to any of the above items, wherein the antigen component includes one capable of eliciting an immune response mediated by CD4-positive T cells. (Item A35) A method according to any of the above items, wherein it is determined whether the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, and if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, the composition is administered. (Item A36) A method for treating or preventing a disease, disorder, or symptom associated with immune abnormality in a subject, comprising administering to the subject an effective amount of an antigen component specific in the subject to a component different from a causative factor of the disease, disorder, or symptom; the disease, disorder, or condition comprises melanoma; the antigen component is a protein or a part thereof, or a peptide, and is capable of eliciting an immune response mediated by CD4-positive T cells; The cancer includes those that can be treated or prevented by an immune response mediated by CD4-positive T cells, Here, whether or not the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells is confirmed, and if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, the antigen component is administered. method. (Item A37) A method for treating or preventing cancer or tumor in a subject, comprising the step of administering an effective amount of a non-tumor antigen component, wherein the non-tumor antigen component activates regulatory T cells (Tregs) that are suppressed in the subject and have immune memory to the non-tumor antigen, and the Tregs have a regulatory activity or an effect of promoting anti-tumor immunity against cancer or tumor. (Item A38) A method for manufacturing or otherwise providing a composition for preventing or treating cancer in a subject, the method comprising: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting those with immunological memory; C) manufacturing or otherwise providing the selected non-tumor antigen; The method includes: (Item A39) B) A method according to any one of the preceding items, having one or more features according to any one of the preceding items. (Item A40) A method for determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising: B) determining whether the non-tumor antigen has immunological memory in the subject, identifying said immunological memory, if present, as capable of preventing or treating cancer in said subject. The method includes: (Item A41) B) A method according to any one of the preceding items, having one or more features according to any one of the preceding items. (Item A42) a) obtaining an antigen responsiveness profile of the subject; b) identifying an antigenic component or combination of antigenic components from the antigen responsiveness profile, the antigenic component or combination of antigenic components being identified based on the subject's current or past immune responsiveness to the antigenic component or antigenic components; 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; A method for preventing or treating a disease, disorder or condition associated with immune abnormalities, comprising: (Item A43) The method according to any of the above items, wherein the disease, disorder or condition includes cancer. (Item A44) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition, and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item A45) A method according to any of the above items, wherein obtaining the antigen responsiveness profile comprises identifying an antigen component or a combination of antigen components that elicits an immune response mediated by CD4-positive T cells. (Item A46) A method according to any of the above items, wherein i) the antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof, and / or ii) the confirmation of the responsiveness includes collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens associated with the antigenic profile, as well as other biomarkers. (Item A47) The method according to any one of the above items, further comprising periodically testing the responsiveness to the antigen to confirm that the responsiveness is maintained. (Item A48) The above a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens corresponding to the physical condition and other biomarkers; iii) identifying an appropriate antigen component or combination of antigen components from the results of ii); The method according to any of the preceding items, wherein the method is carried out by (Item A49) A method according to any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item A50) A method according to any of the above items, wherein the physical condition includes a history of infection, and the cancer vaccine includes an antigen component or a combination of antigen components against the infection. (Item A51) A method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item A52) A method according to any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component or combination of antigen components includes a hot water extract of Mycobacterium tuberculosis. (Item A53) A method according to any of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or antigenic responsiveness to influenza virus, and the antigen component or combination of antigen components includes influenza virus. (Item A54) The method according to any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item A55) The method according to any one of the above items, wherein the subject is in a state before the onset of cancer, after cancer treatment, in the early stage of cancer, or in a precancerous state. (Item A56) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, carcinomas that progress relatively slowly, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas to which CD8-positive T cells are usually not effective. (Item A57) The method described in any of the above items, wherein the subject exhibits immune resistance. (Item A58) A method according to any of the above items, wherein step ii) comprises measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item A59) The method according to any one of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item A60) The method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item A61) The method described in any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of influenza infection and an influenza virus. (Item A62) A method according to any of the preceding items, wherein the past physical condition and the antigen component or combination of antigen components are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item A63) The subject has a confirmed history of BCG vaccination, tuberculosis infection, or antigen responsiveness, The method according to any of the preceding items, characterized in that the tuberculosis Mycobacterium extract is administered prophylactically before the onset of cancer or at the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from tuberculosis Mycobacterium is administered subcutaneously or intradermally by conventional methods. (Item A64) The subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed, The method according to any one of the preceding items, wherein the influenza vaccine is administered prophylactically before the onset of cancer, administered to prevent recurrence after treatment, or administered at an early stage of cancer onset, and wherein the influenza vaccine is administered subcutaneously or intradermally at an early stage of cancer onset or in a precancerous state. (Item A65) A method for preventing or treating cancer immunity based on any of the above items, comprising revaccinating with the antigen component or combination of antigen components. (Item A66) A method for preventing or treating cancer in a subject using a non-tumor component, the component being an antigen or extract identified by medical interview and / or by reference to the subject's medical history and vaccination history, the subject being an individual who has had an infection or vaccination as described in any of the above items, the method comprising administering to the subject an effective amount of the component for prevention of recurrence after treatment, prophylactic administration before onset, or at the early stage of cancer onset, and, if necessary, administering an effective amount of the component at the early stage of cancer onset or in a precancerous state. (Item A67) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, carcinomas that progress relatively slowly, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas to which CD8-positive T cells are usually not effective. (Item A68) The method according to any of the above items, wherein the subject is a patient exhibiting immune resistance. (Item A69) A method according to any of the above items, characterized in that the responsiveness is identified by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item A70) The method according to any one of the above items, wherein the tuberculosis extract is a hot water extract of human tuberculosis or an extract from another tuberculosis bacterium (a highly safe extract). (Item A71) The method according to any one of the above items, wherein the influenza virus is an extract (highly safe extract) from a human influenza virus or another influenza virus. (Item A72) The method described in any of the above items, wherein the antigen component is a protein. (Item A73) A vaccine formulation comprising an antigen according to any one of the above items and an adjuvant base. (Item A74) A vaccine formulation according to any of the preceding items, wherein the adjuvant base contains a substance that promotes a Th1-type immune response. (Item A75) The vaccine preparation according to any one of the preceding items, wherein the vaccine preparation is used for personalized medicine. (Item A76) A method for treating or preventing a disease, disorder, or symptom associated with immune abnormality in a subject, the method comprising the step of subcutaneously or intratumorally administering an effective amount of an antigen component specific in the subject to a component other than the causative factor of the disease, disorder, or symptom once daily (in the first week) and once a week (from the second week onwards). (Item A77) The method according to any of the above items, wherein the antigen component is contained in an amount of about 0.001 μg or more per unit preparation. (Item A78) A method for treating or preventing cancer or tumors in a subject, comprising: a) identifying non-tumor antigens specific to the subject based on the antigenic response profile; b) determining whether the subject has immune memory against the non-tumor antigen and identifying the subject with immune memory; c) administering to the subject identified as having immunological memory an effective amount of the non-tumor antigen; The method includes: (Item A79) A method described in any of the above items, wherein the antigenic response profile includes vaccination history and / or infection history. (Item A80) A method according to any of the above items, in which the step of identifying a subject with immune memory comprises stimulating peripheral blood mononuclear cells (PBMCs) 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 whose cytokine production level has increased by a predetermined fold compared to before stimulation as a subject with immune memory. (Item A81) The method according to any of the preceding items, wherein the non-tumor antigen is administered once a day (first week) and once a week (second week and thereafter). (Item A82) The method according to any one of the preceding items, wherein the non-tumor antigen is administered at a dose of about 0.001 μg / single dose to about 1 mg / single dose. (Item A83) A method for treating or preventing a disease, disorder or symptom associated with an immune abnormality in a subject, the method comprising administering mHSP10 and / or MTB12 and / or lipoprotein LpqH. (Item A84) A method according to any of the above items, comprising administering multiple agents containing the antigen component. (Item A85) A method according to any of the above items, wherein each component of the multiple drugs is administered as a separate composition. (Item B1) A non-target antigen component for activating regulatory T cells (Tregs) that have immune memory to the non-target antigen component and are suppressed in a subject against the target. (Item B2) An antigen component according to any of the above items, wherein activation of the Treg confers killing ability or immunostimulatory effect on the target. (Item B3) A non-tumor antigen component for activating regulatory T cells (Tregs) that have immune memory to the non-tumor antigen component and are suppressed in a subject. (Item B4) An antigen component according to any one of the above items, wherein activation of the Treg confers tumor-killing ability or immunostimulatory activity against tumors. (Item B5) The antigen component according to any one of the above items, wherein the Treg is a memory T cell. (Item B6) The antigen component according to any one of the above items, wherein the Treg is CD4 positive. (Item B7) The antigen component according to any one of the above items, wherein the antigen component comprises a protein. (Item B8) The antigen component according to any of the above items, wherein the antigen component comprises an antigen selected from the group consisting of an infectious disease pathogen or a part thereof, an antigen associated with medical history, and an antigen associated with vaccination history. (Item B9) The antigen component according to any one of the above items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis or an influenza virus antigen. (Item B9A) An antigen component according to any one of the preceding items, further comprising one or more of the features described in any one of the preceding items or in any one or more of the following items. (Item B9B) An extract containing an antigen component according to any one of the above items. (Item B10) An antigen component, characterized in that it is used in a method comprising determining whether the antigen component has Treg immune memory in the subject, and administering the antigen component to the subject if the subject has immune memory against the antigen component. (Item B11) An antigen component specific in a subject to a component different from the causative agent of a disease, disorder or symptom associated with an immune abnormality in the subject, for treating or preventing the disease, disorder or symptom. (Item B12) The antigen component according to any of the above items, wherein the disease, disorder or condition includes cancer, and preferably the antigen component is a non-tumor antigen component. (Item B13) The antigen component according to any of the above items, wherein the antigen component is specific to memory T cells of the subject. (Item B14) The antigen component according to any one of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing). (Item B15) The antigen component according to any one of the above items, wherein the antigen component has an immunostimulatory effect. (Item B16) The antigen component according to any one of the above items, wherein the antigen component acts on memory CD4-positive 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 the activity of shifting the ratio of Foxp3-positive Treg cells to IFN-γ-producing T cells. (Item B18) The antigen component according to any one of the above items, wherein the bias is to increase 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 the activity of shifting the ratio of Foxp3-positive Treg cells to type 1 helper T cells. (Item B20) An antigen component according to any of the above items, wherein the IFN-γ-producing T cells include type 1 helper T cells. (Item B21) The antigen component according to any one of the above items, wherein the antigen component has the activity of shifting the proportion of Th1 cells present. (Item B22) An antigen component according to any of the above items, wherein the IFN-γ-producing T cells are T-bet-positive Th1 cells. (Item B23) The specific antigen component according to any of the above items has the ability to enhance at least one selected from the group consisting of IFN-γ production ability, IL-2 production ability, and TNF-α production ability in a sample derived from the subject. (Item B24) The antigen component according to any one of the above items, wherein the antigen component is a protein. (Item B25) A biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the biomarker comprising at least one selected from the group consisting of whether the antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability. (Item B26) A composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, wherein the biomarker includes at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability. (Item B27) The (non-tumor) antigen component according to any one of the above items, wherein the (non-tumor) antigen component comprises an antigen associated with medical history or vaccination history. (Item B28) The antigen component according to any of the above items, wherein the subject has a history of contracting an infectious disease, and the antigen component comprises an antigen against the infectious disease. (Item B29) A composition according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item B30) The subject is a subject with a history of BCG vaccination, tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component comprises a hot water extract of Mycobacterium tuberculosis, according to any of the above items. (Item B31) The antigen component according to any of the above items, wherein the subject has a history of influenza vaccination, influenza infection, or antigenic responsiveness to influenza virus, and the antigen component comprises influenza virus. (Item B32) The antigen component according to any one of the above items, wherein the disease, disorder or condition includes melanoma. (Item B33) The antigen component according to any one of the above items, wherein the antigen component comprises a protein, a part thereof, or a peptide. (Item B34) The antigen component according to any of the above items, including an antigen component capable of eliciting an immune response mediated by CD4-positive T cells. (Item B35) An antigen component described in any of the above items, characterized in that it is confirmed whether the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, and the antigen component is administered if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells. (Item B36) An antigen component for treating or preventing a disease, disorder, or symptom associated with immune abnormality in a subject, wherein the antigen component is an antigen component specific in the subject to a component different from the causative agent of the disease, disorder, or symptom; the disease, disorder, or condition comprises melanoma; the antigen component is a protein or a part thereof, or a peptide, and is capable of eliciting an immune response mediated by CD4-positive T cells; The cancer includes those that can be treated or prevented by an immune response mediated by CD4-positive T cells, wherein whether or not the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells is confirmed, and if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, the antigen component is administered. Antigenic components. (Item B37) An antigen component for treating or preventing cancer or tumor in a subject, the antigen component comprising a non-tumor antigen component, which activates regulatory T cells (Tregs) that have immune memory to the non-tumor antigen and are suppressed in the subject, and the Tregs have a regulatory activity or an effect of promoting anti-tumor immunity against cancer or tumor. (Item B38) A method for manufacturing or otherwise providing a composition for preventing or treating cancer in a subject, the method comprising: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting those with immunological memory; C) manufacturing or otherwise providing the selected non-tumor antigen; The method includes: (Item B39) A method according to any one of the preceding items, wherein B) has one or more features according to any one of the preceding items. (Item B40) A method for determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising: B) determining whether the non-tumor antigen has immunological memory in the subject, identifying said immunological memory, if present, as capable of preventing or treating cancer in said subject. The method includes: (Item B41) A method according to any one of the preceding items, wherein B) has one or more features according to any one of the preceding items. (Item B42) a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigenic component or combination of antigenic components from the antigen responsiveness profile, the antigenic component or combination of antigenic components being identified based on the subject's current or past immune responsiveness to the antigenic component or antigenic components; 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; A method for preventing or treating a disease, disorder or condition associated with immune abnormalities, comprising: (Item B43) The method according to any of the above items, wherein the disease, disorder or condition includes cancer. (Item B44) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition, and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item B45) A method according to any of the above items, wherein obtaining the antigen responsiveness profile comprises identifying an antigen component or a combination of antigen components that elicits an immune response via CD4-positive T cells. (Item B46) A method according to any of the above items, wherein i) the antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof, and / or ii) the confirmation of the responsiveness includes collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens associated with the antigenic profile, as well as other biomarkers. (Item B47) The method according to any one of the above items, further comprising periodically testing the responsiveness to the antigen to confirm that the responsiveness is maintained. (Item B48) The above a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens corresponding to the physical condition and other biomarkers; iii) identifying an appropriate antigen component or combination of antigen components from the results of ii); The method according to any of the preceding items, wherein the method is carried out by (Item B49) A method according to any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item B50) A method according to any of the above items, wherein the physical condition includes a history of infection, and the cancer vaccine includes an antigen component or a combination of antigen components against the infection. (Item B51) A method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item B52) A method according to any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component or combination of antigen components includes a hot water extract of Mycobacterium tuberculosis. (Item B53) A method according to any of the above items, 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 antigen component or combination of antigen components includes an influenza virus. (Item B54) The method according to any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item B55) The method according to any one of the above items, wherein the subject is in a state before cancer develops, after cancer treatment, in the early stage of cancer, or in a precancerous state. (Item B56) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas to which CD8-positive T cells are usually not effective. (Item B57) The method according to any of the above items, wherein the subject exhibits immune resistance. (Item B58) A method according to any of the above items, wherein step ii) comprises measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item B59) The method according to any one of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item B60) The method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item B61) The method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of influenza infection and an influenza virus. (Item B62) A method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item B63) The subject is a subject whose history of BCG vaccination, history of tuberculosis infection, or antigen responsiveness has been confirmed, The method according to any of the preceding items, characterized in that the tuberculosis Mycobacterium extract is administered prophylactically before the onset of cancer or at the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from tuberculosis Mycobacterium is administered subcutaneously or intradermally by conventional methods. (Item B64) The subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed, The method according to any one of the preceding items, wherein the influenza vaccine is administered prophylactically before the onset of cancer, administered to prevent recurrence after treatment, or administered at an early stage of cancer onset, and wherein the influenza vaccine is administered subcutaneously or intradermally at an early stage of cancer onset or in a precancerous state. (Item B65) A method for preventing or treating cancer immunity based on any of the above items, comprising revaccinating with the antigen component or combination of antigen components. (Item B66) A method for preventing or treating cancer in a subject using a non-tumor component, wherein the component is an antigen or extract identified by medical interview and / or by reference to the subject's medical history and vaccination history, the subject is an individual who has had an infection or vaccination as described in any of the above items, and the component is administered to the subject to prevent recurrence after treatment, as a prophylactic administration before onset, or at the early stage of cancer onset, and if necessary, the component is administered at the early stage of cancer onset or in a precancerous state. (Item B67) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas to which CD8-positive T cells are usually not effective. (Item B68) The method according to any of the above items, wherein the subject is a patient exhibiting immune resistance. (Item B69) A method described in any of the above items, characterized in that the responsiveness is identified by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item B70) The method according to any one of the above items, wherein the tuberculosis extract is a hot water extract of human tuberculosis or an extract from another tuberculosis bacterium (a highly safe extract). (Item B71) The method according to any one of the above items, wherein the influenza virus is an extract (highly safe extract) from a human influenza virus or another influenza virus. (Item B72) The method according to any of the above items, wherein the antigen component is a protein. (Item B73) A vaccine formulation comprising an antigen according to any one of the above items and an adjuvant base. (Item B74) A vaccine formulation according to any of the preceding items, wherein the adjuvant base contains a substance that promotes a Th1-type immune response. (Item B75) The vaccine preparation according to any one of the above items, wherein the vaccine preparation is used for personalized medicine. (Item B76) An antigen component for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, which is specific in the subject to a component different from the causative factor of the disease, disorder, or symptom, and is administered subcutaneously or intratumorally once a day (first week) and once a week (second week and thereafter). (Item B77) The antigen component according to any of the above items, wherein the antigen component is contained in an amount of about 0.001 μg or more per unit preparation. (Item B78) A non-tumor antigen component for use in a method for treating or preventing cancer or tumors in a subject, the method comprising: a) identifying non-tumor antigens specific to the subject based on the antigenic response profile; b) determining whether the subject has immune memory against the non-tumor antigen and identifying the subject with immune memory; c) administering the non-tumor antigen to the subject identified as having the immunological memory. The antigen component includes: (Item B79) The antigen component according to any of the above items, wherein the antigenic response profile includes vaccination history and / or infection history. (Item B80) The step of identifying a subject with immune memory comprises stimulating peripheral blood mononuclear cells (PBMCs) 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 whose cytokine production level has increased by a predetermined fold compared to before stimulation as a subject with immune memory, an antigen component described in any of the above items. (Item B81) The antigen component according to any one of the preceding items, wherein the non-tumor antigen is administered once a day (first week) and once a week (second week and thereafter). (Item B82) The antigen component according to any one of the above items, wherein the non-tumor antigen is administered at a dose of about 0.001 μg / single dose to about 1 mg / single dose. (Item B83) mHSP10 and / or MTB12 and / or lipoprotein LpqH for treating or preventing a disease, disorder or condition associated with an immune abnormality in a subject. (Item B84) A composition, antigen component, kit, biomarker, vaccine formulation, or method described in any of the above items, characterized in that multiple agents containing the antigen component are administered. (Item B85) A composition, antigen component, kit, biomarker, vaccine formulation, or method described in any of the above items, characterized in that each component of the multiple drugs is administered as a separate composition. (Item C1) Use of a non-target antigen component in the manufacture of a composition for activating regulatory T cells (Tregs) that have immune memory to a non-target antigen component and are suppressed in a subject against the target. (Item C2) The use according to any of the above items, wherein activation of the Treg confers killing ability or immunostimulatory effect on the target. (Item C3) Use of the non-tumor antigen component in the manufacture of a composition for activating regulatory T cells (Tregs) that have immune memory to the non-tumor antigen component and are suppressed in a subject. (Item C4) The use according to any of the above items, wherein the activation of Tregs confers tumor-killing ability or immunostimulatory effect against tumors. (Item C5) The use according to any of the above items, wherein the Tregs are memory T cells. (Item C6) The use according to any of the above items, wherein the Treg is CD4 positive. (Item C7) The use according to any of the above items, wherein the antigen component comprises a protein. (Item C8) The use according to any of the above items, wherein the antigen component comprises an antigen selected from the group consisting of an infectious disease pathogen or a part thereof, an antigen associated with medical history, and an antigen associated with vaccination history. (Item C9) The use according to any of the above items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis or an influenza virus antigen. (Item C9A) The use according to any of the preceding items, further comprising one or more of the features described in any of the preceding items or in one or more of the following items. (Item C10) Use of the antigen component in the manufacture of a composition for use in a method comprising determining whether the antigen component has Treg immune memory in the subject, and administering the antigen component to the subject if the subject has immune memory against the antigen component. (Item C11) Use of an antigen component in the manufacture of a composition for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, wherein the antigen component is an antigen component specific in the subject to a component different from the causative agent of the disease, disorder, or symptom. (Item C12) The use according to any of the above items, wherein the disease, disorder or condition includes cancer, and preferably the antigen component is a non-tumor antigen component. (Item C13) The use described in any of the above items, wherein the antigen component is specific to memory T cells of the subject. (Item C14) The use according to any of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing). (Item C15) The use according to any of the above items, wherein the antigen component has immunostimulatory activity. (Item C16) The use according to any of the above items, wherein the antigen component acts on memory CD4-positive T cells in an antigen-dependent manner. (Item C17) The use according to any one of the above items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to IFN-γ-producing T cells. (Item C18) The use described in any of the above items, wherein the bias is to increase IFN-γ-producing T cells compared to Foxp3-positive Treg cells. (Item C19) The use according to any one of the above items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to type 1 helper T cells. (Item C20) The use described in any of the above items, wherein the IFN-γ-producing T cells include type 1 helper T cells. (Item C21) The use according to any of the above items, wherein the antigen component has the activity of shifting the proportion of Th1 cells present. (Item C22) The use described in any of the above items, wherein the IFN-γ-producing T cells are T-bet-positive Th1 cells. (Item C23) A use described in any of the above items, wherein the specific antigen component has the ability to enhance at least one selected from the group consisting of IFN-γ production ability, IL-2 production ability, and TNF-α production ability in a sample derived from the subject. (Item C24) The use according to any of the above items, wherein the antigen component is a protein. (Item C25) A biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the biomarker comprising at least one selected from the group consisting of whether the antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability. (Item C26) A composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, wherein the biomarker includes at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability. (Item C27) The use of any of the above items, wherein the (non-tumor) antigen component includes an antigen associated with medical history or vaccination history. (Item C28) The use according to any of the above items, wherein the subject has a history of an infectious disease, and the antigen component includes an antigen against the infectious disease. (Item C29) The use according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item C30) The use according to any of the above items, wherein the subject has a history of BCG vaccination, tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component comprises a hot water extract of Mycobacterium tuberculosis. (Item C31) The use according to any of the above items, wherein the subject has a history of influenza vaccination, influenza infection, or antigenic responsiveness to influenza virus, and the antigen component comprises influenza virus. (Item C32) The use according to any of the above items, wherein the disease, disorder or symptom includes melanoma. (Item C33) The use according to any of the above items, wherein the antigen component comprises a protein, a part thereof, or a peptide. (Item C34) The use described in any of the above items, wherein the antigen component includes one capable of eliciting an immune response mediated by CD4-positive T cells. (Item C35) The use described in any of the above items, characterized in that it is confirmed whether the subject is capable of initiating an anti-tumor immune response mediated by CD4-positive T cells, and the composition is administered if the subject is capable of initiating an anti-tumor immune response mediated by CD4-positive T cells. (Item C36) Use of an antigen component in the manufacture of a composition for treating or preventing a disease, disorder, or symptom associated with immune abnormality in a subject, wherein the antigen component is an antigen component specific in the subject to a component different from a causative agent of the disease, disorder, or symptom; the disease, disorder, or condition comprises melanoma; the antigen component is a protein or a part thereof, or a peptide, and is capable of eliciting an immune response mediated by CD4-positive T cells; The cancer includes those that can be treated or prevented by an immune response mediated by CD4-positive T cells, and determining whether the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, and administering the composition to the subject if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells. use. (Item C37) Use of a non-tumor antigen component in the manufacture of a composition for treating or preventing cancer or tumors in a subject, wherein the non-tumor antigen component activates regulatory T cells (Tregs) that are suppressed in the subject and have immune memory to the non-tumor antigen, and the Tregs have a regulatory activity or an effect of promoting anti-tumor immunity against cancer or tumors. (Item C38) A method for manufacturing or otherwise providing a composition for preventing or treating cancer in a subject, the method comprising: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting those with immunological memory; C) manufacturing or otherwise providing the selected non-tumor antigen; The method includes: (Item C39) A method according to any one of the preceding items, wherein B) the method has one or more features according to any one of the preceding items. (Item C40) A method for determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising: B) determining whether the non-tumor antigen has immunological memory in the subject, identifying said immune memory, if present, as capable of preventing or treating cancer in said subject. The method includes: (Item C41) A method according to any one of the preceding items, wherein B) the method has one or more features according to any one of the preceding items. (Item C42) a) obtaining an antigen responsiveness profile of the subject; b) identifying an antigenic component or combination of antigenic components from the antigen responsiveness profile, the antigenic component or combination of antigenic components being identified based on the subject's current or past immune responsiveness to the antigenic component or antigenic components; 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; A method for preventing or treating a disease, disorder or condition associated with immune abnormalities, comprising: (Item C43) The method according to any of the above items, wherein the disease, disorder or condition includes cancer. (Item C44) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition, and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item C45) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes identifying an antigen component or a combination of antigen components that elicits an immune response mediated by CD4-positive T cells. (Item C46) A method according to any of the preceding items, wherein i) the antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof, and / or ii) the confirmation of the responsiveness includes collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens associated with the antigenic profile, as well as other biomarkers. (Item C47) A method according to any of the above items, further comprising periodically testing the responsiveness to the antigen to confirm that the responsiveness is maintained. (Item C48) a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens corresponding to the physical condition and other biomarkers; iii) identifying an appropriate antigen component or combination of antigen components from the results of ii); The method according to any of the preceding items, wherein the method is carried out by (Item C49) A method according to any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item C50) A method according to any of the above items, wherein the physical condition includes a history of infection, and the cancer vaccine includes an antigen component or a combination of antigen components against the infection. (Item C51) A method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item C52) A method described in any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component or combination of antigen components includes a hot water extract of Mycobacterium tuberculosis. (Item C53) A method according to any of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or antigenic responsiveness to influenza virus, and the antigen component or combination of antigen components includes influenza virus. (Item C54) The method according to any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item C55) A method according to any of the above items, wherein the subject is in a state before cancer develops, after cancer treatment, in the early stage of cancer, or in a precancerous state. (Item C56) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas to which CD8-positive T cells are usually not effective. (Item C57) A method according to any of the above items, wherein the subject exhibits immune resistance. (Item C58) A method according to any of the above items, wherein step ii) comprises measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item C59) The method according to any one of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item C60) A method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item C61) The method described in any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of influenza infection and an influenza virus. (Item C62) A method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item C63) The subject is a subject whose history of BCG vaccination, tuberculosis infection, or antigen responsiveness has been confirmed, The method according to any of the preceding items, characterized in that the tuberculosis Mycobacterium extract is administered prophylactically before the onset of cancer or at the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from tuberculosis Mycobacterium is administered subcutaneously or intradermally by conventional methods. (Item C64) The subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed, The method according to any one of the preceding items, wherein the influenza vaccine is administered prophylactically before the onset of cancer, administered to prevent recurrence after treatment, or administered at an early stage of cancer onset, and wherein the influenza vaccine is administered subcutaneously or intradermally at an early stage of cancer onset or in a precancerous state. (Item C65) A method for preventing or treating cancer immunity based on any of the above items, comprising revaccinating with the antigen component or combination of antigen components. (Item C66) A method for preventing or treating cancer in a subject using a non-tumor component, wherein the component is an antigen or extract identified by medical interview and / or by reference to the subject's medical history and vaccination history, the subject is an individual who has had an infection or vaccination as described in any of the above items, and the component is administered to the subject to prevent recurrence after treatment, as a prophylactic administration before onset, or at the early stage of cancer onset, and if necessary, the component is administered at the early stage of cancer onset or in a precancerous state. (Item C67) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas, which are usually not sensitive to CD8-positive T cells. (Item C68) The method described in any of the above items, wherein the subject is a patient exhibiting immune resistance. (Item C69) A method described in any of the above items, characterized in that the responsiveness is identified by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item C70) The method according to any one of the above items, wherein the tuberculosis extract is a hot water extract of human tuberculosis or an extract from another tuberculosis bacterium (a highly safe extract). (Item C71) The method according to any one of the above items, wherein the influenza virus is an extract (highly safe extract) from a human influenza virus or another influenza virus. (Item C72) A method according to any of the above items, wherein the antigen component is a protein. (Item C73) A vaccine formulation comprising an antigen according to any one of the above items and an adjuvant base. (Item C74) A vaccine formulation according to any of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1-type immune response. (Item C75) The vaccine preparation according to any of the above items, wherein the vaccine preparation is used for personalized medicine. (Item C76) Use of an antigen component specific in a subject relative to a component different from the causative agent of the disease, disorder, or symptom associated with an immune abnormality in the subject, in the manufacture of a composition for treating or preventing the disease, disorder, or symptom, characterized in that the composition is administered subcutaneously or intratumorally once daily (in the first week) and once a week (from the second week onwards). (Item C77) The use according to any of the above items, wherein the antigen component is contained in an amount of about 0.001 μg or more per unit preparation. (Item C78) Use of a non-tumor antigen component in the manufacture of a composition for use in a method for treating or preventing cancer or tumors in a subject, the method comprising: a) identifying non-tumor antigens specific to the subject based on the antigenic response profile; b) determining whether the subject has immune memory against the non-tumor antigen and identifying the subject with immune memory; c) administering the non-tumor antigen to the subject identified as having the immunological memory. encompasses, uses. (Item C79) The use of any of the above items, wherein the antigenic response profile includes vaccination history and / or infection history. (Item C80) The use described in any of the above items, wherein the step of identifying a subject having immune memory comprises stimulating peripheral blood mononuclear cells (PBMCs) 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 whose cytokine production level has increased by a predetermined fold compared to before stimulation as a subject having immune memory. (Item C81) The use according to any of the above items, wherein the non-tumor antigen is administered once a day (first week) and once a week (second week and thereafter). (Item C82) The use according to any of the above items, wherein the non-tumor antigen is administered at a dose of about 0.001 μg / single dose to about 1 mg / single dose. (Item C83) Use of mHSP10 and / or MTB12 and / or lipoprotein LpqH in the manufacture of a composition for treating or preventing a disease, disorder or symptom associated with an immune abnormality in a subject. (Item C84) A use or method described in any of the above items, characterized in that the antigen component is administered together with multiple drugs. (Item C85) The use or method described in any of the above items, wherein the multiple drugs are provided as separate compositions. (Item X1) A composition for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the composition comprising an antigen component that is specific in the subject (or to which the subject has immunological memory) to a component that is different from the causative agent of the disease, disorder, or symptom. (Item X2) The composition according to any of the above items, wherein the disease, disorder or condition includes cancer. (Item X3) The composition described in any of the above items, wherein the non-tumor antigen component is specific to memory T cells of the subject. (Item X4) The composition according to any of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing). (Item X5) The composition according to any of the above items, wherein the non-tumor antigen component has an immunostimulatory effect. (Item X6) The composition according to any of the above items, wherein the non-tumor antigen component acts on memory CD4-positive T cells in an antigen-dependent manner. (Item X7) The composition according to any one of the above items, wherein the non-tumor antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to IFN-γ-producing T cells. (Item X8) A composition described in any of the above items, wherein the bias is to increase IFN-γ-producing T cells compared to Foxp3-positive Treg cells. (Item X9) The composition according to any one of the above items, wherein the non-tumor antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to type 1 helper T cells. (Item X10) A composition described in any of the above items, wherein the IFN-γ-producing T cells include type 1 helper T cells. (Item X11) The composition according to any of the above items, wherein the non-tumor antigen component has the activity of shifting the proportion of Th1 cells present. (Item X12) A composition described in any of the above items, wherein the IFN-γ-producing T cells are T-bet-positive Th1 cells. (Item X13) A composition described in any of the above items, wherein the specific non-tumor antigen component (or the subject has immune memory for) has the ability to enhance at least one selected from the group consisting of IFN-γ production ability, IL-2 production ability, and TNF-α production ability in a sample derived from the subject. (Item X14) A biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the biomarker comprising at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability. (Item X15) A composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, wherein the biomarker includes at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, and (iv) alters IL-2 production ability. (Item X16) A method, biomarker, composition or kit according to any of the above items, wherein the (non-tumor) antigen component includes an antigen associated with medical history and vaccination history. (Item X17) A method, biomarker, composition, or kit according to any of the above items, wherein the subject has a history of an infectious disease, and the antigen component includes an antigen against the infectious disease. (Item X18) The method, biomarker, composition, or kit according to any of the preceding items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, Salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item X19) A method, biomarker, composition, or kit according to any of the above items, wherein the subject has a history of BCG vaccination, tuberculosis infection, or antigen responsiveness to Mycobacterium tuberculosis, and the antigen component comprises a hot water extract of Mycobacterium tuberculosis. (Item X20) A method for producing a composition for preventing or treating cancer in a subject, the method comprising: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting those with immunological memory; C) producing the selected non-tumor antigen; The method includes: (Item X21) The method according to Item X20, wherein in B), one or more features according to any one of Items X2 to X20 are present. (Item X22) A method for determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising: B) determining whether the non-tumor antigen has immunological memory in the subject, identifying said immunological memory, if present, as capable of preventing or treating cancer in said subject. The method includes: (Item X23) The method according to Item X22, wherein in B), one or more features according to any one of Items X2 to X21 are present. (Item X23A) A method for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the method comprising administering to the subject an effective amount of an antigen component that is specific in the subject (or to which the subject has immunological memory) to a component that is different from the causative agent of the disease, disorder, or symptom. (Item X23AA) The method according to Item X23A, having one or more features according to any one of Items X2 to X23. (Item X23B) An antigen component for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, wherein the antigen component is an antigen component that is specific in the subject (or to which the subject has immunological memory) to a component that is different from the causative agent of the disease, disorder, or symptom. (Item X23BB) An antigen component according to Item X23B, having one or more characteristics according to any one of Items X2 to X23. (Item X23C) Use of an antigen component that is specific in a subject (or to which the subject has immunological memory) to a component that is different from the causative agent of the disease, disorder, or symptom in a method for manufacturing a pharmaceutical for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in the subject. (Item X23CC) The use according to Item X23C, having one or more features according to any one of Items X2 to X23. (Item X24) a) obtaining an antigen responsiveness profile of the subject; b) identifying an antigen or a combination of antigens to which the subject is responsive based on the antigen responsiveness profile; c) administering said component to said subject in an amount sufficient to elicit an immune response in said subject; A method for preventing or treating a disease, disorder or condition associated with immune abnormalities, comprising: (Item X25) A method according to any of the above items, wherein the disease, disorder or condition includes cancer. (Item X26) The method described in Item X24 or X25, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item X27) i) The antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof; and / or ii) The responsiveness can be confirmed by collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines (IL-2, IFN-γ, TNF-α, etc.) in response to antigens related to the antigen profile, and measuring other biomarkers. The method according to any one of the preceding items, comprising: (Item X28) A method according to any of the above items, further comprising periodically testing the responsiveness to the antigen to confirm that the responsiveness is maintained. (Item X29) The above a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines (IL-2, IFN-γ, TNF-α, etc.) in response to antigens corresponding to the physical condition, and other biomarkers; iii) identifying an appropriate antigen or combination thereof based on the results of ii); The method according to any of the preceding items, wherein the method is carried out by (Item X30) A method according to any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item X31) A method described in any of the above items, wherein the physical condition includes a history of an infectious disease, and the cancer vaccine includes an antigen against the infectious disease. (Item X32) A method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item X33) A method described in any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigen responsiveness to Mycobacterium tuberculosis, and the antigen or a combination thereof includes a hot water extract of Mycobacterium tuberculosis. (Item X34) The method described in any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item X35) A method according to any of the above items, wherein the subject is before the onset of cancer, after cancer treatment, in the early stage of cancer, or in a precancerous state. (Item X36) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas, which are usually not sensitive to CD8-positive T cells. (Item X37) A method according to any of the above items, wherein the subject exhibits immune resistance. (Item X38) A method according to any of the above items, wherein step ii) includes measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item X39) A method according to any of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item X40) A method according to any of the above items, wherein the past physical condition and the component are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item X41) A method according to any of the above items, wherein the past physical condition and the component are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item X42) The subject is a patient with a history of BCG vaccination or tuberculosis infection, or a healthy individual whose antigen responsiveness has been confirmed. The subject is a person with a history of vaccination, infection, tuberculosis infection, or BCG vaccination, The method according to any of the preceding items, characterized in that the tuberculosis Mycobacterium extract is administered prophylactically before the onset of cancer or at the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from tuberculosis Mycobacterium is administered subcutaneously or intradermally by conventional methods. (Item X43) A method for preventing or treating cancer immunity based on any of the above items, comprising re-vaccinating with the antigen. (Item X44) A method for preventing or treating cancer in a subject using a non-tumor component, wherein the component is an antigen or extract related to the subject's medical history and vaccination history, the subject is an individual who has had an infection or vaccination history described in any of the above items, and the component is administered to the subject as a preventive administration before the onset of cancer, to prevent recurrence after treatment, or at the early stage of cancer onset, and if necessary, the component is administered at the early stage of cancer onset or in a precancerous state. (Item X45) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas to which CD8-positive T cells are usually not effective. (Item X46) A method according to any of the above items, wherein the subject is a patient exhibiting immune resistance. (Item X47) A method described in any of the above items, characterized in that the responsiveness is identified by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item X48) A method according to any of the above items, wherein the tuberculosis mycobacterium extract is a hot water extract of human tuberculosis mycobacterium or an extract from another tuberculosis mycobacterium (a highly safe extract). (Item X49) A vaccine formulation comprising an antigen according to any one of the above items and an adjuvant base. (Item X49A) A vaccine formulation comprising an antigen against at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria, and an adjuvant base. (Item X49B) The vaccine formulation described in Item X49A, wherein the physical condition of the subject of the vaccine formulation includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to tuberculosis bacteria, and the antigen includes a hot water extract of Mycobacterium tuberculosis. (Item X50) A vaccine formulation according to any of the above items, wherein the adjuvant base contains a substance that promotes a Th1-type immune response (e.g., a nucleic acid-based base such as CpG). (Item X50A) A composition for preventing or treating a disease, disorder, or symptom associated with immune abnormalities in a subject, the composition comprising a component identified by the steps of: a) obtaining an antigen responsiveness profile of the subject; and b) identifying an antigen or combination of antigens to which the subject is responsive based on the antigen responsiveness profile, in an amount sufficient to elicit an immune response in the subject. (Item X50A1) A composition for preventing or treating cancer in a subject, comprising a non-tumor component, the component being an antigen or extract associated with a medical history and vaccination history, the subject being an individual with a history of infection or vaccination as described in any of the above items, the component being administered to the subject as a preventive administration before onset, to prevent recurrence after treatment, or at the early stage of cancer onset, and, if necessary, the component being administered at the early stage of cancer onset or in a precancerous state. (Item X50AA) The component according to Item X50A or X50A1, having one or more characteristics according to any one of Items X1 to X50. (Item X50B) A component for preventing or treating a disease, disorder, or symptom associated with an immune abnormality in a subject, the component being identified by the steps of: a) obtaining an antigen responsiveness profile of the subject; and b) identifying an antigen or combination of antigens to which the subject is responsive based on the antigen responsiveness profile. (Item X50B1) A non-tumor component for preventing or treating cancer in a subject, the component being an antigen or extract associated with medical history and vaccination history, the subject being an individual with a history of infection or vaccination as described in any of the above items, the component being administered to the subject as a preventive administration before onset, for the prevention of recurrence after treatment, or at the early stage of cancer onset, and, if necessary, the component being administered at the early stage of cancer onset or in a precancerous state. (Item X50BB) The component described in Item X50B or X50B1, having one or more characteristics described in any of Items X1 to X50AA. (Item X50C) Use of an ingredient in the manufacture of a medicament for the prevention or treatment of a disease, disorder or symptom associated with an immune abnormality in a subject, wherein the ingredient is identified by the steps of: a) obtaining an antigen responsiveness profile of the subject; and b) identifying an antigen or combination of antigens to which the subject is responsive based on the antigen responsiveness profile. (Item X50C1) Use of a non-tumor component in the manufacture of a medicament for preventing or treating cancer in a subject, the component being an antigen or extract associated with medical history and vaccination history, the subject being an individual with a history of infection or vaccination as described in any of the above items, the component being administered to the subject as a prophylactic treatment before onset, for the prevention of recurrence after treatment, or at the early stage of cancer onset, and, if necessary, administering the component at the early stage of cancer onset or in a precancerous state. (Item X50CC) The use according to Item X50C or X50C1, having one or more features according to any one of Items X1 to X50BB.

[0006] The present disclosure also provides: (Item 1) A composition for treating or preventing a disease, disorder, or symptom associated with an immune abnormality in a subject, the composition comprising an antigen component specific in the subject to a component that is different from the causative agent of the disease, disorder, or symptom. (Item 2) The composition according to the above item, wherein the disease, disorder or symptom includes cancer, and preferably the antigen component is a non-tumor antigen component. (Item 3) The composition described in any of the above items, wherein the antigen component is specific to memory T cells of the subject. (Item 4) The composition according to any of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing). (Item 5) The composition according to any of the above items, wherein the antigen component has an immunostimulatory effect. (Item 6) The composition according to any of the preceding items, wherein the antigen component acts on memory CD4-positive T cells in an antigen-dependent manner. (Item 7) The composition according to any one of the above items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to IFN-γ-producing T cells. (Item 8) The composition described in any of the above items, wherein the bias is to increase IFN-γ-producing T cells compared to Foxp3-positive Treg cells. (Item 9) The composition according to any one of the preceding items, wherein the antigen component has the activity of shifting the ratio of Foxp3-positive Treg cells to type 1 helper T cells. (Item 10) The composition described in any of the above items, wherein the IFN-γ-producing T cells include type 1 helper T cells. (Item 11) The composition according to any of the above items, wherein the antigen component has the activity of shifting the proportion of Th1 cells present. (Item 12) The composition described in any of the above items, wherein the IFN-γ-producing T cells are T-bet-positive Th1 cells. (Item 13) The composition described in any of the above items, wherein the specific antigen component has the ability to enhance at least one selected from the group consisting of IFN-γ production ability, IL-2 production ability, and TNF-α production ability in a sample derived from the subject. (Item 14) A biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the biomarker comprising at least one biomarker selected from the group consisting of whether the antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability. (Item 14A) A method for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, the method comprising the step of determining at least one of whether the antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability. (Item 15) A composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject, wherein the biomarker is at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability. (Item 15A) A composition or kit for determining whether a non-tumor antigen component has an anti-cancer effect in a subject, the composition or kit comprising an agent or device for determining at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability. (Item 16) The composition according to any of the above items, wherein the (non-tumor) antigen component comprises an antigen associated with medical history and vaccination history. (Item 17) The composition according to any of the above items, wherein the subject has a history of an infectious disease, and the antigen component comprises an antigen against the infectious disease. (Item 18) The composition according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, Salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item 19) The composition according to any of the above items, wherein the subject has a history of BCG vaccination, tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component comprises a hot water extract of Mycobacterium tuberculosis. (Item 20) The composition according to any of the above items, wherein the subject has a history of influenza vaccination, influenza infection, or antigenic response to influenza virus, and the antigen component comprises influenza virus. (Item 21) A method for manufacturing or otherwise providing a composition for preventing or treating cancer in a subject, the method comprising: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting those with immunological memory; C) manufacturing or otherwise providing the selected non-tumor antigen; The method includes: (Item 22) A method according to any one of the preceding items, wherein B) has one or more features according to any one of the preceding items. (Item 23) A method for determining whether a non-tumor antigen of a subject can prevent or treat cancer in the subject, the method comprising: B) determining whether the non-tumor antigen has immunological memory in the subject, identifying said immunological memory, if present, as capable of preventing or treating cancer in said subject. The method includes: (Item 24) A method according to any one of the preceding items, wherein B) has one or more features according to any one of the preceding items. (Item 25) a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigenic component or combination of antigenic components from the antigen responsiveness profile, the antigenic component or combination of antigenic components being identified based on the subject's current or past immune responsiveness to the antigenic component or antigenic components; 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; A method for preventing or treating a disease, disorder or condition associated with immune abnormalities, comprising: (Item 26) The method according to any of the above items, wherein the disease, disorder or condition comprises cancer. (Item 27) A method described in any of the above items, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition, and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item 28) i) the antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof; and / or ii) the confirmation of the responsiveness includes collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and measuring whether the peripheral blood cells produce cytokines in response to antigens associated with the antigenic profile, as well as other biomarkers. (Item 29) The method according to any of the above items, further comprising periodically testing the responsiveness to the antigen to confirm that the responsiveness is maintained. (Item 30) a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens corresponding to the physical condition and other biomarkers; iii) identifying an appropriate antigen component or combination of antigen components from the results of ii); The method according to any of the preceding items, wherein the method is carried out by (Item 31) A method according to any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item 32) A method according to any of the above items, wherein the physical condition includes a history of infection, and the cancer vaccine includes an antigen component or a combination of antigen components against the infection. (Item 33) The method according to any of the above items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item 34) A method described in any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen component or combination of antigen components includes a hot water extract of Mycobacterium tuberculosis. (Item 35) A method according to any of the above items, 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 antigen component or combination of antigen components includes an influenza virus. (Item 36) The method according to any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item 37) A method according to any of the above items, wherein the subject is in a state before cancer develops, after cancer treatment, in the early stages of cancer, or in a precancerous state. (Item 38) A method according to any of the above items, wherein the cancer is selected from the group consisting of common carcinomas, relatively slow-growing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas, which are usually not sensitive to CD8-positive T cells. (Item 39) The method described in any of the above items, wherein the subject exhibits immune resistance. (Item 40) The method according to any of the above items, wherein step ii) comprises measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item 41) The method according to any of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item 42) A method according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item 43) The method described in any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of influenza infection and an influenza virus. (Item 44) The method according to any of the above items, wherein the past physical condition and the component are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. (Item 45) The subject is a patient with a history of BCG vaccination or tuberculosis infection, or a subject whose antigen responsiveness has been confirmed, The method according to any of the preceding items, characterized in that the Mycobacterium tuberculosis extract is administered prophylactically before onset, administered to prevent recurrence after treatment, or administered in the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from Mycobacterium tuberculosis is administered subcutaneously or intradermally by conventional methods. (Item 46) The subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed, The method according to any one of the preceding items, wherein the influenza vaccine is administered prophylactically before the onset of cancer, administered to prevent recurrence after treatment, or administered at an early stage of cancer onset, and wherein the influenza vaccine is administered subcutaneously or intradermally at an early stage of cancer onset or in a precancerous state. (Item 47) A method for preventing or treating cancer immunity based on any of the above items, comprising revaccinating with the antigen component or combination of antigen components. (Item 48) A method for preventing or treating cancer in a subject using a non-tumor component, wherein the component is an antigen or extract identified by medical interview and / or by reference to the subject's medical history and vaccination history, the subject is an individual who has had an infection or vaccination as described in any of the above items, and the component is administered to the subject to prevent recurrence after treatment, as a prophylactic administration before onset, or at the early stage of cancer onset, and if necessary, the component is administered at the early stage of cancer onset or in a precancerous state. (Item 49) A method according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-growing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas, which are usually not sensitive to CD8-positive T cells. (Item 50) The method described in any of the above items, wherein the subject is a patient exhibiting immune resistance. (Item 51) A method according to any of the above items, characterized in that the responsiveness is determined by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item 52) The method according to any of the above items, wherein the tuberculosis extract is a hot water extract of Mycobacterium tuberculosis or an extract from another tuberculosis bacterium (a highly safe extract). (Item 53) The method according to any of the above items, wherein the influenza virus is an extract (highly safe extract) from a human influenza virus or another influenza virus. (Item 54) A vaccine formulation comprising an antigen according to any of the preceding items and an adjuvant base. (Item 54A) A vaccine formulation comprising an antigen against at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria, and an adjuvant base. (Item 54B) A vaccine formulation according to any of the above items, wherein the physical condition of the subject of the vaccine formulation includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to Mycobacterium tuberculosis, and the antigen comprises a hot water extract of Mycobacterium tuberculosis. (Item 55) A vaccine formulation according to any of the preceding items, wherein the adjuvant base comprises a substance that promotes a Th1-type immune response. (Item 56) The vaccine preparation according to any of the above items, wherein the vaccine preparation is used for personalized medicine. (Item 25A) a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigenic component or combination of antigenic components from the antigen responsiveness profile, the antigenic component or combination of antigenic components being identified based on the subject's current or past immune responsiveness to the antigenic component or antigenic components; 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; An antigen component or a combination of antigen components for use in a method for preventing or treating a disease, disorder or symptom associated with immune abnormality, comprising the antigen component or a combination of antigen components, or a composition for preventing or treating a disease, disorder or symptom associated with immune abnormality, comprising the antigen component or a combination of antigen components. (Item 26A) An antigen component or combination of antigen components, or composition according to any of the above items, wherein the disease, disorder or condition includes cancer. (Item 27A) An antigen component or combination of antigen components, or composition described in any of the above items, wherein obtaining the antigen responsiveness profile includes confirming the subject's past physical condition, and confirming whether one or more antigen candidates are responsive in a sample derived from the subject, or both. (Item 28A) An antigen component or a combination of antigen components, or a composition according to any of the preceding items, wherein i) the antigenic response profile includes at least one selected from the group consisting of a medical interview, a medical history based on a maternal and child health handbook or its equivalent, a vaccination history, and a combination thereof, and / or ii) the confirmation of the responsiveness includes collecting a body fluid (e.g., blood) from the subject, separating peripheral blood cells, and measuring whether the peripheral blood cells produce cytokines in response to antigens associated with the antigen profile, as well as other biomarkers. (Item 29A) An antigen component or combination of antigen components, or composition described in any of the above items, further comprising the step of periodically testing the antigen responsiveness and confirming that the responsiveness is maintained. (Item 30A) a) and b) are the following steps: i) obtaining a past physical condition of the subject; ii) collecting blood from the subject, separating peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to antigens corresponding to the physical condition and other biomarkers; iii) identifying an appropriate antigen component or combination of antigen components from the results of ii); An antigen component or a combination of antigen components, or a composition according to any of the preceding items, which is carried out by (Item 31A) The antigen component or combination of antigen components, or composition described in any of the above items, wherein the past physical condition includes medical history and vaccination history. (Item 32A) An antigen component or combination of antigen components, or composition described in any of the above items, wherein the physical condition includes a history of infection and the cancer vaccine includes an antigen component or combination of antigen components against the infection. (Item 33A) The antigen component or combination of antigen components, or composition according to any of the preceding items, wherein the infectious disease includes at least one selected from the group consisting of tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, Salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item 34A) An antigenic component or combination of antigenic components, or composition described in any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic responsiveness to tuberculosis bacteria, and the antigenic component or combination of antigenic components includes a hot water extract of Mycobacterium tuberculosis. (Item 35A) An antigen component or combination of antigen components, or composition described in any of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or antigenic responsiveness to influenza virus, and the antigen component or combination of antigen components includes influenza virus. (Item 36A) The antigen component or combination of antigen components, or composition described in any of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item 37A) The antigen component or combination of antigen components, or composition according to any of the above items, wherein the subject is before the onset of cancer, after cancer treatment, in the early stage of cancer, or in a precancerous state. (Item 38A) The antigen component or combination of antigen components, or composition described in any of the above items, wherein the cancer is selected from the group consisting of common carcinomas, carcinomas that progress relatively slowly, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas that are typically not sensitive to CD8-positive T cells. (Item 39A) The subject exhibits immune resistance, and the antigen component or combination of antigen components, or composition described in any of the above items. (Item 40A) The antigen component or combination of antigen components, or composition described in any of the preceding items, wherein step ii) comprises measuring the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously. (Item 41A) An antigen component or a combination of antigen components, or a composition described in any of the above items, wherein the antigen responsiveness profile is obtained by prior companion diagnosis based on medical history and vaccination history. (Item 42A) An antigenic component or combination of antigenic components, or composition, described in any of the above items, wherein the past physical condition and the antigenic component or combination of antigenic components are a history of tuberculosis infection and a hot water extract of Mycobacterium tuberculosis. (Item 43A) An antigen component or combination of antigen components, or composition according to any of the above items, wherein the past physical condition and the antigen component or combination of antigen components are a history of influenza infection and influenza virus. (Item 44A) An antigen component or a combination of antigen components, or a composition according to any of the preceding items, wherein the past physical condition and the component are one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MERS, rabies, and diphtheria. (Item 45A) The subject is a subject whose history of BCG vaccination, tuberculosis infection, or antigen responsiveness has been confirmed, The antigen component or combination of antigen components, or composition described in any of the preceding items, characterized in that the tuberculosis Mycobacterium extract is administered prophylactically before the onset of cancer or in the early stage of cancer onset, and in the early stage of cancer onset or in a precancerous state, an extract from tuberculosis Mycobacterium is administered subcutaneously or intradermally by conventional methods. (Item 46A) The subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed, The antigen component or combination of antigen components, or composition described in any of the above items, characterized in that the influenza vaccine is administered prophylactically before the onset of cancer, administered to prevent recurrence after treatment, or administered in the early stage of cancer onset, and the influenza vaccine is administered subcutaneously or intradermally in the early stage of cancer onset or in a precancerous state. (Item 47A) An antigen component, a combination of antigen components, or a composition for use in a method for preventing or treating cancer immunity based on any of the above items, the method comprising re-vaccinating the antigen component or combination of antigen components. (Item 48A) A non-tumor component for use in a method for preventing or treating cancer in a subject, the component being an antigen or extract identified by medical interview and / or by reference to the medical history and vaccination history of the subject, the subject being an individual who has had an infection or vaccination as described in any of the above items, the component being administered to the subject for the prevention of recurrence after treatment, as a prophylactic administration before onset, or at the early stage of cancer onset, and, if necessary, the component being administered at the early stage of cancer onset or in a precancerous state. (Item 49A) A non-tumor component according to any of the above items, wherein the cancer is selected from the group consisting of ordinary carcinomas, relatively slow-progressing carcinomas, carcinomas that are less sensitive to the immune system, oral squamous cell carcinoma, cervical cancer, and MHC class I-negative carcinomas that are typically not sensitive to CD8-positive T cells. (Item 50A) The non-tumor component according to any of the above items, wherein the subject is a patient exhibiting immunoresistance. (Item 51A) The antigen or combination of antigens, or non-tumor component described in any of the above items, characterized in that the responsiveness is determined by measuring a history of previous infection, a history of vaccination, and the induction of cells that produce IFN-γ, IL-2, TNF-α, or multiple of these cytokines simultaneously using peripheral blood. (Item 52A) An antigen or combination of antigens according to any of the preceding items, wherein the tuberculosis extract is a hot water extract of Mycobacterium tuberculosis or an extract from another tuberculosis bacterium (a highly safe extract). (Item 53A) The antigen or combination of antigens according to any of the preceding items, wherein the influenza virus is a human influenza virus or another influenza virus (highly safe extract).

[0007] It is contemplated that one or more of the above features may be provided in combinations other than those explicitly stated. Further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. [Effects of the Invention]

[0008] The present disclosure provides a technology that can effectively prevent or treat intractable diseases such as cancer by utilizing the immunological memory possessed by the host.

[0009] Immunotherapy using tumor antigens has been actively studied in cancer immunotherapy, but no clear therapeutic effects have been obtained. This disclosure has resolved this issue. Furthermore, this disclosure unexpectedly discovered that a hot water extract of Mycobacterium tuberculosis, which was previously thought to be a "non-specific" immunotherapy using non-tumor components, can also be used as a "specific" immunotherapy, leading to the idea of ​​providing this as a specific immunotherapy. This has made it possible to provide not only specific treatment but also preventative use. Furthermore, by clarifying the mechanism of action of this specific immunotherapy, it has been demonstrated that it is possible to select appropriate patients and provide appropriate treatment as personalized medicine, and various applications have been discovered.

[0010] Regulatory T cells (Treg cells) are involved in many immune control processes, particularly immunosuppression, and some checkpoint molecule inhibitors enhance immunity by relieving the immunosuppression of regulatory T cells. However, while these drugs exhibit beneficial effects, they also have significant side effects. These drugs only respond to a limited number of patients, and there are no clear diagnostics for patient selection. In addition, improper patient selection can result in severe side effects. Selection is therefore necessary, but this has traditionally been nearly impossible. The present disclosure utilizes the mechanism of immunological memory to select patients and administer appropriate drugs, thereby providing appropriate treatment and prevention methods. This was confirmed by demonstrating a novel immunotherapy and cancer treatment and prevention method using a non-tumor antigen-induced memory response as a personalized marker, based on the regulatory activity of non-tumor antigen-dependent regulatory T cells (Treg cells) induced by previous vaccinations, using a hot water extract of Mycobacterium tuberculosis (confirmed to be safe in humans) as a representative example. Thus, the present disclosure provides a novel immunotherapy. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 is a diagram verifying the correlation between Mycobacterium tuberculosis infection and memory T cells. The diagram shows the results of an experiment conducted under the conditions described in Example 1. The diagram, from left to right in the upper row, shows the correlation between IFN-γ, IL-2, and TNF-α producer cells induced by PPD and those induced by Extract A. The middle row, from left to right, shows the correlation between IFN-γ, IL-2, and TNF-α producer cells induced by CMV and those induced by Extract A. The bottom row, from left to right, shows the correlation between IFN-γ, IL-2, and TNF-α producer cells induced by MHSP10 and those induced by Extract A. [Figure 2]Figure 2 shows the results of examining the antitumor effect of Extract A depending on the immune status. The details are described in Example 2. Figure 2A shows the administration schedule of BCG or Extract A + Freund's incomplete adjuvant (E+FIA), tumor cells, and Extract A. The upper panel of Figure 2B shows the results of transplantation of B16BL6 cells into (B) naive mice, (C) BCG-infected mice, and (D) Extract A emulsion-immunized mice. The lower panel shows the results of transplantation of B16F10 cells into (E) naive mice, (F) BCG-infected mice, and (G) Extract A emulsion-immunized mice. The horizontal axis shows the number of days after tumor transplantation, and the vertical axis shows the change in tumor volume. * indicates a statistically significant difference. [Figure 3-1] Figures 3-1 and 3-2 show the experimental results of tumor growth suppression when a model antigen is administered to animals with model antigen-specific memory cells. Figure 3-1 shows the progression of B16BL6 tumor growth when ovalbumin is administered to naive mice (A) and ovalbumin + FIA + Extract A-immunized mice (B). [Figure 3-2] Figure 3-2 shows the progression of B16BL6 tumor volume after ovalbumin administration in Rag2-deficient mice (left) and IL2Rγ chain Rag2 double-deficient mice (right). CD4 T cells differentiated into ovalbumin-specific Th1 were transferred to these mice. [Figure 4]Figure 4 shows the tumor weight of B16BL6 when Extract A was administered to mice immunized with vaccine preparations containing various adjuvant bases. A detailed explanation is provided in Example 4. From the left, the vaccines used for immunization 4 weeks and 2 weeks prior are shown. The figures show the results for mice administered phosphate-buffered saline (PBS), FIA, the adjuvant K3-SPG (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 (id) administration of Extract A, Extract A + FIA, Extract A + K3-SPG, Extract A + K3 + cGAMP, and Extract A + K3 + alum (Alum). Black circles indicate the results for animals administered saline, and red circles indicate the results for animals administered Extract A. [Figure 5] Figure 5 shows the effect of Extract A on tumor-infiltrating lymphocytes (TILs) in transplanted tumors, assessed by flow cytometry, as described in detail in Example 5. The left panel shows, from left, T-bet-positive, Foxp3-negative, T-bet-positive, Foxp3-positive, and T-bet-negative, Foxp3-positive TILs. The right panel shows typical flow cytometry results. [Figure 6] Figure 6 shows the results of flow cytometry analysis of the effect of Extract A on tumor-infiltrating lymphocytes (TILs) in transplanted tumors, as described in detail in Example 6. From left to right, the following TILs were shown: T-bet-positive, Foxp3-negative; T-bet-positive, Foxp3-positive; T-bet-negative, Foxp3-positive; and T-bet-negative, Foxp3-negative TILs that produced IFN-γ upon stimulation with Extract A. [Figure 7]Figure 7 shows the results of a related experiment to identify cells essential for the antitumor effect of Extract A. The details are described in Example 8. Figure 7A shows the administration schedule of BCG, tumor cells, Extract A, anti-CD4 antibody, and anti-IFN-γ antibody to mice. Figures 7B to 7D show the time course of subcutaneously implanted B16BL6 cells in mice in which CD4-positive cells were depleted using an anti-CD4 antibody after BCG infection (Figure 7B), CD4 knockout mice (Figure 7C), and MHC class II knockout mice (Figure 7D), respectively, after BCG infection and subsequent administration of saline (S) or Extract A (E). Figure 7E shows the results of BCG-infected mice administered saline or Extract A, splenocytes collected, stimulated with Extract A, stained for intracellular cytokines, and subjected to FACS analysis. Figure 7F shows tumor volume in mice infected with BCG and depleted of IFN-γ using an anti-IFN-γ antibody, after which saline (S) or Extract A (E) was administered. Figure 7G shows the amount of IFN-γ produced by spleen cells from BCG-infected wild-type mice (WT), CD4 knockout mice (CD4 KO), and MHC class II knockout mice (MHCII KO) stimulated with Extract A. Figure 7H shows the amount of IFN-γ produced by spleen cells from BCG-infected wild-type mice (WT) and CD1d1 knockout mice (CD1d1) stimulated with Extract A. Figure 7I shows the amount of IFN-γ produced by spleen cells from CD4- or CD8-depleted mice stimulated with Extract A. [Figure 8]Figure 8 shows the time course of B16BL6 tumor volume in BCG-infected mice when Extract A was administered. The details are described in Example 9. Figure 8A shows the experimental schedule. Figures 8B to 8G show the tumor volume in Rag2-deficient mice (Figure 8B), mice depleted of CD8-positive cells (Figure 8C), CD1d1-deficient mice and FcR-deficient mice (Figure 8D), mice depleted of NK1.1-positive cells (Figure 8E), IL12p40-deficient mice (Figure 8F), and Batf3-deficient mice (Figure 8G), respectively, when saline (S) or Extract A (E) was administered after BCG infection. [Figure 9] Figure 9 shows the antitumor effect of administering a non-tumor antigen to BCG-infected mice. The details are described in Example 10. Figure 9A shows the amount of IFN-γ secreted by spleen cells isolated from BCG-infected mice treated with subtilisin-treated Extract A (Sub), heat-inactivated subtilisin-treated Extract A (HI-Sub), trypsin-treated Extract A (Trp), or heat-inactivated trypsin-treated Extract A (HI-Trp). The amount is expressed as a relative value, with the amount of IFN-γ produced by stimulation with Extract A set at 100%. Figure 9B shows the amount of IFN-γ produced by spleen cells isolated from BCG-infected mice stimulated with Extract A or LpqH. Figure 9C shows the tumor volume in naive and BCG-infected mice treated with saline or LpqH. [Figure 10]Figure 10 shows the results of tumor microenvironment analysis after administration of Extract A, as described in detail in Example 11. The left panel of Figure 10A shows the number of TIL cells per milligram of tumor in naive mice administered saline or Extract A, and the right panel shows the number of TIL cells per milligram of tumor in BCG-infected mice administered saline or Extract A. Figure 10B shows the correlation between tumor weight and the number of TIL cells per milligram of tumor. Figure 10C shows the number of CD3-positive TIL cells, CD3-positive CD8-positive TIL cells, and CD3-positive CD4-positive TIL cells per milligram of tumor in BCG-infected mice administered saline or Extract A. Figure 10D shows typical results of flow cytometry analysis of T-bet and Foxp3 expression in TILs from naive mice administered saline or Extract A. Figures 10E-G show the correlation between T-bet-positive Foxp3-negative TIL cells (Figure 10E), T-bet-positive Foxp3-positive TIL cells (Figure 10F), and T-bet-negative Foxp3-positive TIL cells (Figure 10G) and tumor weight. [Figure 11] Figure 11 shows the correlation between the antitumor effect of Extract A and the number of TILs producing IFN-γ. The details are described in Example 12. The left panel of Figure 11A shows the experimental protocol, and the right panel shows typical flow cytometry results for IFN-γ and T-bet expression in TILs in BCG-infected mice administered saline or Extract A. Figure 11B shows the number of IFN-γ-positive TIL cells per mg of tumor under unstimulated conditions. Figure 11C shows the number of IFN-γ-positive TIL cells per mg of tumor under Extract A or LpqH stimulation conditions. Figures 11D-F show the correlation between the number of IFN-γ-positive TIL cells under unstimulated conditions (Figure 11D), Extract A stimulation conditions (Figure 11E), and LpqH stimulation conditions and tumor weight. [Figure 12]Figure 12 shows the results of examining the antitumor effect of influenza vaccines depending on immune status. The details are described in Example 13. Figure 12A shows the administration schedule of influenza virus PR8, tumor cells, and influenza vaccine. Figure 12B shows the results when B16BL6 was transplanted into naive mice, and Figure 12C shows the results when B16BL6 was transplanted into PR8-infected mice. The horizontal axis shows the number of days after tumor transplantation, and the vertical axis shows the change in tumor volume. * indicates a statistically significant difference. [Figure 13A] FIG. 13A is an example of a clinical protocol schematic. [Figure 13B] FIG. 13B is another example of a clinical protocol schematic. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure will be described below, illustrating some of the best modes. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0013] (definition) The terms used in this specification are explained below.

[0014] As used herein, the term "specific" with respect to a substance or component refers to the property of the substance or component eliciting a particular response in a subject. As a representative example, particularly in the fields of treatment and prevention, "specific" refers to the subject having immunological memory. In particular, this term can refer to specificity for memory T cells in the subject.

[0015] As used herein, whether a subject has "immune memory" of a certain component or substance can be assessed by measuring whether the component or substance (i) enhances cytokine production in an antigen-dependent manner in memory CD4-positive T cells or has a proliferation-promoting effect in the subject or in a biological component (e.g., cell, etc.) derived from the subject, (ii) alters the expression of surface antigens on memory regulatory T cells, (iii) changes the ratio of Treg and Th1, (iv) induces IFN-γ production from T-bet-positive Th1 cells, (v) alters the ability to produce IFN-γ, (vi) alters the ability to produce IL-2, and (vii) alters the ability to produce TNF-α, or (viii) has an antibody specific to the component or substance in the blood, and confirming that at least one of these results is positive.

[0016] As used herein, the term "antigen component" refers to a component capable of eliciting an antigen-antibody reaction in a subject, and is sometimes referred to herein as an "antigen." It may be a single component (substance) or a complex. Antigen components may be provided in multiple different combinations, in which case they are referred to as "combinations of antigen components." As used herein, antigen components may be provided as isolated substances, complexes thereof, or extracts containing them.

[0017] As used herein, the term "non-tumor antigen component" refers to an antigen component that is not a cancer antigen. Whether a component or substance is a "non-tumor antigen component" can be confirmed, for example, by comprehensively identifying and comparing proteins or mRNAs in tumor and other sites. Mass spectrometry, microarrays, and next-generation sequencers are primarily used for this identification, and confirmation can be achieved by examining sequence information. An "antibody" refers to a protein that recognizes and eliminates foreign substances. In this case, the foreign substance is called an "antigen." Proteins and other components that are specific to or present in excess in cancer are generally called "cancer antigens." Therefore, a non-tumor antigen (component) can be any component other than a cancer antigen. As used herein, a non-tumor antigen component may have immunostimulatory activity (or adjuvant activity).

[0018] As used herein, antigen components in the present disclosure may be antigens related to medical history and vaccination history, or antigens against infectious diseases.

[0019] As used herein, "antigens associated with medical history and vaccination history" refer to antigenic components contained in medical history or vaccines, and can be confirmed by ELISA, which tests for the presence of specific antibodies, or FACS or ELISPOT, which confirm the presence of antigen-specific T cells.

[0020] As used herein, the term "antigen against infectious disease" refers to a component derived from an organism or virus that causes an infectious disease and that can induce an immune response, and can be confirmed by a technique called ELISA, which tests for the presence of specific antibodies, or by the presence of antigen-specific T cells.

[0021] As used herein, the term "infectious disease" refers to any infectious disease, such as tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria. Preferably, the infectious disease is tuberculosis. When tuberculosis is used as the infectious disease, the subject preferably has a history of BCG vaccination, tuberculosis infection, or antigenic response to Mycobacterium tuberculosis.

[0022] As used herein, the term "antigen responsiveness" has the same meaning as known in the art, and refers to the induction of an antigen-antibody reaction in a subject against a specific substance or the like.

[0023] As used herein, the term "antigen responsiveness profile," when referring to a subject, refers to a collective term (profile) summarizing the antigen responsiveness of that subject to various substances. An antigen responsiveness profile can be obtained by various techniques, such as by ascertaining past physical conditions, such as medical history (e.g., history of infectious diseases) and vaccination history, or by confirming antigen responsiveness using an antigen panel. These can be achieved, for example, by interviewing the subject, ascertaining medical history and vaccination history based on a maternal and child health handbook or equivalent, or by a combination of these. Responsiveness can also be confirmed by collecting body fluids (e.g., blood) from the subject, separating peripheral blood cells, and then determining whether the peripheral blood cells produce cytokines (e.g., IL-2, IFN-γ, TNF-α, and combinations of two or more thereof) in response to antigens associated with the antigen profile, or by measuring other biomarkers.

[0024] As used herein, "memory T cells" or "memory T cells" refer to cells that function to maintain immunological memory by remaining in the body for a long period of time. In the body, 90% of effector T cells die after 1-2 weeks unless they are continuously exposed to the same antigen. Some of the remaining T cells then differentiate into two major cell populations, which function as "memory cells" by remaining in the body for a long period of time and function to maintain immunological memory. Memory cells can be broadly classified into central memory T cells (T CM ) and effector memory T cells (T EM These two types of memory T cells survive for a long period of time, allowing for a rapid immune response when the same pathogen invades again. Not only do the memory T cells generated when the body first encounters an antigen survive, but a new pool of memory T cells is formed each time the body encounters the same antigen again.

[0025] T CM These cells are similar to naive T cells in terms of cell surface markers, expressing CCR7, a chemokine receptor, and CD62L, an adhesion factor, and are primarily present in the T cell area of ​​secondary lymphoid tissues. When exposed to the same antigen again, they produce IL-2 and rapidly proliferate, and some of them become T EM It is said to differentiate into cells.

[0026] On the other hand, T EM The cells have reduced expression of adhesion factors such as CCR7 and CD62L, and are present mainly in the local area of ​​inflammation (e.g., lungs, liver, intestinal tract, etc.) rather than in secondary lymphoid tissues. They are said to produce large amounts of cytokines such as IL-4, IFN-γ, and IL-5 when stimulated with the same antigen.

[0027] In a preferred embodiment, the memory T cells targeted by the components of the present disclosure may be memory regulatory T cells (IL-2-producing). Regulatory T cells (Treg) are a type of T cell that blocks excessive immune responses. Treg cells are broadly divided into two types: endogenous Treg (natural Treg; nTreg) cells that arise naturally in the thymus, and inducible Treg (induced Treg; iTreg) cells that arise in peripheral tissues in response to stimulation with cytokines and the like. "Memory regulatory T cells (IL-2-producing)" are cells that have both the characteristics of "memory T cells" and "regulatory T cells."

[0028] As used herein, the term "immunostimulating effect" refers to the effect of nonspecifically activating the immune function of the body and enhancing weakened defenses. Whether a substance has an "immunostimulating effect" can be confirmed by conducting a reporter gene assay of innate immune receptors or a test that evaluates the activation of immune cells using lymphocytes or the like as an indicator of cytokine production.

[0029] As used herein, "activation" refers to a state in which the function of a cell (e.g., a T cell), a protein, a polypeptide, a gene, or the like is increased. "Activation" encompasses states in which a change or increase in cell function is observed, a state in which cell proliferation is enhanced, a state in which the expression of a protein, polypeptide, gene, or the like is increased or the expression pattern is changed, a state in which a cell with suppressive ability is suppressed, and a state in which suppressed function is released. In particular, in the present disclosure, "activation" refers to the activation of regulatory T cells (Tregs). The activation of regulatory T cells (Tregs) is sometimes referred to as the conversion of regulatory T cells (Tregs), although the two terms are synonymous. As used herein, "activation of Tregs" may refer to a specific target, in which case it refers to the activation of Tregs against the target and the exertion of a disease preventive or therapeutic effect. In this case, targets include, but are not limited to, cancers or cancer-derived factors. Whether or not immune cells are "activated" can be confirmed by the tests described in the "Immunostimulating effect" section. Gene "activation" can be quantified using real-time PCR, RNA-Seq, Northern hybridization, hybridization using DNA arrays, or the like, and the expression level of a polypeptide can be quantified using an antibody that recognizes the polypeptide or a staining compound that binds to the polypeptide. In addition to the quantification methods listed above, conventional methods used in the technical field may also be used. As used herein, the term "antigenic components other than the target" refers to components other than a certain target (for example, cancer) (for example, non-tumor components when the target is cancer).

[0030] As used herein, the term "adjuvant" refers to a substance used to enhance the efficacy (immunogenicity) of a drug such as a vaccine (antigen), and is derived from the Latin word "adjuvare," which means "to help." Whether a substance functions as an "adjuvant" for another substance (e.g., an antigen) can be confirmed by administering the substance together with the antigen to mice and evaluating the production of antigen-specific antibodies.

[0031] As used herein, the term "antigen-dependent" "action" of a certain component refers to, when referring to a target such as a T cell, the component producing an action on the target as a result of an antigen-antibody reaction, and this can be confirmed by, for example, the disappearance of the action when the antigen-antibody reaction is inhibited.

[0032] As used herein, "memory CD4-positive T cells" refer to memory T cells that are CD4-positive. Here, CD4 positivity is defined as being positive when stained at a higher level than the staining level with a nonspecific antibody used as a negative control, as determined by immunostaining using a CD4-specific antibody labeled with a fluorescent dye or the like.

[0033] As used herein, "Foxp3-positive Treg cells" refer to Treg cells that are positive for Foxp3. Here, Foxp3 positivity is defined as a higher level of staining, as determined by immunostaining using a Foxp3-specific antibody labeled with a fluorescent dye or the like, compared to the level of staining using a nonspecific antibody used as a negative control.

[0034] As used herein, "IFN-γ-producing T cells" refers to T cells that have the ability to produce interferon-γ (IFN-γ). IFN-γ-producing T cells can be identified by immunostaining using an IFN-γ-specific antibody labeled with a fluorescent dye or the like, and by observing a higher level of staining compared to the level of staining using a nonspecific antibody used as a negative control.

[0035] As used herein, "type 1 helper T cells," also referred to as "Th1 cells," are a subpopulation of CD4+ T cells (so-called helper T cells), such as naive CD4+ T cells that mature in the thymus. These cells rapidly enter the bloodstream, migrate to the site of infection, secrete cytokines such as IFN-γ and IL-2, and activate macrophages and induce inflammatory responses. Th1 cells are responsible for cellular immunity, a localized immune response in which CTLs and macrophages directly attack cells. A subpopulation of CD4+ T cells also includes type 2 helper T cells (Th2 cells). Th2 cells secrete cytokines such as IL-4 and IL-5 and activate naive B cells that recognize the same antigen in secondary lymphoid tissues. Th2 cells are responsible for humoral immunity, an immune response centered on B cells and antibodies.

[0036] As used herein, "T-bet-positive Th1 cells" refer to Th1 cells that are T-bet-positive. Here, T-bet positivity is defined as a higher level of staining, as determined by immunostaining using a T-bet-specific antibody labeled with a fluorescent dye or other dye, compared to the level of staining using a nonspecific antibody used as a negative control. In Th1 cells, the transcription factor T-bet, encoded by the Tbx21 gene, acts as a lineage-defining transcription factor and directly regulates interferon-γ production through positive feedforward regulation. Interferon-γ is classified as a type II interferon and is a member of the interferon family with anti-pathogenic and anti-tumor effects. It is known to induce the expression of T-bet, a transcription factor that defines Th1 cells, and maintain interferon-γ production through feedforward regulation.

[0037] As used herein, "enhanced" ability to produce IFN-γ, IL-2, TNF-α, or the like means that the amount of IFN-γ and IL-2 produced or the number of IFN-γ- and IL-2-producing cells produced in response to stimulation by an antigen or the like is significantly increased compared to a negative control, as determined by immunostaining or other methods using antibodies specific to IFN-γ, IL-2, or TNF-α labeled with a label (substance, etc.) such as 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.

[0038] As used herein, the term "biomarker" refers to a substance or event, such as a protein, that is measured in a biological sample, such as blood, and whose presence or absence, concentration, or level reflects the existence or progression of a specific physical condition, such as a disease. Therefore, as used herein, biomarkers are understood to include events such as whether they act on memory CD4-positive T cells in an antigen-dependent manner, whether they alter memory regulatory T cells, whether they change the ratio of Tregs to Th1s, whether they induce IFN-γ production from T-bet-positive Th1 cells, whether they alter IFN-γ production ability, whether they alter IL-2 production ability, or whether they alter TNF-α production ability.

[0039] Whether or not the antibody acts on memory CD4-positive T cells in an antigen-dependent manner can be determined by FACS analysis, based on a statistically significant increase in the number of cells positive for the antibody used for staining.

[0040] Whether or not memory regulatory T cells are altered can be determined by FACS analysis, which shows a statistically significant increase in the number of cells positive for the antibody used for staining.

[0041] Whether the ratio of Tregs to Th1 cells changes and whether IFN-γ production from T-bet-positive Th1 cells is induced can be determined by measuring the cytokine production by FACS after intracellular cytokine staining and transcription factor staining, or by measuring the cytokine production by ELISA.

[0042] Whether or not the IFN-γ, IL-2, and TNF-α production abilities are altered can be determined by measuring them by FACS after intracellular cytokine staining and transcription factor staining, or by measuring the produced cytokines by ELISA.

[0043] As used herein, the term "bias" in the "abundance ratio" of cells refers to a statistically significant difference in the ratio of multiple types of cells compared to the ratio present under normal conditions. Whether or not a bias exists can be determined by referring to the results of cell analysis obtained by any method for analyzing cells (e.g., FACS, etc.).

[0044] As used herein, "hot water extract of Mycobacterium tuberculosis" refers to a substance typically produced by Mycobacterium tuberculosis, and is a mixture containing polysaccharides primarily composed of arabinose, mannose, and glucose. The anti-cancer effects of hot water extract of Mycobacterium tuberculosis have long been studied, but the details of its mechanism of action have not been fully elucidated, and it has not been used as a prophylactic drug. In addition, the extract may contain trace components such as proteins, peptides, amino acids, nucleic acids, and lipids (glycolipids), as appropriate.

[0045] A typical method for producing a hot water extract of Mycobacterium tuberculosis is as follows.

[0046] Mycobacterium tuberculosis is cultured in a 37°C incubator for 3–7 weeks, after which the membrane-like cells that form on the medium are filtered and the medium components are removed by washing with water. The wet cells are used as the extraction material. The cells are suspended in distilled water at a volume 15–40 times their wet weight and heated at 90–120°C for 80–180 minutes for extraction. The bacterial residue is removed using a sterilizing filter. The extract is concentrated to less than 60%. Acetone, trichloroacetic acid, ammonium sulfate, or sulfosalicylic acid is added to the extract to a concentration of 0.5–3% (w / v). The mixture is stirred and allowed to stand. The resulting precipitate is removed by centrifugation, and the supernatant is dialyzed under running water. The dialyzed solution is concentrated under reduced pressure to 1 / 20–1 / 4 of its original volume. Sodium chloride is added to the concentrate to a concentration of 0.5–1% (w / v), followed by the addition of 2–4 volumes of ethanol, and the mixture is allowed to stand. The precipitate is then centrifuged and removed. Furthermore, 2 to 6 volumes of ethanol are added to the supernatant, and the mixture is left to stand, followed by centrifugation to collect the precipitated polysaccharides. Those skilled in the art will understand that similar products can be obtained even if the above conditions are appropriately changed.

[0047] In the present disclosure, "prevention" refers to the act of administering the active ingredient of the present disclosure to a person who has not developed the target disease, for example, with the purpose of preventing the onset of the disease.

[0048] In the present disclosure, "treatment" refers to the act of administering, for example, an active ingredient of the present disclosure to a person (subject, patient) who has been diagnosed by a physician or equivalent practitioner as having a disease, for the purpose of, for example, alleviating the disease or symptoms, preventing the growth of carcinoma, or restoring the state to a state before the onset of the disease. Furthermore, even if the purpose of administration is to prevent the worsening of the disease or symptoms or the growth of carcinoma, it is still a therapeutic act if the person receiving the administration is a patient.

[0049] As used herein, the term "immune disorder" refers to any disease, disorder, or condition caused or suspected to be caused, at least in part, by a disorder of the immune system, including, but not limited to, cancer, autoimmune diseases, and the like.

[0050] Prevention or treatment of an immune disorder includes preventing an immune disorder, recovering from an immune disorder, or preventing an immune disorder from occurring in the first place.

[0051] DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. It is also understood that the following embodiments of the present disclosure can be used alone or in combination.

[0052] The present disclosure is based on the discovery that the use of non-tumor antigen components to which a subject has immunological memory can provide specific and effective therapeutic and preventive effects against malignant neoplasms such as cancer.

[0053] <Disease prevention and treatment based on immune memory mechanisms> The present disclosure generally provides compositions for preventing or treating a disease, disorder, or condition in a subject, or therapeutic or prophylactic methods using the same principle, based on an immune memory mechanism, wherein the composition comprises an antigen component specific in the subject or an antigen component to which the subject has immune memory, against a component distinct from the causative agent of the disease, disorder, or condition.

[0054] In one exemplary aspect, the present disclosure provides a composition for activating (or converting or transforming) regulatory T cells (Tregs) that have been suppressed in a subject and have immunological memory to the non-target antigen component against a target, the composition comprising an antigen component other than the target. Alternatively, the present disclosure provides a method for activating (or converting or transforming) regulatory T cells (Tregs) that have been suppressed in a subject and have immunological memory to the non-target antigen component against a target, the method comprising administering an effective amount of an antigen component other than the target to the subject. In the present disclosure, it has been found that activation of Tregs confers killing ability or immunostimulatory effect on the target, and the improvement of healing ability due to the conferring of such immune ability is unexpected from the viewpoint of normal immunological memory. In the present disclosure, it has been found that, apart from non-specific immune effects, the components contained (non-target components) exert anti-target immunity similar to or superior to the target (antigen), and by confirming this with other components, it has been found that non-target antigen components specific to a subject (or to which the subject has immunological memory) can be widely used to treat or prevent a target (e.g., cancer). For example, in BCG-infected animals (i.e., animals that can be evaluated as having immunological memory against antigenic components of Mycobacterium tuberculosis) or influenza virus-infected animals used as models, it has been demonstrated that a hot water extract of Mycobacterium tuberculosis or an influenza virus antigen containing the antigen exhibits preventive and therapeutic effects against the onset of diseases other than tuberculosis or influenza (e.g., cancer). Furthermore, in subjects with immune memory against a specific component, such as BCG-infected animals or influenza virus-infected animals, the therapeutic and / or preventive effect of the specific component (in the case of BCG, a hot water extract of Mycobacterium tuberculosis) is not only due to the previously thought immunostimulatory effect that promotes infiltration of lymphocytes and other cells into the target (e.g., tumor) site, but also to the antigen responsiveness of the specific component (e.g., a hot water extract of Mycobacterium tuberculosis), and the researchers have newly discovered that the mechanism behind this is that an antigen response due to immune memory caused by a previously administered vaccine (antigen), etc., is evoked, and that the antigen response due to an antigen other than the target promotes immune action against the target. In one embodiment, the present disclosure provides a composition for activating regulatory T cells (Tregs) that are suppressed in a subject and have immunological memory to the non-tumor antigen component, the composition comprising a non-tumor antigen component. Alternatively, the present disclosure provides a method for activating regulatory T cells (Tregs) that are suppressed in the subject and have immunological memory to the non-tumor antigen component, the method comprising administering an effective amount of the non-tumor antigen component to the subject. In the present disclosure, activation of Tregs can confer tumor-killing ability or immunostimulatory effect against tumors. In one embodiment, the Tregs are memory T cells and / or are CD4 positive, as, without wishing to be bound by theory, they have been found to be associated with immunological memory and also have activity via CD4 positive cells. In another embodiment, the antigen component comprises a protein, a portion thereof, or a peptide. In one embodiment, the antigenic component comprises an antigen selected from the group consisting of an infectious disease pathogen or part thereof, an antigen associated with medical history, and an antigen associated with vaccination history, hi one specific embodiment, the antigenic component comprises a hot water extract of Mycobacterium tuberculosis or an influenza virus antigen. In another embodiment, the antigen component is used in a method comprising determining whether the antigen component has Treg immune memory in the subject, and administering the antigen component to the subject if the subject has immune memory against the antigen component. In the conversion technology of the present disclosure, various components may employ various embodiments of the same type of components described in this specification, and it is understood that combinations thereof are also within the scope of the present disclosure.

[0055] In one aspect, the present disclosure provides a composition for preventing or treating cancer in a subject, the composition comprising a non-tumor antigen component specific to the subject or a non-tumor antigen component for which the subject has immunological memory.

[0056] In this way, the present disclosure identifies the responsiveness of a subject to a component effective as a cancer vaccine based on the subject's past physical condition, and prevents or treats cancer by administering to the subject the component that is responsive to that physical condition.

[0057] Thus, in another aspect, the present disclosure provides a method for preventing or treating cancer, comprising the steps of: a) obtaining a subject's past physical condition; b) identifying the subject's responsiveness to a component effective as a cancer vaccine based on the physical condition; and c) administering to the subject the component that is responsive to the physical condition.

[0058] In one embodiment, the present disclosure provides that the active ingredient, such as a non-tumor antigen component, is specific for memory T cells of the subject, which means that the subject has immunological memory for a particular antigen.

[0059] In one embodiment, a specific example of the compounds discovered in the present disclosure can be a cancer treatment drug. In this case, the antitumor activity of a hot water extract of Mycobacterium tuberculosis (MTTB) is noteworthy. Previously, MTTB hot water extracts have been considered to have nonspecific immunotherapy properties, with immunostimulatory activity being their primary mechanism of action. However, the inventors, through extensive research, have discovered that, in addition to nonspecific immune activity, the components contained in the extract exert antitumor immunity similar to or superior to cancer antigens. By confirming this in other components, the inventors have discovered that nontumor antigen components specific to a subject (or for which the subject has immunological memory) can be used broadly to treat or prevent cancer. For example, using BCG-infected animals (i.e., animals that can be evaluated as having immunological memory for MTTB components) as a model, the inventors demonstrated that a MTTB hot water extract containing the antigen exhibited preventive and therapeutic effects against cancer onset. Furthermore, the therapeutic and / or preventive effects of a specific component (in the case of BCG, a hot water extract of Mycobacterium tuberculosis) in subjects with immune memory against that component, such as BCG-infected animals, depend not only on the immunostimulatory effect that has been conventionally thought to promote the infiltration of lymphocytes and other cells into tumor sites, but also on the antigen responsiveness of the specific component (e.g., a hot water extract of Mycobacterium tuberculosis).The researchers have newly discovered that the mechanism behind this is that an antigen response due to immune memory arising from a previously administered vaccine (antigen), etc., is evoked, and that this antigen response due to a non-tumor antigen promotes anti-tumor immune action.

[0060] In one embodiment, the memory T cells associated with immune memory targeted by the present disclosure are memory regulatory T cells, and IL-2 production can be observed as an indicator thereof. Examples of indicators include IL-2 production, IFN-γ production, TNF-α production, or a combination of two or three of these. That is, to determine the presence of immune memory, an antigen of interest is added to a test system containing T cells, and then an increase in IL-2 production, IFN-γ production, TNF-α production, or a combination of two or three of these is observed, thereby determining the presence of immune memory against that antigen.

[0061] In one embodiment, a specific component, such as a non-tumor antigen component, of the present disclosure has immunostimulatory activity (e.g., adjuvant activity). The immunostimulatory activity can be confirmed by any method known in the art. For example, the effect on innate immune receptors, the ability to induce specific antibody production, etc. can be evaluated.

[0062] In one embodiment, a specific component, such as a non-tumor antigen component, of the present disclosure acts on memory CD4-positive T cells in an antigen-dependent manner. Whether or not a component acts on memory CD4-positive T cells in an antigen-dependent manner can be confirmed by any method known in the art. For example, flow cytometry analysis using an MHCII tetramer and a specific antigen peptide, or flow cytometry analysis of IFN-γ-producing cells after stimulation with a specific antigen can be used.

[0063] In one embodiment, a specific component, such as a non-tumor antigen component, of the present disclosure has the activity of shifting the abundance ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells. The shift in the abundance ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells can be confirmed by any cell analysis technique (e.g., FACS), typically by measuring by FACS after intracellular cytokine staining and transcription factor staining. In this case, the criterion for determining the shift in the abundance ratio between Foxp3-positive Treg cells and IFN-γ-producing T cells may be, but is not limited to, an increase in the number of IFN-γ-producing T cells compared to Foxp3-positive Treg cells. The IFN-γ-producing T cells may include type 1 helper T cells. Alternatively, in another embodiment, a specific component, such as a non-tumor antigen component, of the present disclosure has the activity of shifting the abundance ratio between Foxp3-positive Treg cells and type 1 helper T cells.

[0064] Without wishing to be bound by theory, the present inventors have considered the mechanism of action of shifting the ratio of Foxp3+ Treg cells to IFN-γ-producing T cells as an important aspect, and have discovered that specific components (components that induce immunological memory), such as a hot water extract of Mycobacterium tuberculosis, act on memory CD4+ T cells in an antigen-dependent manner to shift the ratio of Foxp3+ Treg cells to IFN-γ-producing T cells, such as type 1 helper T cells (Th1 cells), thereby shifting the ratio toward anti-tumor immunity and increasing IFN-γ-producing T cells within tumors. In other words, the present disclosure is expected to promote lymphocyte infiltration into tumors and, in addition, to activate dormant T cells through the use of non-tumor antigen components contained in the agent, thereby shifting the balance between suppressor T cells and anti-tumor immunity, thereby more strongly expressing tumor antigen-dependent anti-tumor immunity in vivo. In one embodiment, the present disclosure includes an antigen component capable of eliciting an immune response mediated by CD4-positive T cells. In one embodiment, the present disclosure is characterized in that a subject is determined to be capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, and the composition is administered if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells. In a further embodiment, the immune response is not mediated by CD8-positive T cells.

[0065] In one embodiment, in the present disclosure, the targeted IFN-γ-producing T cells may include type 1 helper T cells. Without wishing to be bound by theory, this is because they act on memory CD4-positive T cells in an antigen-dependent manner to convert them into anti-tumor immune cells such as type 1 helper T cells (Th1 cells), and can increase the number of IFN-γ-producing T cells in the tumor, thereby enhancing the anti-cancer effect.

[0066] In another embodiment, in the present disclosure, the IFN-γ-producing T cells are T-bet-positive Th1 cells. Without wishing to be bound by theory, it is known that in host defense, interferon γ induces the expression of T-bet, a transcription factor that defines Th1 cells, and maintains interferon γ production through feedforward regulation. A novel role for T-bet in the recognition of autocrine interferon by Th1 cells has also been investigated, and in the absence of T-bet, interferon γ induces an aberrant type I interferon response. T-bet preferentially suppresses genes and pathways activated by autocrine type I interferon, thereby suppressing the aberrant amplification of the type I interferon signaling pathway. Therefore, T-bet not only actively induces differentiation into Th1 cells, but also plays a role in suppressing the abnormal autocrine expression of type I interferon and its downstream signaling pathway in Th1 cells (see, for example, Harms Pritchard, G., Hall, AO, Christian, DA et al.: Diverse roles for T-bet in the effector responses required for resistance to infection. J. Immunol., 194, 1131-1140 (2015)).

[0067] In one embodiment, in the present disclosure, the specific non-tumor antigen component (or the subject has immune memory for) preferably has the ability to enhance at least one selected from the group consisting of IFN-γ production, IL-2 production, and TNF-α production in a sample derived from the subject, because, without wishing to be bound by theory, IFN-γ production, IL-2 production, and TNF-α production are advantageous in terms of anti-cancer effects.

[0068] The BCG infection model used herein is an infection model similar to that used in previous vaccination and medical history. Based on the data demonstrated by this model, it is believed that memory T cells established by previous vaccination and remaining dormant are reactivated by stimulation with a specific antigen, and that these cells promote anti-tumor immune responses independently of tumor antigens. This hypothesis has been substantiated through experiments using other immune memory models. Therefore, it is understood that disease treatment based on the immune memory model disclosed herein can be applied to any disease, not just the examples. Similar effects can also be observed in clinical trials.

[0069] Furthermore, without wishing to be bound by theory, the mechanism of action of the present disclosure is thought to be that in animal models, a bias in the ratio of Th1 cells to Foxp3+ Treg cells and IFN-γ production are important, and that in peripheral blood-derived cells (such as in humans), the initial response of a specific component of the present disclosure is memory regulatory T cells (IL-2-producing) based on vaccination history and medical history, and that the specific component of the present disclosure induces IFN-γ production, and over time, experiments have shown that it changes the ratio of Foxp3+ regulatory T cells (Treg) to T-bet+ Th1 cells and induces IFN-γ production from T-bet+ Th1 cells, which is also an important functioning mechanism. The finding that IFN-γ production, IL-2 production, and TNF-α production from memory regulatory T cells based on the subject's immune memory, such as vaccination history and medical history, are involved was previously unknown and was discovered as a result of extensive research by the present inventors. Therefore, it can be said that the present disclosure demonstrates that IFN-γ production, IL-2 production, and TNF-α production using peripheral blood-derived cells from humans and other animals can be biomarkers for selecting responders.

[0070] This indicates that the IFN-γ, IL-2, and TNF-α production capabilities of this drug can be confirmed in advance for individual subjects using cells derived from human peripheral blood, suggesting its potential as a companion diagnostic. Furthermore, because this biomarker is not a response to cancer antigens, it can also be used in healthy individuals who do not have cancer antigens, making preventive treatment possible.

[0071] These new findings, based on scientific evidence, regarding the antitumor immune effects of a hot water extract of Mycobacterium tuberculosis, which has already been confirmed to be safe, have led to the invention of a new antitumor immunotherapy and prevention method that can be used to treat appropriate subjects. It is also expected to enhance the effects of previously known cancer immunotherapies, such as checkpoint molecule inhibitors. Furthermore, this mechanism is not limited to Mycobacterium tuberculosis; it is expected to enhance the antitumor effects of antigen treatments based on a patient's infection history or vaccination history for other infectious diseases, allowing for the provision of optimal treatment for each individual.

[0072] Before transplanting cancer cells into animals, normal animals were first administered a mixture of a hot water extract of Mycobacterium tuberculosis and an adjuvant base in a vaccine-like manner, and then the animals were administered the hot water extract of Mycobacterium tuberculosis using conventional methods, after which cancer cells were transplanted and the antitumor effect was evaluated.As a result, it was found that even under conditions where the hot water extract of Mycobacterium tuberculosis alone or the adjuvant base alone was ineffective, pre-treatment with the mixture of the hot water extract of Mycobacterium tuberculosis and the adjuvant base (vaccine-like treatment) can produce a strong antitumor effect different from conventional treatments.

[0073] After inoculation of mice with BCG, administration of a Mycobacterium tuberculosis extract at a time when the effectiveness of BCG had weakened enhanced the antigen response ability (triple response of IFN-γ, TNF-α, and IL-2) of CD4+CD44+ cells derived from spleen cells. These results indicate the discovery of a useful treatment method that can maintain vaccine effectiveness, addressing the current issue of increased infections due to weakened vaccine effectiveness.

[0074] This disclosure is expected to enhance antitumor efficacy not only in Mycobacterium tuberculosis infection, but also in antigen-specific treatments based on a history of infection or vaccination against other infectious diseases. Specifically, this disclosure provides a personalized cancer immunotherapy and prevention method for individuals with a history of infection or vaccination, in which efficacy can be predicted in advance based on memory T cell responses. Unlike conventional immunotherapies, which require specific cancer antigens to be identified, this method offers the advantage of selecting immunotherapy with a specific antigen vaccine based on each individual's infection and vaccination history. Furthermore, because it does not use cancer antigens, it can be applied to healthy individuals, enabling preventive treatment. In particular, this method uses a hot water extract of Mycobacterium tuberculosis, whose safety in humans has been established, as an active ingredient. This method, with its unique formulation and administration method, provides effective treatment and prevention, even for cancers for which subcutaneous administration alone does not provide preventive or therapeutic effects.

[0075] <Biomarkers> In one aspect, the present disclosure provides a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect in a subject. Here, the biomarker in the present disclosure can be an event such as whether the (non-tumor) antigen component of the present disclosure (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, or (iii) induces IFN-γ production from T-bet-positive Th1 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 whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) modulates memory regulatory T cells, (iii) modulates IFN-γ production ability, (iv) modulates IL-2 production ability, and (v) modulates TNF-α production ability.

[0076] Therefore, in another aspect, the present disclosure provides a composition or kit including a means for detecting a biomarker for determining whether a (non-tumor) antigen component has an anti-cancer effect in a subject. The means for detecting the biomarker may be any means capable of determining whether the non-tumor antigen component acts on memory CD4-positive T cells in an antigen-dependent manner, modulates memory regulatory T cells, or modulates the ability of T-bet-positive Th1 cells to produce IFN-γ, IL-2, and TNF-α, and various publicly known or commercially available kits can be used. Therefore, the present disclosure also provides a composition or kit for determining whether a non-tumor antigen component has an anti-cancer effect in a subject, the composition or kit comprising an agent or device for determining at least one selected from the group consisting of whether the non-tumor antigen component (i) acts on memory CD4-positive T cells in an antigen-dependent manner, (ii) alters memory regulatory T cells, (iii) alters IFN-γ production ability, (iv) alters IL-2 production ability, and (v) alters TNF-α production ability.

[0077] In a specific embodiment, peripheral mononuclear cells are isolated from a subject, memory CD4-positive cells contained therein are stimulated with various antigens, and an antigen responsiveness profile is obtained by staining intracellular cytokines or transcription factors. In another embodiment, in implementing the biomarkers of the present disclosure, any one or more of the features described in <Prevention and treatment of diseases based on immune memory mechanisms> can be applied in combination.

[0078] <Manufacturing method and other methods of providing> In another aspect, the present disclosure provides a method for manufacturing or otherwise providing a composition for preventing or treating a disease or disorder in a subject. This method comprises the steps of: A) identifying an antigen that is specific to the subject but non-specific to the disease or disorder; B) identifying whether the non-specific antigen has immune memory in the subject and selecting an antigen with immune memory; and C) manufacturing or otherwise providing the selected non-tumor antigen. As used herein, "or providing in another manner" refers to any method of providing other than newly manufacturing a subject, and may be, for example, a method of isolating, purifying, or obtaining the subject from an appropriate source. In step C), the non-tumor antigen may be newly manufactured or provided by isolation from another source.

[0079] In another aspect, the present disclosure provides a method for manufacturing or otherwise providing a composition for preventing or treating cancer in a subject. This method includes the steps of: A) identifying a non-tumor antigen specific to the subject; B) identifying whether the non-tumor antigen has immunological memory in the subject and selecting one with immunological memory; and C) manufacturing or otherwise providing the selected non-tumor antigen. In step C), the non-tumor antigen may be newly manufactured or may be provided by isolation from another source.

[0080] In the production method of the present disclosure, any one or more of the features described in <Prevention and treatment of diseases based on immune memory mechanisms> can be applied as appropriate.

[0081] <Treatment, prevention, companion diagnostics, treatment and medicine>

[0082] In one aspect, the present disclosure provides a method for preventing or treating a disease, comprising the steps of: a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigen or combination of antigens to which the subject is responsive based on the antigen responsiveness 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 preventing or treating a disease, disorder, or symptom associated with an immune abnormality, comprising the steps of: a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigen or combination of antigens from the antigen responsiveness profile, wherein the antigen or combination of antigens has been or is shown to present an immune response in the subject; and c) administering the antigen or combination of antigens identified in step b) to the subject in an amount sufficient to elicit an immune response in the subject. The present disclosure further provides an antigen or combination of antigens for use in a method for preventing or treating a disease, disorder, or condition associated with immune abnormalities, comprising the steps of: a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigen or combination of antigens from the antigen responsiveness profile, wherein the antigen or combination of antigens has been or is shown to present 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.

[0083] In certain aspects, the present disclosure provides a method for preventing or treating cancer, comprising the steps of: a) obtaining an antigen responsiveness profile of a subject; b) identifying an antigen or combination of antigens to which the subject is responsive based on the antigen responsiveness profile; and c) administering the component to the subject in an amount sufficient to elicit an immune response in the subject.

[0084] In one aspect, the present disclosure provides a method for determining whether a non-tumor antigen in a subject can prevent or treat cancer in the subject. This method includes the step of B) identifying whether the non-tumor antigen has immunological memory in the subject, and if so, identifying the non-tumor antigen as capable of preventing or treating cancer in the subject. In this method of the present disclosure, any one or more features described in <Prevention and treatment of diseases based on immune memory mechanisms> can be applied as appropriate.

[0085] The present disclosure also provides compositions or pharmaceutical compositions comprising an antigen or a combination of antigens to which a subject is responsive, obtained based on such antigen responsiveness profiles. Alternatively, the present disclosure also provides an antigen or a combination of antigens to which a subject is responsive, obtained based on such antigen responsiveness profiles, for treating or preventing a disease or disorder. Alternatively, the present disclosure also provides use of an antigen or a combination of antigens to which a subject is responsive, obtained based on such antigen responsiveness profiles, in a medicine for treating or preventing a disease or disorder.

[0086] Thus, the present disclosure provides compositions for preventing or treating a disease, disorder, or condition in a subject using components identified by the above methods, which will include an antigen component that is specific in the subject (or to which the subject has immunological memory) to a component that is distinct from the causative agent of the disease, disorder, or condition.

[0087] In one embodiment, the prevention or treatment method of the present disclosure may include the steps of: a) obtaining the subject's past physical condition; b) identifying the subject's responsiveness to a component effective as a cancer vaccine based on the physical condition; and c) administering to the subject the component that is responsive to the physical condition.

[0088] In certain embodiments, obtaining an antigen responsiveness profile in the present disclosure can also be confirmed by a method that includes determining the subject's past physical condition and determining whether one or more antigen candidates are responsive in a sample from the subject, or both.

[0089] In another embodiment, the present disclosure provides a method for preventing or treating cancer, comprising the steps of: a) obtaining a subject's past physical condition; b) identifying the subject's responsiveness to a component effective as a cancer vaccine based on the physical condition; and c) administering to the subject the component that is responsive to the physical condition.

[0090] In a specific embodiment, the past physical conditions that may be utilized include medical history and vaccination history. Medical history and vaccination history may be obtained, for example, from a maternal and child health handbook or its equivalent, a medical record, or other medical information (including electronically recorded information about the subject, such as stored in the cloud or on an electronic chip). A maternal and child health handbook (MCH handbook) is a book containing essential information maintained by families to promote and maintain the health of mothers and children (2009 International Committee on MCH Handbook (ICMCHH)).

[0091] In a specific embodiment, the physical condition that can be used includes a history of infectious diseases, and the cancer vaccine that can be used includes an antigen against the infectious disease. The infectious disease that can be used can be any type, for example, tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, rabies, and diphtheria.

[0092] The infectious disease used in the present disclosure may be any infectious disease described herein. Therefore, in the context of describing a physical condition herein, when terms such as "history of BCG vaccination," "history of tuberculosis infection," or "antigen responsiveness to tuberculosis bacteria" are used, these physical conditions may be replaced with any infectious disease described herein. Although not limiting, it is described and demonstrated in Example 13 that the therapeutic methods, preventive methods, and medicaments of the present disclosure may also be used in cases where a patient has a "history of influenza infection," as an example of any infectious disease.

[0093] In a preferred embodiment, the infectious disease utilized is tuberculosis. In this case, the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or antigenic response to Mycobacterium tuberculosis. In a preferred embodiment, when the infectious disease is tuberculosis, the antigen component or cancer vaccine may advantageously include a hot water extract of Mycobacterium tuberculosis. The present disclosure can be used for treatment, as well as for prevention.

[0094] The antigen or cancer vaccine of the present disclosure may be provided in the form of a pharmaceutical composition. In certain embodiments, the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, where the one or more compounds can be converted in a subject to at least one compound (i.e., a prodrug), such as Extract A (see Examples). In certain embodiments, the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, where the one or more compounds can be converted in a subject to at least one (non-tumor) antigen component (i.e., a prodrug). When multiple drugs are included, they may be included in a single composition (combined drug) or in separate compositions. When formulated as a single composition, the formulation may be formulated using forms known in the art, including those exemplified herein. In addition to the antigen (component) or cancer vaccine of the present disclosure, multiple drugs may be provided together with one or more other medications (e.g., surgery, chemotherapy, anti-cancer drugs such as immune checkpoint inhibitors) or to achieve a therapy (e.g., anti-cancer drug administration, radiation therapy, etc.). The antigen (component) or cancer vaccine of the present disclosure can be provided or administered in combination with one or more other pharmaceutical agents or therapies (e.g., surgery, chemotherapy, radiation therapy, anti-cancer agents such as immune checkpoint inhibitors). In one embodiment, the one or more other pharmaceutical agents or therapies (e.g., surgery, chemotherapy, radiation therapy, anti-cancer agents) may be administered an appropriate time after administration of the antigen or cancer vaccine of the present disclosure. When administered separately, the two or more pharmaceutical agents may be provided as a kit.Examples of anti-cancer agents include, but are not limited to, immune checkpoint inhibitors (PD-1 inhibitors (e.g., anti-PD-1 antibodies), PD-L1 inhibitors (e.g., anti-PD-L1 antibodies), CTLA-4 inhibitors (e.g., anti-CTLA-4 antibodies), etc.), antimetabolites, chemotherapeutic agents such as alkylating agents, growth inhibitors, cytotoxic agents, agents used in radiotherapy, anti-angiogenic agents, apoptotic agents, anti-tubulin agents, anti-cancer antibiotics, microtubule-active agents, tyrosine kinase inhibitors, proteasome inhibitors, anaplastic lymphoma kinase inhibitors, Janus kinase inhibitors, CDK inhibitors, MEK inhibitors, Raf kinase inhibitors, molecularly targeted therapeutic agents such as PARP inhibitors and antibody drugs, platinum agents, immunotherapy such as dendritic cell therapy, gene therapy, other small molecule drugs, and other drugs for treating cancer.

[0095] As used herein, the term "carrier" refers to a pharmaceutically acceptable substance, composition, or excipient, such as a liquid or solid filler, diluent, additive, solvent, or encapsulating material, which pertains to or enables the carrying or transport of a subject pharmaceutical compound from one organ or part of the body to another. "Pharmaceutically acceptable" means compatible with other ingredients in the formulation and not harmful to the patient. Non-limiting examples of pharmaceutically acceptable carriers, carriers, and / or diluents include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and perfuming agents, preservatives, and antioxidants can also be included in the compositions.

[0096] As used herein, "parenteral administration" refers to any route of administration other than oral administration, and includes any form of administration that provides a dosage in a form and at a level effective for the treatment or prevention of a target disease, such as cancer treatment or prevention. Parenteral administration methods include administration via transdermal or transmucosal absorption, including injection or infusion, and combinations thereof. For example, transdermal or transmucosal administration involves contacting a transdermal formulation, such as a liniment, patch, or spray, with the skin or mucosa, allowing the drug in the formulation to penetrate the body through the skin or mucosa, thereby exerting its effects. Administration via injection or infusion includes intravenous, intradermal, subcutaneous, intramuscular, and enteral (enema) administration, and may be by bolus administration and / or continuous infusion. These may include suspensions, solutions, emulsions, or implants in oily or aqueous media, containing other formulation substances such as suspending agents, stabilizers, and / or dispersants. For enteral (enema) administration, continuous delivery to the proximal small intestine can be achieved using a tube and a portable infusion pump via percutaneous endoscopic gastrostomy. Subcutaneous or intradermal administration is more preferred. Parenteral administration (e.g., transdermal administration) can also be achieved using tapes / patches, powders, sprays, ointments, pastes, creams, lotions, gels, and solutions. Compositions suitable for parenteral administration can comprise at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, implant, or sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0097] Compositions disclosed herein suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (usually with a flavored base, which is sucrose and acacia or tragacanth), powder, granules, solutions in aqueous or non-aqueous liquids, suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups, lozenges (with an inert base, such as gelatin, glycerin, sucrose, and / or acacia), and / or mouthwashes, each containing a predetermined amount of at least one compound of the present disclosure.

[0098] The compositions disclosed herein may be administered as a bolus, electuary, or paste.

[0099] The antigen or cancer vaccine of the present disclosure can be administered in any dosage form, and any dosage form can be used, whether oral or parenteral, as long as it is effective. Parenteral administration is preferred.

[0100] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) may comprise one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; agar, calcium carbonate, potato or tapioca starch, alginic acid, certain The pharmaceutical composition may be mixed with any of disintegrating agents such as silicates, sodium carbonate, and sodium starch glycolate, solution retarders such as paraffin, absorption accelerators such as quaternary ammonium compounds, wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polypropylene oxide copolymers, absorbents such as kaolin and bentonite clay, lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0101] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins such as hydroxypropyl-β-cyclodextrin may be used to dissolve the compound.

[0102] Components of the present disclosure can include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, coloring agents, perfumes, and preservatives. Suspensions can contain suspending agents in addition to one or more compounds according to the present disclosure, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0103] The compositions disclosed herein can be made into suppositories for rectal or vaginal administration and can be prepared by mixing one or more compounds according to the present disclosure with one or more suitable non-irritating excipients or carriers, including cocoa butter, polyethylene glycol, suppository waxes, or salicylates, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the compound of the present disclosure. Pharmaceutical compositions suitable for vaginal administration can also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art to be appropriate.

[0104] Dosage forms for topical or transdermal administration of the compositions of this disclosure may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Pharmaceutical compositions or tablets may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0105] The ointments, pastes, creams, and gels can contain, in addition to the compositions of the present disclosure, additives such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0106] Powders and sprays can contain, in addition to the pharmaceutical composition or tablets of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Additionally, sprays can contain common propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0107] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also intended to be within the scope of this disclosure.

[0108] Compositions suitable for parenteral administration can comprise at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, or sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0109] As used herein, the term "salt" 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 those salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, and / or the like, balanced by a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19, describes pharmaceutically acceptable salts in detail.

[0110] Pharmaceutically acceptable salts can be formed with inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic acids 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 adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanoate, and the like. Examples of suitable salts include benzoyl benzoates, ... In some embodiments, organic acids that can yield salts include, for example, 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.

[0111] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the compounds with a suitable base or acid, respectively. Non-limiting examples of pharmaceutically acceptable salts derived from bases include alkali metal, alkaline earth metal, ammonium, and N(C1-4 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. Additionally, non-limiting examples of suitable pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, as appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Non-limiting examples of suitable organic bases from which salts can be formed include primary amines, secondary amines, tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In certain embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0112] In embodiments of the present disclosure, the subject may be a patient before the onset of cancer, after cancer treatment, in the early stage of cancer, or in a precancerous state. Alternatively, the subject may be a healthy individual. When the subject is a healthy individual, the method is carried out as a preventive method.

[0113] Cancers of interest in the present disclosure include, but are not limited to, esophageal cancer, gastroesophageal junction cancer, renal cell carcinoma, lung cancer, gastrointestinal 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 carcinoma, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, sarcoma, genitourinary cancer, gynecological cancer, and adrenocortical carcinoma. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is colorectal adenocarcinoma. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is renal cell carcinoma. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the cancer may be unresectable. In certain embodiments, the cancer may be progressive. In certain embodiments, the cancer may be refractory. In certain embodiments, the cancer may be recurrent. In certain embodiments, the cancer may be metastatic. In various embodiments of the present disclosure, the target cancer may include common carcinomas, relatively indolent carcinomas (e.g., those that are less sensitive to the immune system), oral squamous cell carcinoma, cervical cancer, MHC class I-negative carcinomas that are less susceptible to CD8-positive T cells, cancers resistant to immune checkpoint inhibitors, etc. A cancer patient refers to a patient suffering from the above-mentioned "cancer." In one embodiment, the disease, disorder, or symptom targeted by the present disclosure includes melanoma.

[0114] The subject of the present disclosure may be a subject exhibiting immune resistance, such as a subject for whom immune checkpoint inhibitors are ineffective, a subject for whom treatment with chimeric antigen receptor-expressing cells is resistant, or a subject for whom treatment with a monoclonal antibody is ineffective.

[0115] In the present disclosure, a step of identifying an antigen or a combination of antigens to which the subject is responsive is carried out based on the antigen responsiveness profile. Here, the responsiveness in the subject may be any responsiveness related to disease treatment or prevention, particularly any responsiveness suggested to be related to immunological memory, and may include, for example, responsiveness to any of IFN-γ production, IL-2 production, TNF-α production, or any two or three thereof.

[0116] In another aspect, the present disclosure provides a companion diagnostic agent or diagnostic method for preventing or treating cancer, as well as a therapeutic or preventive method or medicament based thereon.

[0117] In one specific embodiment, the confirmation of responsiveness is characterized by prior companion diagnosis based on medical history and vaccination history, and the feasibility of such companion diagnosis is demonstrated in the Examples herein. Those skilled in the art will understand that prior companion diagnosis is also possible for other diseases and disorders based on such Examples or other specific descriptions.

[0118] In the present specification, "preliminary companion diagnosis based on medical history and vaccination history" can be carried out as follows. Obtaining antigen response profiles by non-invasive methods, interviews, medical history from maternal and child health handbooks or equivalents, or vaccination history. - Confirmation of actual responsiveness using an antigen panel and peripheral mononuclear cells isolated from the subject. The antigens or combinations of antigens that showed a reaction above will be evaluated as preventive or therapeutic drugs.

[0119] An example of such a companion diagnosis or treatment is to use a tuberculosis infection history as the past physical condition to determine whether a Mycobacterium tuberculosis hot water extract can be used as an antigen component. Without wishing to be bound by theory, for example, by using a tuberculosis infection history as the past physical condition to determine whether a subject can be prevented from developing cancer or the like using a Mycobacterium tuberculosis hot water extract, thereby enabling cancer prevention. Alternatively, for example, by using a tuberculosis infection history as the past physical condition to determine whether a subject can be prevented from developing cancer or the like using a Mycobacterium tuberculosis hot water extract, thereby enabling cancer treatment.

[0120] The past physical condition and the component may be one or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile fever, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza virus, MARS, rabies, and diphtheria.

[0121] In one embodiment, the subject of the present disclosure is a patient with a history of BCG vaccination or tuberculosis infection, or a healthy individual with confirmed antigen responsiveness, and the method of the present disclosure is a personalized therapy. Here, the subject may be a person with a history of vaccination, infection, tuberculosis infection, or BCG vaccination.

[0122] Furthermore, the tuberculosis Mycobacterium extracts that can be used in the present disclosure are administered prophylactically before onset, to prevent recurrence after treatment, or in the early stages of cancer onset. In the early stages of cancer onset or in a precancerous state, extracts produced by the methods exemplified in this specification, as well as extracts from tuberculosis Mycobacterium obtained by improved methods, are administered subcutaneously or intradermally.

[0123] In one specific embodiment, the present disclosure provides a method for preventing or treating cancer immunity by prior companion diagnosis based on medical history and vaccination history, which comprises revaccination with the antigen. The ability to prevent or treat cancer immunity by prior companion diagnosis based on medical history and vaccination history is described and demonstrated in Example 2.

[0124] In one specific embodiment, the present disclosure provides a method for preventing or treating cancer in a subject using a non-tumor component, wherein the component is an antigen or extract identified through interview and / or based on the subject's medical history and vaccination history, and the subject is confirmed to have had an infection or been vaccinated based on the medical history and vaccination history, and the component is administered to the subject to prevent recurrence after treatment, to prevent the onset of cancer, or at the early stage of cancer development, and optionally at the early stage of cancer development or in a precancerous state. Examples of such methods are demonstrated in Examples 1, 2, 3, 10, and 13. The present disclosure also provides a non-tumor component for use in a method for preventing or treating cancer in a subject, the component being an antigen or extract identified by interview and / or identified with reference to the medical history and vaccination history of the subject, the subject being an individual who has had an infection or vaccination as described in the present disclosure, the component being administered to the subject for prevention of recurrence after treatment, prophylactic administration before onset, or at the early stage of cancer onset, and optionally administering the component at the early stage of cancer onset or in a precancerous state.

[0125] In one aspect, the present disclosure provides a vaccine formulation comprising any one of the antigens disclosed herein and an adjuvant base. In one embodiment, this vaccine formulation is used for personalized medicine. In this personalized medicine, a vaccine can be appropriately provided for each patient or subject based on the companion medicine provided in the present disclosure. In certain embodiments of the present disclosure, the cancers targeted by the present disclosure may be common carcinomas, relatively indolent carcinomas (less susceptible to the immune system), oral squamous cell carcinoma, cervical cancer, etc., and MHC class I-negative carcinomas, which are typically not effectively treated with CD8-positive T cells. In certain embodiments, the subject of the present disclosure is a patient exhibiting immune resistance.

[0126] In one embodiment, in the treatment or prevention of the present disclosure, the responsiveness of a subject can be determined using any of a history of previous infection, a history of vaccination, and responsiveness to IFN-γ production, IL-2 production, TNF-α production, or any two or three thereof using peripheral blood. "Response to IFN-γ production, IL-2 production, TNF-α production, or any two or three thereof using peripheral blood" can be performed as follows. Peripheral blood mononuclear cells are isolated from the subject's blood. Peripheral blood mononuclear cells are cultured in the presence of stimulating substances such as the substance in question, or purified protein derivative (PPD), tuberculosis antigens, and protein transport inhibitors such as brefeldin A and monensin. After culturing for a certain period of time, peripheral blood mononuclear cells are collected and stained with fluorescently labeled antibodies specific to cell surface markers and intracellular cytokines, and the stained cells are analyzed using a flow cytometer. In memory CD4 T cells (CD3 positive, CD4 positive, CD45RA negative), stimulation with Extract A or tuberculosis antigen is used as an indicator to determine whether various cytokine-producing cells are increased. Extract A is exemplified and described in detail in Example 1, etc.

[0127] In one specific embodiment, the tuberculosis extract used in the present disclosure is a hot water extract of Mycobacterium tuberculosis or an extract from other tuberculosis bacteria (a highly safe extract). Compositions such as those used in tuberculin are also preferred.

[0128] In one aspect, the present disclosure provides a vaccine formulation comprising an antigen provided herein and an adjuvant base (e.g., a substance that promotes a Th1-type immune response). In a specific embodiment, the vaccine formulation is used for personalized medicine. In this personalized medicine, an appropriate vaccine is prepared for each patient or subject based on companion medicine such as that provided herein. In one embodiment, the pharmaceutical or antigen component provided herein may be provided as a vaccine formulation comprising a hot water extract of Mycobacterium tuberculosis or an extract (highly safe extract) or extract component, or antigen from other Mycobacterium tuberculosis, and an adjuvant base. Such a vaccine formulation can be produced by mixing the respective materials at any desired concentrations, and the results are exemplified in Example 4. In a specific embodiment, the vaccine formulation is intended for use in personalized medicine.

[0129] Adjuvant bases that can be used in vaccine formulations include the following: Innate immune receptor-activating adjuvant substrates (e.g., TLR agonists, bacterial membrane-derived substances, DNA, RNA, dinucleotides, NOD1, NOD2 agonists). · Aluminum-containing adjuvant bases such as aluminum hydroxide. Adjuvant bases that can be used to create emulsions, such as ISA51 and ISA720. Adjuvant bases containing cytokines (IL-2, IL-12, IFN-α, GM-CSF). Preferably, the adjuvant base contains a substance that promotes a Th1-type immune response (e.g., a nucleic acid-based base such as CpG).

[0130] In one specific embodiment, the present disclosure provides a composition for treating or preventing a disease, disorder, or symptom associated with immune abnormality in a subject, the composition comprising an antigen component specific in the subject to a component different from a causative factor of the disease, disorder, or symptom, the disease, disorder, or symptom comprising melanoma, the antigen component comprising a protein or a portion thereof, a peptide, or the like, and capable of eliciting an immune response mediated by CD4-positive T cells, the cancer comprising a cancer that can be treated or prevented by an immune response mediated by CD4-positive T cells; Here, the present disclosure provides a composition, characterized in that it is determined whether the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells, and the composition is administered to the subject if the subject is capable of eliciting an anti-tumor immune response mediated by CD4-positive T cells. The present disclosure also provides preventive and therapeutic methods related to the composition. In a further embodiment, the immune response is not mediated by CD8 positive T cells. In another embodiment, the present disclosure provides a composition for treating or preventing cancer or tumor in a subject, the composition comprising a non-tumor antigen component that activates regulatory T cells (Tregs) that are suppressed in the subject and have immune memory to the non-tumor antigen, and the Tregs have a regulatory activity or an effect of promoting anti-tumor immunity against cancer or tumor. The present disclosure also provides preventive and therapeutic methods related to the composition.

[0131] In another aspect, the present disclosure provides a composition for treating or preventing a disease, disorder, or symptom associated with immune abnormality in a subject, the composition comprising an antigen component (the antigen component may be isolated, or may be an extract or other form containing the antigen component) specific in the subject to a component different from the causative agent of the disease, disorder, or symptom, and administered in an appropriate manner and dosage (e.g., subcutaneous or intratumoral administration once daily (in the first week) and approximately once a week (from the second week onward)). The present disclosure also provides prophylactic and therapeutic methods related to this composition. In one embodiment, the antigen component is contained in an amount of approximately 0.001 μg or more per unit dosage form. In another aspect, the present disclosure provides a method for treating or preventing cancer or tumor in a subject, comprising: a) identifying a non-tumor antigen specific to the subject based on an antigenic response profile; b) determining whether the subject has immune memory against the non-tumor antigen and identifying a subject having the immune memory; and c) administering the non-tumor antigen to the subject identified as having the immune memory. The present disclosure may include preventive and therapeutic methods, pharmaceutical compositions, antigen components, etc. related to this method. In one embodiment, the antigenic response profile includes vaccination history and / or infection history. In another embodiment, the step of identifying a subject with immune memory involves stimulating peripheral blood mononuclear cells (PBMCs) 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 whose cytokine production level has increased by a predetermined fold compared to before stimulation as a subject with immune memory (also referred to as a responder). In one embodiment, the non-tumor antigen is administered once daily, three times weekly, twice weekly, once weekly, once every two weeks, or once monthly, and the dose may be increased or decreased as appropriate, such as once daily for the first dose and once weekly thereafter. In another embodiment, the non-tumor antigen of the present disclosure is administered at about 0.1 pg / dose to about 1 mg / dose. <Ingredients> In another aspect, the present disclosure provides compositions comprising mHSP10 and / or MTB12 and / or lipoprotein LpqH for treating or preventing a disease, disorder, or condition associated with an immune abnormality in a subject. The present disclosure also provides preventive and therapeutic methods related to the compositions.

[0132] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be adopted. The same applies to "or." When it is stated in this specification that "within a range of two values," the range includes the two values ​​themselves.

[0133] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0134] The present disclosure has been described above by showing preferred embodiments for ease of understanding. Hereinafter, the present disclosure will be described based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims. [Example]

[0135] Examples are described below. Where necessary, the handling of animals used in the following examples complied with the institutional guidelines of the National Institute of Biomedical Innovation and other relevant ethical standards and guidelines, and was carried out in accordance with the Declaration of Helsinki. While the reagents used were specifically those listed in the examples, equivalent products from other manufacturers (Sigma-Aldrich, Wako Pure Chemical Industries, Nakarai, R&D Systems, USCN Life Science Inc., etc.) can also be used.

[0136] (Manufacturing example) Extract A used in this example was prepared as follows. Mycobacterium tuberculosis strain Aoyama B, which had been freeze-dried and stored at -20°C, was cultured in a soy-based potato medium. (1) This seed culture is then cultured at 37±1°C. (2) The resulting cells were transferred to a 0.45 μm membrane filter and cultured at 37±1°C for 5–7 weeks (main culture). The resulting cells were washed with water for injection, then 20 times the wet cell weight of water for injection was added and heated at 100°C for 120 minutes to obtain an extract. This extract was then filtered through a 0.45 μm membrane filter and concentrated under reduced pressure to a sugar content (D-arabinose equivalent by the phenol-sulfuric acid method) of 4.0–6.0 mg / mL. Next, to remove proteins, 1% w / v sulfosalicylic acid was added to the concentrate, which was then left at or below 10°C for 15–20 minutes. The precipitate was then centrifuged (10°C or below, 1150 × G, 10 minutes), and the supernatant was collected. The protein concentration of the supernatant was 0.30 mg / mL (Lowry method, tyrosine equivalent). The sulfosalicylic acid was then removed until the supernatant was below the detection limit (10 ppm or less, ferric chloride solution method). This solution is concentrated under reduced pressure to a sugar content of 1.8-2.2 mg / mL. Sodium chloride (0.9% w / v) and an equal volume of cold ethanol to the concentrate are added, and the mixture is left at or below 10°C for at least 40 hours. The precipitate (high molecular weight polysaccharides) is then centrifuged (10°C or below, 2040 x G, 10 minutes). Next, a four-fold volume of cold ethanol is added to the supernatant, and the mixture is left at or below 10°C for at least 40 hours. The precipitate is then recovered by centrifugation (10°C or below, 2040 x G, 10 minutes). The precipitate is dissolved in water for injection, the sugar content is adjusted to 1.8-2.2 mg / mL, and the mixture is filtered through a 0.45 μm membrane filter and autoclaved (121°C, 20 minutes) to give Extract A.

[0137] (1): Sauton potato medium Washed potato pieces are immersed in Sauton medium, sterilized at 115°C for 15 minutes, and then used as Sauton potato medium. Sauton's medium L-Asparagine (monohydrate) 4.0g Citric acid (monohydrate) 2.0g Magnesium sulfate (heptahydrate) 0.5g Potassium hydrogen phosphate (anhydrous) 0.5g Ferrous ammonium citrate 0.05g 60mL of glycerin Dissolve the above in water to make 1000 mL. Adjust the pH to 7.0-7.3 with sodium hydroxide solution.

[0138] (2): Production medium L-Asparagine (monohydrate) 4.0g Citric acid (monohydrate) 2.0g Magnesium sulfate (heptahydrate) 0.5g Potassium hydrogen phosphate (anhydrous) 0.5g Ferrous ammonium citrate 0.05g 60mL of glycerin Dissolve the above in water to make 1000 mL and sterilize by high-pressure steam (121°C, 20 minutes). Adjust the pH to 7.0-7.3 with sodium hydroxide solution.

[0139] The physicochemical properties of the obtained Extract A solution were as follows: (1) Appearance Slight yellow clear liquid (2) pH 4.50~5.30 (3) Protein content 3.5% by weight (as amino acids) in the freeze-dried product (4) Nucleic acid content 0.1% by weight in freeze-dried product (5) The main monosaccharides constituting polysaccharides Mannose 43.4% by weight, arabinose 18.2% by weight, glucose 10.4% by weight. (After hydrolysis with 2N trifluoroacetic acid at 100°C for 2 hours, the product was analyzed by liquid chromatography using 2-cyanoacetamide fluorescent derivative. (S.Honda,et al,Anal.Chem.,52,1079(1980))

[0140] Extract A prepared by the method described in the above Preparation Example can be diluted appropriately before use. In the following Examples, it was diluted 1 to 50,000 times to adjust to an appropriate concentration before use.

[0141] Example 1: Verification of the correlation between Mycobacterium tuberculosis infection and memory T cells In this example, the effectiveness of personalized treatment was verified by stimulating patients with a history of BCG vaccination or tuberculosis infection, or healthy individuals with confirmed antigen responsiveness, and analyzing the memory T cell response.

[0142] (method) Frozen human peripheral blood mononuclear cells (PBMCs) were purchased from CTL (USA), washed using CTL anti-aggregate wash (CTL Europe, Germany), and suspended in RPMI 1640 (R10) containing 10% fetal bovine serum (FBS). PBMCs were plated at 1 × 10 in a 96-well plate. 6PBMCs were seeded at a concentration of 1000 cells / well and cultured overnight at 37°C under 5% CO2. PBMCs were then stimulated with Extract A (100 μg / mL), PPD (3 μg / mL), CMV pp65 overlapping peptides (3 μg / mL), or recombinant Mycobacterium tuberculosis (TB) proteins (10 μg / mL each) in each culture. Anti-CD28 (CD28.2), Golgi stop, and Golgi plug antibodies (BD Biosciences) were simultaneously added at 1 μg / mL. PBMCs were harvested 6 hours after stimulation and washed with PBS. PBMCs were then stained with a Live / Dead fixable blue stain kit (Life Technologies), blocked with Human TruStain FcX (Biolegend), and surface stained with the following fluorescently labeled antibodies: anti-CD4 (OKT4), anti-CD8 (RPA-T8), anti-CD45RA (HI100), and anti-CCR7 (G043H). After fixation and permeabilization with BD Cytofix / Cytoperm (BD Biosciences), cells were 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 analyzed by flow cytometry using an LSRII and FlowJo software (BD Biosciences).

[0143] (result) The results are shown in Figure 1. Extract A promoted the secretion of Th1 cytokines (IFN-γ, IL-2, and TNF-α) from memory T cells in human PBMCs. IFN-γ secretion was also induced by stimulation with PPD. A strong positive correlation was observed between Extract A and PPD in human PBMCs. On the other hand, no correlation was observed between Extract A and CMV. Furthermore, MHSP10, one of the antigens contained in Extract A, induced the production of IFN-γ, showing a positive correlation with Extract A. Correlations were also observed between Extract A and PPD, and between Extract A and MHSP10, for the production of IL-2 and TNF-α.

[0144] (Consideration) It was shown that memory T cells that respond to Extract A are present in PBMCs that contain memory T cells that produce Th1 cytokines in response to PPD.

[0145] Example 2: Differences in immune status on the antitumor effect of Extract A In this example, the antitumor effect of Extract A was examined using mice with different immune states.

[0146] (method) (BCG infection model) A 1 mg / mL BCG vaccine solution was prepared by suspending 12 mg of dried BCG vaccine in 12 mL of saline. Mice were infected twice with 100 μL of the vaccine solution via subcutaneous injection into the base of the tail, 5 weeks and 2 weeks before tumor cell implantation.

[0147] (Extract A emulsion immune model) Extract A and Freund's incomplete adjuvant (FIA) were mixed at a 1:1 volume ratio and an Extract A emulsion was prepared using a GP syringe connector (Brightpath Bio) and a Luer-Lok syringe (HENKE SASS WOLF). 100 μL of Extract A emulsion was administered intradermally into the base of the tail of mice using a 1 mL syringe with a 25G needle twice, 4 weeks and 2 weeks before tumor cell implantation. An Extract A emulsion immunization model was established.

[0148] (tumor cell transplantation) B16BL6 cells and B16F10 cells were used as tumor cells. These cells were made dormant about one week before transplantation and passaged twice or more. B16BL6 cells were used at a density of 3 × 10 6 The cells were diluted with PBS to 3.0 × 10 cells / mL and administered to anesthetized naive mice, BCG-infected mice, and the Extract A emulsion immunization model. 5 Extract A was diluted 10-fold with saline and 100 μL per mouse was administered subcutaneously in the right groin using a 1 mL syringe with a 26G needle. Control animals received an equal volume of saline. Extract A was administered subcutaneously every other day from 8 days before transplantation until autopsy.

[0149] From day 6 onwards, the three dimensions of the tumor (width, length and height) were measured using electronic calipers, and the product of these measurements was used to calculate the tumor volume. Statistical analysis was performed using Excel (Microsoft), and a p-value of 0.05 or less was considered significant using a t-test without assuming equal variance.

[0150] (result) When Extract A was administered to naive mice, no antitumor effect was observed against either B16BL6 or B16F10 cells (Fig. 2B and 2E). In contrast, an antitumor effect was observed in mice inoculated with BCG (Fig. 2C and F). Furthermore, administration of Extract A also demonstrated an antitumor effect against both B16BL6 and B16F10 cells in mice immunized with Extract A emulsion (Fig. 2D and G).

[0151] (Consideration) These results demonstrate that the changes induced in mice by BCG infection play an important role in the antitumor effect of Extract A. Furthermore, a similar effect was observed in the Extract A emulsion immunization model, strongly suggesting that the changes are related to adaptive immune responses.

[0152] Example 3: Antitumor effect when a model antigen is administered to an animal having model antigen-specific memory cells In this example, the inhibitory effect of tumor growth after immunization with a model antigen was examined.

[0153] (method) (Tumor growth suppression effect after immunization with a model antigen) For emulsion immunization, 1 / 50th of a 10 mg / mL OVA protein solution was added (final dose: 20 μg) to prepare an emulsion solution, which was then used to immunize mice. Subsequently, 2 μg of ovalbumin was administered instead of Extract A. Other methods were the same as those for the Extract A emulsion model and tumor cell transplantation in Example 2.

[0154] (Tumor growth suppression effect of Th1 transfer) CD4 T cells were isolated from OT-II mice (mice expressing MHC class II-restricted TCR specific to ovalbumin) or OT-II rag1 knockout (KO) mice, and CD11c-positive cells from wild-type mice using a CD4 T cell isolation kit (Miltenyi Biotec) or CD11c beads (Miltenyi Biotec), respectively, using an AutoMACS system according to the respective manufacturer's instructions. 10 CD4 T cells per mL were isolated. 7 1-2 × 10 CD11c-positive cells 6 The solution was prepared in a volume of 10 μg / mL, containing 10 μg / mL of anti-IL-4 antibody, 7.5 ng / mL of IL-12p70, 10 ng / mL of IL-2, and 10 μg / mL of OVA. 323-339 The peptide was added and the cells were cultured. The medium was changed after 3-4 days of culture, and the cells were harvested after 6-7 days. Dead cells were removed by centrifugation using Lymphoryte (Sedarene).

[0155] CD4 T cells derived from OT-II mice differentiated into Th1 cells in vitro were transferred to Rag2KO mice or Rag2 and IL-2 receptor γ chain double KO mice, and ovalbumin was administered 11 or 15 times every other day until the day of sacrifice. B16BL6 cells were transplanted on days 8 or 16 after transplantation of OT-II mouse-derived cells, and the progression of tumor volume was measured over time.

[0156] (result) (Tumor growth suppression effect after immunization with a model antigen) In mice immunized with an emulsion containing ovalbumin, tumor growth was inhibited after administration of ovalbumin (Figure 3-1).

[0157] (Tumor growth suppression effect of ovalbumin administration in ovalbumin-specific Th1-transferred mice) When CD4 T cells were isolated from OT-II mice and differentiated in vitro into Th1 cells, and then transplanted into Rag2 KO mice, administration of ovalbumin suppressed tumor growth (p=0.017, left side of Figure 3-2).Similarly, administration of ovalbumin suppressed tumor growth in Rag2 and IL-2 receptor γ chain double KO mice (p=0.09, right side of Figure 3-2).

[0158] Example 4: Antitumor effects of vaccine preparations containing various adjuvant bases In this example, the antitumor effects of vaccine preparations containing various adjuvant bases were examined.

[0159] (method) Mice were immunized with FIA, K3-SPG, K3-cGAMP, and K3-Alum adjuvants formulated with Extract A. Control mice received PBS, FIA, K3-SPG, and K3-cGAMP adjuvants formulated with saline alone. Each adjuvant was formulated to a final dose of 10 μg K3, 5 μg K3-SPG, and 10 μg 2,3-cGAMP. FIA and alum (alhydrogel, InvivoGen) were administered at 50% or 25%, respectively, in a 100 μL solution. For intradermal administration of Extract A, Extract A was diluted to 1 mg / mL in PBS, and 100 μL was administered intradermally at the base of the tail (id). Thereafter, tumor cells were implanted in the same manner as in (Extract A emulsion immunization model) and (tumor cell implantation) in Example 2, and the weight of the tumor in the mice was measured on the day of dissection.

[0160] (result) The results are shown in Figure 4. It was demonstrated that the antitumor effect of Extract A was exerted when Extract A was administered after treatment with Extract A emulsion or combined treatment of Extract A with a conventional adjuvant.

[0161] Example 5: Evaluation of effects on tumor-infiltrating lymphocytes (TIL) by flow cytometry In this example, the effect of Extract A on tumor-infiltrating lymphocytes (TIL) in transplanted tumors was evaluated by flow cytometry.

[0162] (method) Mice were infected with BCG, and 5 weeks after BCG infection, 2 × 10 5 B16BL6 cells were subcutaneously implanted into mice. Extract A or saline was administered subcutaneously every other day starting 8 days before tumor cell implantation. 14 days after tumor cell implantation, mice were euthanized and tumors were removed. Tumors were dispersed using a tumor dissociation kit (Miltenyi Biotec), followed by density gradient centrifugation to separate tumor cells and lymphocytes. The isolated lymphocytes were washed, then stained for dead cells and Fc receptors were blocked. After staining the cell surface with various fluorescently labeled antibodies, the cells were fixed, permeabilized, and intracellularly stained with fluorescently labeled antibodies.

[0163] (result) The results are shown in Figure 5. Mice that received Extract A after BCG infection had a significantly increased number of T-bet-positive cells in their tumors compared to mice that received saline.

[0164] Example 6: Evaluation of effects on tumor-infiltrating lymphocytes (TIL) by flow cytometry In this example, the effect of Extract A on tumor-infiltrating lymphocytes (TIL) in transplanted tumors was evaluated by flow cytometry.

[0165] (method) BCG-infected mice were administered Extract A or saline, tumor cells were implanted, and tumors were removed using the same method as in Example 5. Tumors were dispersed using a Tumor Dissociation Kit (Miltenyi Biotec), followed by density gradient centrifugation to separate tumor cells and lymphocytes. Each antigen and brefeldin A were added to the culture medium of the separated lymphocytes, and the cells were cultured overnight at 37°C and 5% carbon dioxide. Cells were collected and washed, followed by staining for dead cells and blocking of Fc receptors. After staining the cell surface with various fluorescently labeled antibodies, the cells were fixed and permeabilized, followed by intracellular staining with fluorescently labeled antibodies.

[0166] (result) The results are shown in Figure 6. Mice that received Extract A after BCG infection had a significantly increased number of IFN-γ-expressing T-bet-positive cells in the tumor tissue compared with mice that received saline.

[0167] Example 7: Companion Therapy and Diagnosis Companion therapy and diagnosis can be performed as follows: Obtaining antigen response profiles by non-invasive methods, interviews, medical history from maternal and child health handbooks or equivalents, or vaccination history. - Confirmation of actual responsiveness using an antigen panel and peripheral mononuclear cells isolated from the subject. The antigens or combinations thereof that showed a reaction above are judged as prophylactic or therapeutic drugs and administered.

[0168] Example 8: Identification of cells essential for the antitumor effect of Extract A In this example, the cells essential for the antitumor effect of Extract A were identified.

[0169] (method) (Administration of Extract A to CD4-deficient mice) The administration schedule of BCG, B16BL6 cells, Extract A, anti-CD4 antibody, and anti-IFN-γ antibody is shown in Figure 7A. Specifically, BCG was injected into mice 35 days and 14 days before tumor inoculation, followed by 3.0 × 10 5 B16BL6 melanoma cells were inoculated into the mice. Extract A was administered subcutaneously every other day starting 8 days before tumor inoculation. In experiments to deplete CD4-positive cells, 200 μg of anti-CD4 antibody was intraperitoneally injected 1, 3, 7, and 11 days after tumor inoculation. In experiments to deplete CD8, 200 μg of anti-CD8 antibody was intraperitoneally injected 1, 2, and 3 days before tumor inoculation and 2, 5, 8, and 11 days after tumor inoculation. In experiments to deplete IFN-γ, 200 μg of anti-IFN-γ antibody was intraperitoneally injected immediately before tumor inoculation and 3, 6, 9, and 12 days after tumor inoculation. Naive, CD4-deficient, and MHC class II-deficient mice were used. Control animals received an equivalent volume of saline. Tumor volume was measured using the same method as in Example 2.

[0170] (Measurement of intracellular cytokines) Mice were infected with BCG, and then administered saline or Extract A every other day starting 8 days before sacrifice. Spleens were isolated from the mice, mashed, and centrifuged to obtain a cell pellet. The cell pellet was suspended in Pharm lysis buffer (BD) for 15 minutes, and the cell suspension was centrifuged and suspended in R10. The cell number was counted using a Z1 particle counter (Beckman Coulter) and 2 × 10 cells were collected in R10. 7The cell suspension was adjusted to 100 cells / mL. 100 μL of the cell suspension was dispensed into a 96-well round-bottom microplate (Asahi Technoglass), and the cells were stimulated with 100 μL of R10 containing Extract A. After 30 minutes, Golgi Plug (BD Biosciences) and Golgi Stop (BD Biosciences) were added. Approximately 6 hours later, the cells were harvested and washed with PBS. Cells were stained with a Live / Dead fixable blue stain kit, blocked with anti-mouse CD16 / 32 antibody (Biolegend), and then fixed and permeabilized with BD Cytofix / Cytoperm. Staining was performed with antibodies against IFN-γ (XMG1.2), IL-13 (eBio13A), and IL-17 (TC11-18H10.1). The stained cells were analyzed by flow cytometry using an LSRII and FlowJo software (BD Biosciences).

[0171] (result) (Administration of Extract A to CD4-deficient mice) Administration of Extract A did not show an antitumor effect in mice in which CD4+ cells had been depleted using anti-CD4 antibodies (Fig. 7B). The requirement of CD4 T cells for the antitumor effect of Extract A was also confirmed in experiments using CD4-deficient mice (Fig. 7C) and MHC class II-deficient mice (Fig. 7D). On the other hand, the antitumor effect of Extract A was also observed in mice in which CD8+ cells had been depleted using anti-CD8 antibodies (Fig. 8C) and in Batf3-deficient mice lacking CD8+ DCs (Fig. 8G), demonstrating that CD8+ cells are not essential for the antitumor effect of Extract A.

[0172] (Measurement of intracellular cytokines) Administration of Extract A to BCG-infected mice significantly increased the proportion of IFN-γ-producing memory CD4 T cells. This change was not observed for IL-17 or IL-13 (Fig. 7E). Furthermore, the antitumor effect of Extract A was abolished in mice treated with an IFN-γ neutralizing antibody, suggesting that IFN-γ plays an important role in the antitumor effect of Extract A (Fig. 7F). Furthermore, Extract A-induced IFN-γ secretion from splenocytes of BCG-infected mice was also abolished in CD4-deficient and MHC class II-deficient mice (Fig. 7G). On the other hand, IFN-γ production was maintained in CD1d1-deficient mice (Fig. 7H). Furthermore, splenic IFN-γ secretion in response to Extract A was completely abolished when CD4+ cells were removed from splenocytes (Fig. 7I). These results suggested that CD4 T cells were transformed into Th1 cells and that these cells were the major source of Extract A-induced IFN-γ secretion in BCG-infected mice.

[0173] Example 9: Experiments in a subcutaneous injection model In this example, an analysis of the antitumor effect in a subcutaneous injection experimental model is shown.

[0174] (method) The schedule for the intratumoral injection experiment is shown in Figure 8A. Specifically, BCG was administered to Rag2-deficient, CD1d1-deficient, FcR-deficient, IL12p40-deficient, and Batf3-deficient mice 35 and 14 days before tumor cell inoculation, and Extract A was administered subcutaneously every other day starting 8 days before tumor inoculation. In the experiment corresponding to Figure 8C, anti-CD8 antibody was administered 3, 2, 1, 3, 7, and 11 days before tumor inoculation. In the experiment corresponding to Figure 8E, anti-NK1.1 antibody was administered 1, 3, 7, and 11 days after tumor inoculation. Tumor volume was then measured according to the method described in Example 2.

[0175] (result) In BCG-infected Rag2-deficient mice, the antitumor effect of Extract A was not observed (Figure 8B). In mice depleted of CD8+ cells, the antitumor effect of Extract A was observed (Figure 8C). Furthermore, antitumor activity was observed in Batf3-deficient mice (Figure 8G), indicating that CD8+ cells are not essential for antitumor activity. Furthermore, the antitumor activity of Extract A was maintained in FcR-deficient mice and mice depleted of NK1.1+ cells, indicating that ADCC activity is not essential for the antitumor effect of Extract A (Figures 8D and 8E). To further examine the contribution of NKT cells, we also evaluated Extract A in CD1d1-deficient mice, and the antitumor effect of Extract A was also observed in these mice (Figure 8D). Therefore, it was confirmed that CD4 T cells are essential for the antitumor effect of Extract A, but CD8 T cells, NKT cells, and ADCC activity are not.

[0176] Example 10: Experiment in which pre-immunized mice were injected with non-tumor-associated proteins In this example, the antitumor effect of administering non-tumor-associated proteins contained in Extract A to BCG-infected mice is demonstrated.

[0177] (method) (Protease treatment of Extract A) The proteases used were EDTA-0.5% trypsin solution (Nacalai Tesque) and subtilisin (P5380) (Sigma-Aldrich). These proteases were heat-inactivated (HI) by incubation at 96°C for 15 minutes. The HI-treated or non-HI-treated proteases were mixed with Extract A and incubated for 16 hours. The solutions were then incubated at 96°C for 15 minutes to inactivate the active enzyme.

[0178] (IFN-γ secretion and antitumor activity by protease-treated Extract A) In BCG-infected mice, IFN-γ secretion from splenocytes was induced by saline, Extract A, subtilisin-treated Extract A (Sub), heat-inactivated subtilisin-treated Extract A (HI-Sub), trypsin-treated Extract A (Trp), or heat-inactivated trypsin-treated Extract A (HI-Trp). Each protease was used at four concentrations. The amount of IFN-γ secreted by each stimulation was divided by the amount of IFN-γ secreted by Extract A stimulation.

[0179] (Antitumor activity of LpqH) BCG-infected mice were subcutaneously administered Extract A every other day starting 8 days before tumor cell implantation. 14 days after tumor cell implantation, mice were euthanized and tumors were removed. Tumor fragments were digested using a Tumor Dissociation Kit (Miltenyi Biotec). After digestion, tumor fragments were crushed using a 70 μm mesh. Density gradient centrifugation using Lympholyte-M (Sedarene) was performed to remove tumor cells, red blood cells, and dead cells. The interphase was collected and used as TILs. LpqH (10 μg / mL) was then added, along with Golgi Plug and Golgi Stop. After 10 hours, cells were harvested and washed with PBS. Cells were stained with a Live / Dead fixable blue stain kit, blocked with anti-mouse CD16 / 32 antibody (Biolegend), fixed, and permeabilized with BD Cytofix / Cytoperm. Staining was performed using an antibody against IFN-γ (XMG1.2), and the stained cells were subjected to flow cytometry analysis using LSRII and FlowJo software (BD Biosciences). Naive mice and BCG-infected mice were subcutaneously administered saline, 0.1 μg of LpqH, or 1 μg of LpqH every other day starting 8 days before tumor inoculation. Tumor volumes were then measured using electronic calipers according to the method described in Example 2.

[0180] (result) Unlike heat-inactivated protease treatment, protease treatment tended to reduce the IFN-γ secretion activity of Extract A (Fig. 9A). Mass spectrometry analysis of the treated Extract A identified at least two proteins, MTB12 and LpqH. Stimulation of BCG-infected mice with LpqH induced IFN-γ secretion (Fig. 9B). Injection of recombinant LpqH protein produced an antitumor effect in BCG-infected mice similar to the antitumor effect of Extract A (Fig. 9C). In contrast, injection of LpqH protein did not produce an antitumor effect in naive mice (Fig. 9C). These results suggest that antigen injection into BCG-infected mice can suppress tumor growth and that one of the active components of Extract A is a protein.

[0181] Example 11: Analysis of the correlation between the antitumor effect of Extract A and tumor-infiltrating lymphocytes In this example, the tumor microenvironment after administration of Extract A was investigated and its correlation with tumor-infiltrating lymphocytes was analyzed.

[0182] (method) (Isolation of TIL (tumor infiltrating lymphocytes)) BCG-infected mice were subcutaneously administered Extract A every other day starting 8 days before tumor cell implantation. 14 days after tumor cell implantation, mice were euthanized and tumors were removed. Tumor fragments were digested using a Tumor Dissociation Kit (Miltenyi Biotec). After digestion, tumor fragments were crushed using a 70-μm mesh. Density gradient centrifugation using Lympholyte-M (Sedarene) was performed to remove tumor cells, red blood cells, and dead cells. The interphase was collected and used as TILs. TILs were stained with anti-CD45 (30-F11, BD), anti-CD62L (MEL-14, BD), anti-FOXP3 (FJK-16S, ebioscience), and anti-T-bet (4B10, Biolegend). Antibodies against FOXP3 and T-bet were stained after permeabilization with BD Pharmingen Transcription Factor buffer (BD). Stained cells were analyzed using an LSRII (BD) and FlowJo software.

[0183] (result) Administration of Extract A to BCG-infected mice significantly increased the number of CD3+CD45+ cells in the tumor microenvironment, and a significant negative correlation was found between tumor weight and tumor-infiltrating CD3+CD45+ cells (Fig. 10A). In BCG-infected mice, a positive correlation was observed between tumor weight and the number of TILs (Fig. 10B). Furthermore, when we investigated the cells that increased in the tumor microenvironment, we found an increase in the ratio of CD4+ cells to CD3+CD45+ cells, but no change was observed in the ratio of CD8+ cells to CD3+CD45+ cells (Fig. 10C). Furthermore, focusing on the phenotype of CD4+ T cells, we measured the number of T-bet+ and Foxp3+ cells and found a significant increase in the number of T-bet+ cells. The proportions of T-bet+Foxp3-negative cells and T-bet+CD4+ T cells were increased in the tumor microenvironment, and a significant negative correlation was observed between tumor weight and the number of tumor-infiltrating T-bet+CD4+ cells (Figure 10E).

[0184] Example 12: Analysis of the correlation between the antitumor effect of Extract A and IFN-γ-producing TILs In this example, the correlation between the antitumor effect of Extract A and TILs producing IFN-γ was analyzed.

[0185] (method) Intracellular IFN-γ was measured with or without stimulation with Extract A according to the experimental procedure described in Figure 11A. Isolated TILs were seeded onto culture plates, and antigen and protein transport inhibitors were added. After overnight culture, TILs were collected and analyzed by FACS.

[0186] (result) CD4+ memory T cells producing IFN-γ were detected without stimulation and were shown to be induced in an Extract A antigen-independent manner (Figures 11B and 11D). Under these experimental conditions, tumor-derived cells and their debris were preferably contained in the culture medium, allowing for the detection of T cell responses to tumor antigens. Furthermore, CD4+ T cells capable of producing IFN-γ in response to Extract A and LpqH were found to be present in the tumor tissues of BCG-infected and Extract A-immunized mice (Figures 11C, 11E, and 11F).

[0187] Example 13: Antitumor effect of influenza vaccine In this example, the antitumor effect of influenza vaccines was examined depending on the immune status.

[0188] (method) (PR8 infection model) Influenza virus PR8 was suspended in PBS at 10 pfu / mL to prepare a virus solution. Mice were infected by intranasal administration of 30 μL of the virus solution to create a PR8 infection model. Virus infection was performed under anesthesia.

[0189] (Administration of influenza vaccine) The influenza vaccine was adjusted to 1 μg / mL with physiological saline, and 100 μL was administered subcutaneously to the right groin of each mouse.

[0190] (result) Influenza vaccine administered to naive mice did not have an antitumor effect on the transplanted B16BL6 cells (Fig. 12B), whereas influenza vaccine administered to influenza-infected mice had an antitumor effect (Fig. 12C).

[0191] (Consideration) The changes induced in mice by influenza virus infection were observed when a vaccine containing influenza virus antigens was administered, suggesting that adaptive immunity against non-tumor antigens contributes to anti-tumor effects. Even when infected with pathogenic microorganisms other than tuberculosis, adaptive immunity induced by various infections, including those involving the pathogen, may exert anti-tumor effects when exposed to the same pathogen antigens again.

[0192] Example 14: Prevention, prevention of recurrence, and treatment of cancer In this example, a clinical trial for cancer prevention, recurrence prevention, and / or treatment is conducted.

[0193] (method) (Identification of non-tumor antigens) For the protocol of this example, see Figure 13A. Peripheral blood mononuclear cells (PBMCs) are isolated from cancer remission and / or post-surgical subjects, as well as from normal subjects. The subjects' vaccination and / or infection histories are examined to identify antigen response profiles. Vaccination and infection history may include, but is not limited to, tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile virus, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza (virus), MERS, rabies, diphtheria, etc. The above-isolated PBMCs (e.g., 1.0 x 10 4 ~1.0×10 6 Cells) are stimulated with the non-tumor antigen (0.01 μg / mL to 1 mg / mL) or an extract containing the non-tumor antigen (0.01 μg / mL to 1 mg / mL) for approximately 6 to 24 hours, and cytokine production (e.g., IFN-γ, IL-2, and / or TNF-α) is measured using a detection method commonly used in the art (e.g., ELISA, qPCR, and / or FACS). Subjects whose cytokine production after stimulation is at least twice the amount before stimulation are selected as responders.

[0194] (Administration of non-tumor antigens) The identified non-tumor antigens will be administered according to the following dosing regimen and clinical efficacy will be assessed. Group composition: Placebo or non-tumor antigen (approximately 0.001 μg / single dose to approximately 1 mg / single dose) or two doses of extract containing non-tumor antigen (approximately 0.001 μg / single dose to approximately 1 mg / single dose in terms of non-tumor antigen) Number of subjects: Approximately 100 Route of administration: SC (subcutaneous) or IT (intratumoral) Dosage frequency: Approximately once a day (first week), and approximately once a week (second week and onward) Administration period: Approximately 3 months to 1 year Primary endpoints: progression-free survival (PFS) and overall survival (OS) Secondary endpoints: duration of response, disease control rate, and safety.

[0195] (result) For both the primary and secondary endpoints, the group administered with the non-tumor antigen showed a significant effect compared to the placebo, and examples of effect could be observed within the dose range tested.

[0196] Example 15: Prevention of cancer recurrence In this example, a clinical trial is conducted to prevent cancer recurrence in cancer patients.

[0197] (method) (Identification of non-tumor antigens) See Figure 13B for protocol. Tumor masses are isolated from postoperative cancer patients. In this example, immune cells infiltrated into the tumor mass are analyzed to determine the patient's vaccination and / or infection history, thereby identifying an antigen response profile. Vaccination and infection histories may include, but are not limited to, tuberculosis, malaria, yellow fever virus, smallpox virus, vaccination, measles / rubella, polio, mumps / MUMPS, rotavirus infection, chickenpox, yellow fever, Ebola, West Nile virus, Hib infection, pneumococcal infection, pertussis, Japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E. coli, toxoplasmosis, Zika virus, herpesvirus type 1, EBV / Epstein-Barr virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza (virus), MERS, rabies, diphtheria, etc. The above tumor-infiltrating immune cells (1.0 × 10 4 ~1.0×10 6The cells / samples are stimulated with the non-tumor antigen (0.01 μg / mL to 1 mg / mL) or an extract containing the non-tumor antigen (0.01 μg / mL to 1 mg / mL) for approximately 6 to 24 hours, and cytokine production (e.g., IFN-γ, IL-2, and / or TNF-α) is measured using a detection method commonly used in the art (e.g., ELISA, qPCR, and / or FACS). Subjects whose cytokine production after stimulation is at least twice the amount before stimulation are selected as responders.

[0198] (Administration of non-tumor antigens) The identified non-tumor antigens will be administered according to the following dosing regimen and clinical efficacy will be assessed. Group composition: Placebo or non-tumor antigen (approximately 0.001 μg / single dose to approximately 1 mg / single dose) or two doses of extract containing non-tumor antigen (approximately 0.001 μg / single dose to approximately 1 mg / single dose in terms of non-tumor antigen) Number of subjects: Approximately 100 Route of administration: SC (subcutaneous) or IT (intratumoral) Dosage frequency: Approximately once a day (first week), and approximately once a week (second week and onward) Administration period: Approximately 3 months to 1 year Primary endpoints: progression-free survival (PFS) and overall survival (OS) Secondary endpoints: duration of response, disease control rate, and safety.

[0199] (result) For both the primary and secondary endpoints, the group administered with the non-tumor antigen showed a significant effect compared to the placebo, and examples of effect could be observed within the dose range tested.

[0200] (Note) While the present disclosure has been illustrated using preferred embodiments thereof, it is understood that the scope of the present disclosure should be construed solely in terms of the claims. It is understood that the patents, patent applications, and other documents cited herein are incorporated by reference into this specification as if the contents themselves were specifically set forth herein. This application claims priority to Patent Application No. 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 PCT Application No. 108144810 filed with the Taiwan Intellectual Property Office on December 6, 2019, the contents of which are incorporated by reference into this specification in their entirety. [Industrial Applicability]

[0201] The present disclosure provides novel mechanism-based methods for the prevention and treatment of diseases such as cancer.

Claims

[Claim 1] A composition for activating, against a target, regulatory T cells (Tregs) that have immunological memory to the non-target antigen component and that are suppressed in a subject, the composition comprising a non-target antigen component.

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