WO2021029424A1 - 免疫記憶に基づく新規疾患治療および予防 - Google Patents

免疫記憶に基づく新規疾患治療および予防 Download PDF

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WO2021029424A1
WO2021029424A1 PCT/JP2020/030710 JP2020030710W WO2021029424A1 WO 2021029424 A1 WO2021029424 A1 WO 2021029424A1 JP 2020030710 W JP2020030710 W JP 2020030710W WO 2021029424 A1 WO2021029424 A1 WO 2021029424A1
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antigen
subject
cells
component
history
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English (en)
French (fr)
Japanese (ja)
Inventor
石井　健
小林　伸好
裕太 大平
孝一 瀬戸
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Zeria Pharmaceutical Co Ltd
National Institutes of Biomedical Innovation Health and Nutrition
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Zeria Pharmaceutical Co Ltd
National Institutes of Biomedical Innovation Health and Nutrition
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Priority to EP20851845.6A priority Critical patent/EP4014988A4/en
Priority to US17/634,526 priority patent/US20220401545A1/en
Priority to CN202080071453.7A priority patent/CN114641309A/zh
Priority to JP2021539308A priority patent/JPWO2021029424A1/ja
Publication of WO2021029424A1 publication Critical patent/WO2021029424A1/ja
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Priority to JP2025111120A priority patent/JP2025138799A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • This disclosure relates to the treatment and prevention of new diseases based on immune memory, and in one aspect, the prevention and treatment of cancer based on the mechanism.
  • Specific examples relate to cancer therapies and prophylaxis using memory responses by non-tumor antigens from pathogens of pre-existing infectious diseases such as M. tuberculosis extracts as personalized markers.
  • the technology for the treatment of diseases has been developed by various methods.
  • cancer immunotherapy can be broadly divided into the following three types.
  • a therapeutic method for transferring a cancer-specific antigen (WT1 or cancer-specific neoantigen) together with an adjuvant base a treatment method for transferring a cancer antigen-dependent chimeric T cell, or a treatment method for transferring an antigen-presenting cell (DC). ..
  • WT1 or cancer-specific neoantigen a cancer-specific antigen
  • DC antigen-presenting cell
  • Immune checkpoint molecules are molecules that control T cell responses in vivo.
  • Checkpoint molecule inhibitors inhibit immunosuppressive molecules expressed in host cancer cells and regulatory T cells to promote anti-tumor immunity.
  • these drugs show useful effects, they also release the immune response that should be suppressed, so that there is a problem that side effects are strong, such as an increased risk of developing an autoimmune disease. Therefore, it is not suitable for preventive treatment for healthy people.
  • side effects are strong, such as an increased risk of developing an autoimmune disease. Therefore, it is not suitable for preventive treatment for healthy people.
  • a vaccine that prevents carcinogenesis by preventing infection. It has vaccines aimed at preventing HPV infections associated with cervical cancer, but the target cancers are limited.
  • the present disclosure provides mechanism-based cancer prevention and treatment.
  • Typical examples thereof include cancer treatment methods and preventive methods using a memory response by a non-tumor antigen from a pathogen of a past infectious disease such as an extract of Mycobacterium tuberculosis as an individualized marker.
  • (Item 1) A composition for activating regulatory T cells (Tregs) containing an antigen component other than the target and having immunological memory in the non-target antigen component, which is suppressed in the subject, against the target.
  • (Item 2) The composition according to any one of the above items, wherein activation of the Treg imparts a killing ability to the target or an immunostimulatory effect to the target.
  • (Item 3) A composition for activating regulatory T cells (Treg) containing a non-tumor antigen component and being suppressed in a subject and having immunological memory in the non-tumor antigen component.
  • the antigen component contains a protein.
  • the antigen component is described in any of the above items, including an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a history, and an antigen related to a vaccination history. Composition.
  • composition according to any one of the above items, wherein the antigen component contains a human tubercle bacillus hot water extract or an influenza virus antigen.
  • composition according to any one of the above items, further comprising one or more of the features described in any one or more of the following items.
  • Item 10 To examine whether the antigen component has Treg immune memory in the subject, and if the subject has immune memory to the antigen component, the antigen component is administered to the subject.
  • a composition characterized in that it is used in a method comprising.
  • the disease, disorder or symptom includes cancer, preferably the antigen component is a non-tumor antigen component.
  • the antigen component is specific to the memory T cells of the subject.
  • the memory T cell is a memory type regulatory T cell (IL-2 producing).
  • (Item 15) The composition according to any one of the above items, wherein the antigen component has an immunostimulatory effect.
  • (Item 16) The composition 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 17) The composition according to any one of the above items, wherein the antigen component has an activity of biasing the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells.
  • the bias is to increase IFN- ⁇ -producing T cells as compared to Foxp3-positive Treg cells.
  • the specific antigen component enhances at least one selected from the group consisting of IFN- ⁇ producing ability, IL-2 producing ability, and TNF- ⁇ producing ability in the sample derived from the subject.
  • a biomarker comprising at least one selected from the group consisting of varying TNF- ⁇ producing capacity.
  • a composition or kit comprising an agent or means for detecting a biomarker for determining whether or not a non-tumor antigen component has an anticancer effect on a subject, the biomarker. (Ii) whether the non-tumor antigen component acts antigen-dependently on memory CD4-positive T cells, (ii) changes memory-type regulatory T cells, or (iii) changes IFN- ⁇ production ability.
  • a composition or kit comprising at least one selected from the group consisting of, (iv) varying IL-2 producing ability, and (v) varying TNF- ⁇ producing ability.
  • the (non-tumor) antigen component comprises an antigen related to a medical history or a vaccination history.
  • the antigen component contains an antigen for the infectious disease.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed hemorrhoids, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gifteria.
  • composition described in Crab. (Item 30) The composition according to any one of the above items, wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to tubercle bacilli, and the antigen component contains a human tubercle bacillus hot water extract. Stuff. (Item 31) The composition according to any one of the above items, wherein the subject is a subject having a history of influenza vaccination, a history of influenza infection, or an antigen responsiveness to influenza virus, and the antigen component contains influenza virus. (Item 32) The composition according to any one of the above items, wherein the disease, disorder or symptom comprises melanoma.
  • the antigen component includes one capable of eliciting an immune response via CD4 positive T cells.
  • Item 35 When it is confirmed whether the subject can elicit an anti-tumor immune response mediated by CD4 positive T cells and the subject can elicit an anti-tumor immune response mediated by CD4 positive T cells. , The composition according to any one of the above items, wherein the composition is administered.
  • a composition for treating or preventing a disease, disorder or symptom related to a subject's immune abnormality wherein the composition is for a component different from the causative factor of the disease, disorder or symptom.
  • the disease, disorder or symptom includes melanoma and
  • the antigen component is a protein or a part thereof or a peptide, and can elicit an immune response via CD4-positive T cells.
  • the cancers include those that can be treated or prevented by an immune response mediated by CD4 positive T cells.
  • composition for treating or preventing cancer or tumor in a subject, wherein the composition comprises a non-tumor antigen component, and the non-tumor antigen component is suppressed in the subject.
  • a composition that activates regulatory T cells (Tregs) that have immunological memory in the non-tumor antigen, and the Treg has a regulatory activity or an antitumor immune effect promoting effect on cancer or tumor.
  • (Item 38) A method of producing or otherwise providing a composition for preventing or treating a subject's cancer, wherein the method is: A) A step of identifying a non-tumor antigen specific to the subject, and B) A step of identifying whether or not the non-tumor antigen has immune memory in the subject and selecting one having the immune memory. C) With the step of producing or otherwise providing the selected non-tumor antigen.
  • a method that includes. (Item 39) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item 40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, wherein the method is: B) A step of identifying whether the non-tumor antigen has immune memory in the subject. A step that, if present, is identified as being able to prevent or treat cancer in the subject. A method that includes. (Item 41) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item 42) a) A step of obtaining an antigen-responsive profile of a subject and b) In the step of identifying the antigen component or the combination of the antigen components from the antigen responsiveness profile, the antigen component or the combination of the antigen components is such that the subject is immune responsive to the antigen component or the antigen component. And the process identified based on the present or past presentation, c) A step of administering the antigen component or a combination of the antigen components identified in the step b) to the subject in an amount sufficient to elicit an immune response in the subject.
  • Methods for the prevention or treatment of diseases, disorders or symptoms associated with immune disorders including.
  • Obtaining the antigen responsive profile is to confirm the subject's past physical condition and to confirm whether one or more antigen candidates are responsive in a sample derived from the subject, or The method according to any of the above items, comprising both of them.
  • the method according to any one of the above items, wherein obtaining the antigen-responsive profile includes identifying an antigen component or a combination of antigen components that elicit an immune response via CD4 positive T cells.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to produce cytokines.
  • the method according to any of the above items which also comprises measuring other biomarkers.
  • the method according to any one of the above items further comprising a step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • the steps a) and b) are as follows.
  • infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to tubercle bacilli, and the antigen component or a combination of the antigen components includes a human tuberculosis bacterium hot water extract, any of the above items.
  • the method described. (Item 53) The method according to any one of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection, or antigen responsiveness to influenza virus, and the antigen component or combination of antigen components includes influenza virus.
  • the administration includes subcutaneous administration or intradermal administration.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production or a plurality of these cytokines at the same time.
  • the method described in. (Item 59) The method according to any one of the above items, wherein the antigen-responsive profile is obtained by pre-diagnosing a companion based on a medical history and a vaccination history.
  • the past physical condition and the antigen component or the combination of the antigen components are a history of tuberculosis infection and a human tuberculosis hot water extract.
  • the past physical condition and the antigen component or the combination of the antigen components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, varicella, measles / wind rash, polio, mumps / Mumps, rotavirus infection, varicella, yellow fever, Ebola, western Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenicity
  • One or more selected from Escherichia coli, Toxoplasma, Dicavirus, Herpesvirus 1, EBV / Epstein-Barvirus (Herpesvirus 4), CMV / Cytomegalovirus (Herpesvirus 5), Influenza, MARS, Mad Dog Disease, Zifteria The method according to any one of the
  • the subject is a subject whose history of BCG vaccination, history of tuberculosis infection, or antigen responsiveness has been confirmed.
  • the tubercle bacillus extract is prophylactically administered before the onset or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract from M. tuberculosis is administered subcutaneously or intradermally by a conventional method. The method according to any one of the above items, which is characteristic.
  • the subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed.
  • the influenza vaccine may be administered prophylactically before the onset, prophylactically or in the early stage of cancer onset after treatment, and subcutaneously or intradermally administered with the influenza vaccine in the early stage or precancerous state of cancer.
  • the method according to any one of the above items, which is characteristic.
  • (Item 65) A method for preventing or treating cancer immunity based on any of the above items, which comprises re-inoculating the antigen component or a combination of the antigen components.
  • (Item 66) A method for preventing or treating a subject's cancer with a non-tumor component, wherein the component is identified by interview and / or an antigen identified with reference to the subject's history and vaccination history.
  • the subject is a person with a history of infection or vaccination described in any of the above items
  • the component is a preventive measure against recurrence after treatment and prevention before the onset of the subject.
  • a method comprising a specific administration or administration in the early stage of cancer onset, and, if necessary, administration of the component in the early stage of cancer onset or in a precancerous state.
  • the cancer normal carcinoma, relatively slow-growing carcinoma, those having low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • the identification of the responsiveness includes a history of pre-infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines produced at the same time.
  • the method according to any of the above items which comprises measuring the induction of cells.
  • the tubercle bacillus extract is a hot water extract of human Mycobacterium tuberculosis or an extract from another tubercle bacillus (highly safe extract).
  • (Item 71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or an extract (highly safe extract) from another influenza virus.
  • the antigen component is a protein.
  • (Item 73) A vaccine preparation containing the antigen according to any one of the above items and an adjuvant base.
  • (Item 75) The vaccine preparation according to any one of the above items, wherein the vaccine preparation is used for personalized medicine.
  • compositions for treating or preventing a disease, disorder or symptom associated with a subject's immune abnormality wherein the composition is for a component different from the causative factor of the disease, disorder or symptom.
  • a composition comprising a specific antigenic component in the subject, which is subcutaneously or intratumorally administered once a day (1st week) and once a week (after the 2nd week).
  • the composition according to any one of the above items, wherein the antigen component is contained in an amount of about 0.001 ⁇ g or more per unit preparation.
  • Item 78 A method for treating or preventing cancer or tumor in a subject.
  • a step of identifying a non-tumor antigen specific to the subject based on the antigenic response profile and b) A step of identifying whether the subject has an immune memory against the non-tumor antigen and identifying a subject having the immune memory.
  • infiltrating immune cells isolated from peripheral blood mononuclear cells (PBMC) isolated from the subject or tumor mass are stimulated with the non-tumor antigen.
  • PBMC peripheral blood mononuclear cells
  • the non-tumor antigen is administered once a day (1st week) and once a week (after the 2nd week).
  • compositions comprising mHSP10 and / or MTB12 and / or lipoprotein LpqH for treating or preventing a disease, disorder or symptom associated with a subject's immune disorder.
  • compositions comprising mHSP10 and / or MTB12 and / or lipoprotein LpqH for treating or preventing a disease, disorder or symptom associated with a subject's immune disorder.
  • (Item A1) A method for activating regulatory T cells (Tregs) having immune memory in an antigen component other than the target, which is suppressed in the subject, against the target, and the subject is subjected to other than the target.
  • a method comprising the step of administering an effective amount of an antigenic component.
  • (Item A2) The method according to any one of the above items, wherein activation of the Treg imparts a killing ability to the target or an immunostimulatory effect to the target.
  • (Item A3) A method for activating regulatory T cells (Tregs) having immune memory in a non-tumor antigen component, which is suppressed in a subject, and the subject is given an effective amount of the non-tumor antigen component.
  • a method comprising the step of administering.
  • the Treg is a memory T cell.
  • the Treg is CD4 positive.
  • the antigen component contains a protein.
  • the antigen component includes an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a history, and an antigen related to a vaccination history. the method of.
  • the antigen component comprises a human tubercle bacillus hot water extract or an influenza virus antigen.
  • IFN- ⁇ -producing T cells are T-bet-positive Th1 cells.
  • the specific antigen component enhances at least one selected from the group consisting of IFN- ⁇ producing ability, IL-2 producing ability, and TNF- ⁇ producing ability in the sample derived from the subject.
  • the antigen component is a protein.
  • (Item A25) A method for determining whether or not a non-tumor antigen component has an anticancer effect on a subject, and the antigen component (i) acts antigen-dependently on memory CD4 positive T cells. Whether (iii) memory-type regulatory T cells are altered, (iii) IFN- ⁇ production ability is altered, and (iv) IL-2 production ability is altered, or (v) TNF- A method comprising varying the ⁇ -producing ability or determining by a biomarker comprising at least one selected from the group consisting of.
  • (Item A26) A method for detecting a biomarker for determining whether or not a non-tumor antigen component has an anticancer effect on a subject, wherein the biomarker is a non-tumor antigen component ( i) Whether it acts antigen-dependently on memory CD4-positive T cells, (ii) fluctuates memory-type regulatory T cells, (iii) fluctuates IFN- ⁇ production ability, or (iv) IL- 2 A method comprising at least one selected from the group consisting of varying production capacity and (v) varying TNF- ⁇ production capacity.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gifteria.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps
  • the method described in Crab. (Item A30) The method according to any one of the above items, wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to tubercle bacilli, and the antigen component comprises a human tubercle bacillus hot water extract. .. (Item A31) The method according to any one of the above items, wherein the subject is a subject having a history of influenza vaccination, a history of influenza infection, or an antigen responsiveness to influenza virus, and the antigen component contains influenza virus. (Item A32) The method according to any of the above items, wherein the disease, disorder or symptom comprises melanoma.
  • (Item A33) The method according to any one of the above items, wherein the antigen component comprises a protein, a part thereof or a peptide.
  • (Item A34) The method according to any of the above items, wherein the antigen component can elicit an immune response via CD4 positive T cells.
  • (Item A35) When it is confirmed whether the subject can elicit an anti-tumor immune response mediated by CD4 positive T cells, and the subject can elicit an anti-tumor immune response mediated by CD4 positive T cells. , The method of any of the above items, wherein the composition is administered.
  • the disease, disorder or symptom includes melanoma and
  • the antigen component is a protein or a part thereof or a peptide, and can elicit an immune response via CD4-positive T cells.
  • the cancers include those that can be treated or prevented by an immune response mediated by CD4 positive T cells.
  • the antigen component is administered, Method.
  • Method. A method for treating or preventing cancer or tumor in a subject, comprising the step of administering an effective amount of the non-tumor antigen component, the non-tumor antigen component being suppressed in the subject.
  • (Item A38) A method of producing or otherwise providing a composition for preventing or treating a subject's cancer, wherein the method is: A) A step of identifying a non-tumor antigen specific to the subject, and B) A step of identifying whether or not the non-tumor antigen has immune memory in the subject and selecting one having the immune memory. C) With the step of producing or otherwise providing the selected non-tumor antigen.
  • a method that includes. (Item A39) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item A40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, wherein the method is: B) A step of identifying whether the non-tumor antigen has immune memory in the subject. A step that, if present, is identified as being able to prevent or treat cancer in the subject. A method that includes. (Item A41) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item A42) a) A step of obtaining an antigen-responsive profile of a subject and b) In the step of identifying the antigen component or the combination of the antigen components from the antigen responsiveness profile, the antigen component or the combination of the antigen components is such that the subject is immune responsive to the antigen component or the antigen component. And the process identified based on the present or past presentation, c) A step of administering the antigen component or a combination of the antigen components identified in the step b) to the subject in an amount sufficient to elicit an immune response in the subject.
  • Methods for the prevention or treatment of diseases, disorders or symptoms associated with immune disorders including.
  • Obtaining the antigen responsive profile is to confirm the subject's past physical condition and to confirm whether one or more antigen candidates are responsive in a sample derived from the subject, or The method according to any of the above items, comprising both of them.
  • the method according to any one of the above items, wherein obtaining the antigen responsive profile includes identifying an antigen component or a combination of antigen components that elicit an immune response via CD4 positive T cells.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to produce cytokines.
  • the method according to any of the above items which also comprises measuring other biomarkers.
  • the method according to any one of the above items further comprising a step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • the steps a) and b) are as follows.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • the physical condition includes a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tubercle bacilli, and the antigen component or a combination of the antigen components includes a human tuberculosis bacterium hot water extract, any of the above items.
  • the method described. (Item A53) The method according to any one of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection or antigen responsiveness to influenza virus, and the antigen component or a combination of antigen components includes influenza virus.
  • the administration includes subcutaneous administration or intradermal administration.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production or a plurality of these cytokines at the same time.
  • the method described in. (Item A59) The method according to any one of the above items, wherein the antigen-responsive profile is obtained by pre-diagnosing a companion based on a medical history and a vaccination history. (Item A60) The method according to any one of the above items, wherein the past physical condition and the antigen component or a combination of the antigen components are a history of tuberculosis infection and a human tuberculosis hot water extract.
  • the past physical condition and the antigen component or the combination of the antigen components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / Mumps, rotavirus infection, varicella, yellow fever, Ebola, western Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenicity
  • One or more selected from Escherichia coli, Toxoplasma, Dicavirus, Herpesvirus 1, EBV / Epstein-Barvirus (Herpesvirus 4), CMV / Cytomegalovirus (Herpesvirus 5), Influenza, MARS, Mad Dog Disease, Zifteria The method according to any one of the
  • the subject was a subject whose history of BCG vaccination, history of tuberculosis infection, or antigen responsiveness could be confirmed.
  • the tubercle bacillus extract is prophylactically administered before the onset or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract from M. tuberculosis is administered subcutaneously or intradermally by a conventional method. The method according to any one of the above items, which is characteristic.
  • the subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed.
  • the influenza vaccine may be administered prophylactically before the onset, prophylactically or in the early stage of cancer onset after treatment, and subcutaneously or intradermally administered with the influenza vaccine in the early stage or precancerous state of cancer.
  • the method according to any one of the above items, which is characteristic.
  • (Item A65) A method for preventing or treating cancer immunity based on any of the above items, which comprises re-inoculating the antigen component or a combination of the antigen components.
  • (Item A66) A method for preventing or treating a subject's cancer with a non-tumor component, the component being identified by interview and / or an antigen identified with reference to the subject's history and vaccination history.
  • the subject is a person with a history of infection or vaccination described in any of the above items, and the method is such that the subject is prevented from recurrence after treatment and before the onset of the disease.
  • a method comprising prophylactic administration or administration of an effective amount of the component in the early stage of cancer onset, and optionally administration of an effective amount of the component in the early stage of cancer onset or precancerous state.
  • the cancer normal carcinoma, relatively slow-growing carcinoma, those having low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • the identification of responsiveness includes a history of infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines simultaneously produced.
  • the method according to any of the above items which comprises measuring the induction of cells.
  • the tubercle bacillus extract is a hot water extract of human Mycobacterium tuberculosis or an extract from another tubercle bacillus (highly safe extract).
  • (Item A76) A method for treating or preventing a disease, disorder or symptom related to a subject's immune abnormality, which is specific to the subject for a component different from the causative factor of the disease, disorder or symptom.
  • a method comprising the step of subcutaneously or intratumorally administering an effective amount of an antigenic component once a day (1st week) and once a week (after the 2nd week).
  • the antigen component is contained in an amount of about 0.001 ⁇ g or more per unit preparation.
  • (Item A78) A method for treating or preventing cancer or tumor in a subject.
  • a step of identifying a non-tumor antigen specific to the subject based on the antigenic response profile and b) A step of identifying whether the subject has an immune memory against the non-tumor antigen and identifying a subject having the immune memory.
  • a method that includes. (Item A79) The method according to any of the above items, wherein the antigenic response profile includes a history of vaccination and / or a history of infection.
  • infiltrating immune cells isolated from peripheral blood mononuclear cells (PBMC) isolated from the subject or tumor mass are stimulated with the non-tumor antigen.
  • PBMC peripheral blood mononuclear cells
  • the non-tumor antigen is administered once a day (1st week) and once a week (after the 2nd week).
  • (Item B1) A non-target antigen component for activating a regulatory T cell (Treg) having an immune memory in a non-target antigen component that is suppressed in a subject.
  • (Item B2) The antigen component according to any one of the above items, wherein activation of the Treg imparts a killing ability to the target or an immunostimulatory action to the target.
  • (Item B3) A non-tumor antigen component for activating regulatory T cells (Treg) having immune memory in the non-tumor antigen component, which is suppressed in the subject.
  • (Item B4) The antigen component according to any one of the above items, wherein activation of the Treg imparts a tumor-killing ability or an immunostimulatory effect on the tumor.
  • the antigen component according to any one of the above items, wherein the Treg is a memory T cell.
  • the antigen component according to any one of the above items, wherein the Treg is CD4 positive.
  • the antigen component according to any one of the above items, wherein the antigen component contains a protein.
  • the antigen component includes an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a history, and an antigen related to a vaccination history. Antigen component of.
  • An extract containing the antigenic component according to any one of the above items. (Item B10) To examine whether the antigen component has Treg immune memory in the subject, and if the subject has immune memory to the antigen component, the antigen component is administered to the subject.
  • An antigenic component characterized in that it is used in a method comprising.
  • the antigen component according to any one of the above items, wherein the antigen component is specific to the memory T cell of the subject.
  • the memory T cell is a memory type regulatory T cell (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 an activity of biasing the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells.
  • (Item B18) The antigen component according to any one of the above items, wherein the bias is to increase IFN- ⁇ -producing T cells as compared to Foxp3-positive Treg cells.
  • the specific antigen component enhances at least one selected from the group consisting of IFN- ⁇ producing ability, IL-2 producing ability, and TNF- ⁇ producing ability in the sample derived from the subject.
  • the antigenic component according to any one of the above items, which has the ability to cause.
  • the antigen component according to any one of the above items, wherein the antigen component is a protein.
  • a biomarker comprising at least one selected from the group consisting of varying TNF- ⁇ producing capacity.
  • a composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anticancer effect on a subject, said biomarker.
  • a composition or kit comprising at least one selected from the group consisting of, (iv) varying IL-2 producing ability, and (v) varying TNF- ⁇ producing ability.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed hemorrhoids, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gifteria.
  • the composition described in Crab. (Item B30)
  • the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to tubercle bacilli, and the antigen component is an antigen according to any one of the above items, including a human tuberculosis bacterium hot water extract. component.
  • the antigen component according to any one of the above items, wherein the subject is a subject having a history of influenza vaccination, a history of influenza infection, or an antigen responsiveness to influenza virus, and the antigen component includes influenza virus.
  • the antigenic component according to any one of the above items, wherein the disease, disorder or symptom includes melanoma.
  • An antigen component for treating or preventing a disease, disorder or symptom related to a subject's immune abnormality wherein the antigen component is for a component different from the causative factor of the disease, disorder or symptom.
  • a specific antigen component in the subject, The disease, disorder or symptom includes melanoma and The antigen component is a protein or a part thereof or a peptide, and can elicit an immune response via CD4-positive T cells.
  • the cancers include those that can be treated or prevented by an immune response mediated by CD4 positive T cells.
  • the antigen component is administered.
  • Antigen component (Item B37) An antigen component for treating or preventing cancer or tumor in a subject, wherein the antigen component comprises a non-tumor antigen component, and the non-tumor antigen component is suppressed in the subject.
  • An antigen component that activates regulatory T cells (Tregs) that have immunological memory in the non-tumor antigen, and the Treg has a regulatory activity or an antitumor immune action promoting effect on cancer or tumor.
  • (Item B38) A method of producing or otherwise providing a composition for preventing or treating a subject's cancer, wherein the method is: A) A step of identifying a non-tumor antigen specific to the subject, and B) A step of identifying whether or not the non-tumor antigen has immune memory in the subject and selecting one having the immune memory. C) With the step of producing or otherwise providing the selected non-tumor antigen.
  • a method that includes. (Item B39) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item B40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, wherein the method is: B) A step of identifying whether the non-tumor antigen has immune memory in the subject. A step that, if present, is identified as being able to prevent or treat cancer in the subject. A method that includes. (Item B41) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item B42) a) A step of obtaining an antigen-responsive profile of a subject and b) In the step of identifying the antigen component or the combination of the antigen components from the antigen responsiveness profile, the antigen component or the combination of the antigen components is such that the subject is immune responsive to the antigen component or the antigen component. And the process identified based on the present or past presentation, c) A step of administering the antigen component or a combination of the antigen components identified in the step b) to the subject in an amount sufficient to elicit an immune response in the subject.
  • Methods for the prevention or treatment of diseases, disorders or symptoms associated with immune disorders including.
  • Obtaining the antigen responsive profile is to confirm the subject's past physical condition and to confirm whether one or more antigen candidates are responsive in a sample derived from the subject, or The method according to any of the above items, comprising both of them.
  • the method according to any of the above items, wherein obtaining the antigen responsive profile includes identifying an antigen component or a combination of antigen components that elicit an immune response via CD4 positive T cells.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to produce cytokines.
  • the method according to any of the above items which also comprises measuring other biomarkers.
  • the method according to any one of the above items further comprising a step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • the steps a) and b) are as follows.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed hemorrhoids, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • the physical condition includes a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to M.
  • tuberculosis and the antigen component or a combination of the antigen components includes a human tuberculosis hot water extract, any of the above items.
  • the method described. (Item B53) The method according to any one of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection or antigen responsiveness to influenza virus, and the antigen component or a combination of antigen components includes influenza virus.
  • the administration includes subcutaneous administration or intradermal administration.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production or a plurality of these cytokines at the same time.
  • the method described in. (Item B59) The method according to any one of the above items, wherein the antigen-responsive profile is obtained by pre-diagnosing a companion based on a medical history and a vaccination history.
  • the past physical condition and the antigen component or a combination of the antigen components are a history of tuberculosis infection and a human tuberculosis hot water extract.
  • the past physical condition and the antigen component or the combination of the antigen components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / Mumps, rotavirus infection, varicella, yellow fever, Ebola, western Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenicity
  • One or more selected from Escherichia coli, Toxoplasma, Dicavirus, Herpesvirus 1, EBV / Epstein-Barvirus (Herpesvirus 4), CMV / Cytomegalovirus (Herpesvirus 5), Influenza, MARS, Mad Dog Disease, Zifteria The method according to any one of the
  • the subject was a subject whose history of BCG vaccination, history of tuberculosis infection, or antigen responsiveness could be confirmed.
  • the tubercle bacillus extract is prophylactically administered before the onset or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract from M. tuberculosis is administered subcutaneously or intradermally by a conventional method.
  • the method according to any one of the above items, which is characteristic.
  • the subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed.
  • the influenza vaccine may be administered prophylactically before the onset, prophylactically or in the early stage of cancer onset after treatment, and subcutaneously or intradermally administered with the influenza vaccine in the early stage or precancerous state of cancer.
  • the method according to any one of the above items, which is characteristic.
  • (Item B65) A method for preventing or treating cancer immunity based on any of the above items, which comprises re-inoculating the antigen component or a combination of the antigen components.
  • (Item B66) A method for preventing or treating a subject's cancer with a non-tumor component, wherein the component is identified by interview and / or an antigen identified with reference to the subject's history and vaccination history.
  • the subject is a person with a history of infection or vaccination described in any of the above items
  • the component is a preventive measure against recurrence after treatment and prevention before the onset of the subject.
  • a method comprising a specific administration or administration in the early stage of cancer onset, and, if necessary, administration of the component in the early stage of cancer onset or in a precancerous state.
  • the cancer normal carcinoma, relatively slow-growing carcinoma, those having low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • the identification of responsiveness includes a history of infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines simultaneously produced.
  • the tubercle bacillus extract is a hot water extract of human Mycobacterium tuberculosis or an extract from another tubercle bacillus (highly safe extract).
  • (Item B71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or an extract (highly safe extract) from another influenza virus.
  • the antigen component is a protein.
  • (Item B73) A vaccine preparation containing the antigen according to any one of the above items and an adjuvant base.
  • (Item B75) The vaccine preparation according to any one of the above items, wherein the vaccine preparation is used for personalized medicine.
  • a non-tumor antigenic component for use in a method for treating or preventing cancer or tumor in a subject wherein the method is: a) A step of identifying a non-tumor antigen specific to the subject based on the antigenic response profile, and b) A step of identifying whether the subject has an immune memory against the non-tumor antigen and identifying a subject having the immune memory. c) A step of administering the non-tumor antigen to the subject identified as having the immune memory. Including the antigen component.
  • the antigenic component according to any of the above items, wherein the antigenic response profile includes vaccination history and / or infection history.
  • infiltrating immune cells isolated from peripheral blood mononuclear cells (PBMC) isolated from the subject or tumor mass are stimulated with the non-tumor antigen.
  • PBMC peripheral blood mononuclear cells
  • the antigen component according to any one of the above items, wherein the production of cytokines is measured, and a subject whose cytokine production amount is increased by a predetermined multiple from that before stimulation is identified as a subject having the immune memory.
  • (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 ⁇ g / dose to about 1 mg / dose.
  • (Item B83) mHSP10 and / or MTB12 and / or lipoprotein LpqH for treating or preventing a disease, disorder or condition associated with an immune disorder in a subject.
  • (Item B84) The composition, antigen component, kit, biomarker, vaccine preparation, or method according to any one of the above items, wherein a plurality of drugs containing the antigen component are administered.
  • (Item C3) Use of the non-tumor antigen component in the production of a composition for activating regulatory T cells (Tregs) having immune memory in the non-tumor antigen component, which is suppressed in the subject.
  • (Item C4) The use according to any one of the above items, wherein activation of the Treg imparts a tumor-killing ability or an immunostimulatory effect on the tumor.
  • (Item C5) The use according to any of the above items, wherein the Treg is a memory T cell.
  • (Item C6) The use according to any of the above items, wherein the Treg is CD4 positive.
  • (Item C7) The use according to any one of the above items, wherein the antigen component contains a protein.
  • the antigen component includes an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a history of vaccination, and an antigen related to a history of vaccination.
  • Use of (Item C9) The use according to any one of the above items, wherein the antigen component comprises a human tubercle bacillus hot water extract or an influenza virus antigen. (Item C9A) Use according to any of the above items, including one or more of the features described in any or more of the above items or any or more of the following items.
  • the antigen component is a non-tumor antigen component.
  • the antigen component is specific for the memory T cells of the subject.
  • the memory T cell is a memory type regulatory T cell (IL-2 producing).
  • the antigen component has an immunostimulatory effect.
  • the antigen component acts antigen-dependently on memory CD4 positive T cells.
  • the IFN- ⁇ -producing T cell is a T-bet-positive Th1 cell.
  • the specific antigen component enhances at least one selected from the group consisting of IFN- ⁇ producing ability, IL-2 producing ability, and TNF- ⁇ producing ability in the sample derived from the subject. Use described in any of the above items that have the ability to cause.
  • the antigen component is a protein.
  • a biomarker for determining whether or not a non-tumor antigen component has an anticancer effect on a subject and the biomarker is such that the antigen component is (i) a memory CD4 positive T cell. Whether it acts antigen-dependently, (ii) fluctuates memory-type regulatory T cells, (iii) fluctuates IFN- ⁇ production capacity, and (iv) fluctuates IL-2 production capacity. , (V) A biomarker comprising at least one selected from the group consisting of varying TNF- ⁇ producing capacity.
  • composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anticancer effect on a subject, said biomarker. (Ii) whether the non-tumor antigen component acts antigen-dependently on memory CD4-positive T cells, (ii) changes memory-type regulatory T cells, or (iii) changes IFN- ⁇ production ability.
  • a composition or kit comprising at least one selected from the group consisting of, (iv) varying IL-2 producing ability, and (v) varying TNF- ⁇ producing ability.
  • the (non-tumor) antigen component comprises an antigen associated with a medical history or vaccination history.
  • the subject is a subject having a history of infectious disease, and the antigen component comprises an antigen for the infectious disease.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed hemorrhoids, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • (Item C30) The use according to any one of the above items, wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to M. tuberculosis, and the antigen component comprises a human tuberculosis hot water extract. ..
  • (Item C31) The use according to any one of the above items, wherein the subject is a subject having a history of influenza vaccination, a history of influenza infection, or an antigen responsiveness to influenza virus, and the antigen component contains influenza virus.
  • the disease, disorder or symptom comprises 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 according to any one of the above items, wherein the antigen component can elicit an immune response mediated by CD4 positive T cells.
  • (Item C35) When it is confirmed whether the subject can elicit an anti-tumor immune response mediated by CD4-positive T cells, and when the subject can elicit an anti-tumor immune response mediated by CD4-positive T cells. , The use according to any of the above items, wherein the composition is administered.
  • an antigenic component in the manufacture of a composition for treating or preventing a disease, disorder or symptom associated with a subject's immune disorder, wherein the antigenic component is a causative factor of the disease, disorder or symptom. It is an antigen component specific to the subject with respect to a component different from The disease, disorder or symptom includes melanoma and The antigen component is a protein or a part thereof or a peptide, and can elicit an immune response via CD4-positive T cells.
  • the cancers include those that can be treated or prevented by an immune response mediated by CD4 positive T cells.
  • the composition is administered. use.
  • a non-tumor antigen component in the manufacture of a composition for treating or preventing cancer or tumor in a subject, wherein the non-tumor antigen component is suppressed in the subject.
  • Use which activates regulatory T cells (Tregs) that have immune memory in the antigen, the Tregs having a regulatory or anti-tumor immune effect on cancer or tumor.
  • (Item C38) A method of producing or otherwise providing a composition for preventing or treating a subject's cancer, wherein the method is: A) A step of identifying a non-tumor antigen specific to the subject, and B) A step of identifying whether or not the non-tumor antigen has immune memory in the subject and selecting one having the immune memory. C) With the step of producing or otherwise providing the selected non-tumor antigen.
  • a method that includes. (Item C39) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item C40) A method of determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer, wherein the method is: B) A step of identifying whether the non-tumor antigen has immune memory in the subject. A step that, if present, is identified as being able to prevent or treat cancer in the subject. A method that includes. (Item C41) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • (Item C42) a) A step of obtaining an antigen-responsive profile of a subject and b) In the step of identifying the antigen component or the combination of the antigen components from the antigen responsiveness profile, the antigen component or the combination of the antigen components is such that the subject is immune responsive to the antigen component or the antigen component. And the process identified based on the present or past presentation, c) A step of administering the antigen component or a combination of the antigen components identified in the step b) to the subject in an amount sufficient to elicit an immune response in the subject.
  • Methods for the prevention or treatment of diseases, disorders or symptoms associated with immune disorders including.
  • Obtaining the antigen responsive profile is to confirm the subject's past physical condition and to confirm whether one or more antigen candidates are responsive in a sample derived from the subject, or The method according to any of the above items, comprising both of them.
  • the method according to any of the above items, wherein obtaining the antigen responsive profile comprises identifying an antigen component or a combination of antigen components that elicit an immune response via CD4 positive T cells.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to produce cytokines.
  • the method according to any of the above items which also comprises measuring other biomarkers.
  • the method according to any one of the above items further comprising a step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • the steps a) and b) are as follows.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gift
  • the method described in Crab. The physical condition includes a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tubercle bacilli, and the antigen component or a combination of the antigen components includes a human tuberculosis bacterium hot water extract, any of the above items.
  • the method described. (Item C53) The method according to any one of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection or antigen responsiveness to influenza virus, and the antigen component or a combination of antigen components includes influenza virus.
  • the administration comprises subcutaneous administration or intradermal administration.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production or a plurality of these cytokines at the same time.
  • the method described in. (Item C59) The method according to any one of the above items, wherein the antigen responsive profile is obtained by pre-diagnosing a companion based on a medical history and a vaccination history.
  • the past physical condition and the antigen component or a combination of the antigen components are a history of tuberculosis infection and a human tuberculosis hot water extract.
  • the past physical condition and the antigen component or the combination of the antigen components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / Mumps, rotavirus infection, varicella, yellow fever, Ebola, western Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenicity
  • One or more selected from Escherichia coli, Toxoplasma, Dicavirus, Herpesvirus 1, EBV / Epstein-Barvirus (Herpesvirus 4), CMV / Cytomegalovirus (Herpesvirus 5), Influenza, MARS, Mad Dog Disease, Zifteria The method according to any one of the above items.
  • the subject was a subject whose history of BCG vaccination, history of tuberculosis infection, or antigen responsiveness could be confirmed.
  • the tubercle bacillus extract is prophylactically administered before the onset or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract from M. tuberculosis is administered subcutaneously or intradermally by a conventional method.
  • the method according to any one of the above items, which is characteristic.
  • the subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed.
  • the influenza vaccine may be administered prophylactically before the onset, prophylactically or in the early stage of cancer onset after treatment, and subcutaneously or intradermally administered with the influenza vaccine in the early stage or precancerous state of cancer.
  • the method according to any one of the above items, which is characteristic.
  • (Item C65) A method for preventing or treating cancer immunity based on any of the above items, which comprises re-inoculating the antigen component or a combination of the antigen components.
  • (Item C66) A method for preventing or treating a subject's cancer with a non-tumor component, wherein the component is identified by interview and / or an antigen identified with reference to the subject's history and vaccination history.
  • the subject is a person with a history of infection or vaccination described in any of the above items
  • the component is a preventive measure against recurrence after treatment and prevention before the onset of the subject.
  • a method comprising a specific administration or administration in the early stage of cancer onset, and, if necessary, administration of the component in the early stage of cancer onset or in a precancerous state.
  • the cancers are normal carcinomas, relatively slow-growing carcinomas, those with low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • the identification of responsiveness includes a history of infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines simultaneously produced.
  • the tubercle bacillus extract is a hot water extract of human Mycobacterium tuberculosis or an extract from another tubercle bacillus (highly safe extract).
  • (Item C71) The method according to any one of the above items, wherein the influenza virus is a human influenza virus or an extract (highly safe extract) from another influenza virus.
  • the antigen component is a protein.
  • (Item C73) A vaccine preparation containing the antigen according to any one of the above items and an adjuvant base.
  • (Item C75) The vaccine preparation according to any one of the above items, wherein the vaccine preparation is used for personalized medicine.
  • composition for treating or preventing a disease, disorder or symptom associated with the subject's immune abnormality.
  • the composition is subcutaneously or intratumorally administered once daily (1st week) and once a week (after the 2nd week). use.
  • the antigen component is contained in an amount of about 0.001 ⁇ g or more per unit preparation.
  • a non-tumor antigenic component in the manufacture of a composition for use in a method for treating or preventing cancer or tumor in a subject, wherein the method is: a) A step of identifying a non-tumor antigen specific to the subject based on the antigenic response profile, and b) A step of identifying whether the subject has an immune memory against the non-tumor antigen and identifying a subject having the immune memory. c) A step of administering the non-tumor antigen to the subject identified as having the immune memory. Including, use. (Item C79) The use according to any of the above items, wherein the antigenic response profile includes a history of vaccination and / or a history of infection.
  • infiltrating immune cells isolated from peripheral blood mononuclear cells (PBMC) isolated from the subject or tumor mass are stimulated with the non-tumor antigen.
  • PBMC peripheral blood mononuclear cells
  • the non-tumor antigen is administered once a day (1st week) and once a week (after the 2nd week).
  • (Item X1) A composition for treating or preventing a disease, disorder or symptom related to a subject's immune abnormality, wherein the composition is for a component different from the causative factor of the disease, disorder or symptom.
  • a composition comprising an antigenic component specific to the subject (or the subject has immunological memory).
  • (Item X2) The composition according to any one of the above items, wherein the disease, disorder or symptom includes cancer.
  • the non-tumor antigen component is specific to the memory T cells of the subject.
  • the composition according to any one of the above items, wherein the memory T cell is a memory type regulatory T cell (IL-2 producing).
  • the non-tumor antigen component has an activity of biasing the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells.
  • the bias is to increase IFN- ⁇ -producing T cells as compared to Foxp3-positive Treg cells.
  • the non-tumor antigen component has an activity of biasing the abundance ratio of Th1 cells.
  • the IFN- ⁇ -producing T cells are T-bet-positive Th1 cells.
  • the specific (or subject has immunological memory) non-tumor antigen component can produce IFN- ⁇ , IL-2, and TNF- ⁇ in a sample derived from the subject.
  • a biomarker comprising at least one selected from the group consisting of varying TNF- ⁇ producing capacity.
  • a composition or kit comprising an agent or means for detecting a biomarker for determining whether a non-tumor antigen component has an anticancer effect on a subject, said biomarker.
  • a composition or kit comprising at least one selected from the group consisting of or (iv) varying the ability to produce IL-2.
  • (Item X16) The method, biomarker, composition or kit according to any of the above items, wherein the (non-tumor) antigen component comprises an antigen associated with a medical history and vaccination history.
  • (Item X17) The method, biomarker, composition or kit according to any of the above items, wherein the subject is a subject having a history of infectious disease and the antigen component comprises an antigen for the infectious disease.
  • infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gifteria.
  • infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps /
  • the method, biomarker, composition or kit described in. (Item X19) The method according to any one of the above items, wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to M. tuberculosis, and the antigen component comprises a human tuberculosis hot water extract. , Biomarkers, compositions or kits.
  • (Item X20) A method for producing a composition for preventing or treating a subject's cancer, wherein the method is: A) A step of identifying a non-tumor antigen specific to the subject, and B) A step of identifying whether or not the non-tumor antigen has immune memory in the subject and selecting one having the immune memory.
  • a method that includes. (Item X21) The method according to item X20, which has one or more features according to any one of items X2 to X20 in B).
  • a method that includes. (Item X23) The method according to item X22, which has one or more features according to any one of items X2 to X21 in B).
  • (Item X23A) A method for treating or preventing a disease, disorder or symptom associated with a subject's immune disorder, wherein the method is directed against a component different from the causative factor of the disease, disorder or symptom.
  • a method comprising administering to a subject an effective amount of an antigenic component specific (or having immunological memory) in the subject.
  • (Item X23AA) The method according to item X23A, which has 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 related to a subject's immune abnormality, wherein the antigen component is for a component different from the causative factor of the disease, disorder or symptom.
  • An antigenic component that is a specific (or the subject has immunological memory) antigenic component in the subject is a specific (or the subject has immunological memory) antigenic component in the subject.
  • the antigen component according to item X23B which has one or more characteristics according to any one of items X2 to X23.
  • Use of an antigenic component (or the subject has immunological memory). is the use according to item X23C, which has one or more features according to any of items X2 to X23.
  • the antigen responsive profile is to confirm the subject's past physical condition and to confirm whether one or more antigen candidates are responsive in a sample derived from the subject, or The method of item X24 or X25, comprising both of them.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, medical history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • a body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to perform a cytokine (IL-).
  • the method according to any of the above items including.
  • (Item X28) The method according to any one of the above items, further comprising a step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • (Item X29) The steps a) and b) are as follows. i) The process of obtaining the subject's past physical condition and ii) After collecting the blood of the subject and separating the peripheral blood cells, the peripheral blood cells produce cytokines (IL-2, IFN- ⁇ , TNF- ⁇ , etc.) in response to the antigen corresponding to the physical condition.
  • cytokines IL-2, IFN- ⁇ , TNF- ⁇ , etc.
  • infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gifteria.
  • infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, sputum, measles / wind rash, polio, mumps /
  • the method described in Crab. (Item X33) The method according to any of the above items, wherein the physical condition includes a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness to M. tuberculosis, and the antigen or a combination thereof comprises a human tuberculosis hot water extract. .. (Item X34) The method according to any one of the above items, wherein the administration includes subcutaneous administration or intradermal administration. (Item X35) The method according to any one of the above items, wherein the subject is in the early stage of cancer onset or in the precancerous state after the onset of cancer, after the treatment of cancer.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production or a plurality of these cytokines at the same time. The method described in.
  • the past physical condition and the components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, varicella, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, Water sputum, yellow fever, Ebola, Cytomegalovirus, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, mumps infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, decavirus , Herpesvirus type 1, EBV / Epstein-bar virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, diphtheria, one or more of the above items.
  • the subject is a personalized treatment method for a patient with a history of BCG vaccination or a history of tuberculosis infection or a healthy person with confirmed antigen responsiveness.
  • a subject with a history of BCG vaccination The tubercle bacillus extract is prophylactically administered before the onset or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract from M. tuberculosis is administered subcutaneously or intradermally by a conventional method.
  • the method according to any one of the above items, which is characteristic.
  • (Item X43) A method for preventing or treating cancer immunity based on any of the above items, which comprises re-inoculating the antigen.
  • (Item X44) A method for preventing or treating a subject's cancer with a non-tumor component, wherein the component is an antigen or extract associated with a history and vaccination history, and the subject is described in any of the above items.
  • a person who has a history of infection or vaccination, and the component is administered to the subject prophylactically before the onset, prevention of recurrence after treatment or early stage of cancer onset, and if necessary, cancer.
  • a method comprising administering the component in the early stages of onset or in a precancerous state.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • the identification of responsiveness includes a history of infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines simultaneously produced.
  • tubercle bacillus extract is a hot water extract of human Mycobacterium tuberculosis or an extract from another tubercle bacillus (highly safe extract).
  • Item X49 A vaccine preparation containing the antigen according to any one of the above items and an adjuvant base.
  • Tuberculosis Malaria, Yellow fever virus, Cytomegalovirus, Seed hemorrhoids, Mela / Wind rash, Polio, Mumps / MUMPS, Rotavirus infection, Water pox, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1, EBV / Epstein- A vaccine formulation comprising an antigen and an adjuvant base against at least one selected from the group consisting of barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease and diphtheria.
  • the physical condition of a subject of the vaccine preparation comprises having a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness to tuberculosis bacteria, wherein the antigen comprises a human tuberculosis hot water extract, item X49A.
  • Vaccine preparation. (Item X50) The vaccine preparation according to any one of the above items, wherein the adjuvant base contains a substance that promotes a Th1 type immune response (for example, a nucleic acid-based base such as CpG).
  • compositions for the prevention or treatment of a disease, disorder or symptom associated with an immune disorder in a subject wherein the composition is a) a step of obtaining an antigen responsive profile of the subject and b).
  • a composition comprising an amount of an antigen or a component identified by a step of identifying a combination of antigens that is responsive to the subject based on the antigen responsive profile in an amount sufficient to elicit an immune response in the subject.
  • (Item X50A1) A composition for the prevention or treatment of cancer in a subject containing a non-tumor component, wherein the component is an antigen or extract associated with a history and vaccination history, and the subject is described above.
  • a person with a history of infection or vaccination described in any of the items, and the component should be administered to the subject prophylactically before the onset, prevention of recurrence after treatment, or in the early stage of cancer onset. And, as needed, a composition comprising administering the component in the early stage of onset of cancer or in a precancerous state.
  • the component according to item X50A or X50A1 which has one or more features according to any one of items X1 to X50.
  • (Item X50B) A component for the prevention or treatment of a disease, disorder or symptom associated with an immune disorder in a subject, the component being a) a step of obtaining an antigen responsive profile of the subject and b) the antigen.
  • (Item X50B1) A non-tumor component for the prevention or treatment of a subject's cancer, the component being an antigen or extract associated with a history and vaccination history, the subject being any of the above items.
  • a component which comprises administering the component in the early stage of cancer onset or in a precancerous state.
  • Item X50C Use of a component in the manufacture of a medicament for the prevention or treatment of a disease, disorder or symptom associated with an immune disorder in a subject, wherein the component is a) the step of obtaining an antigen responsive profile of the subject.
  • the disclosure also provides: (Item 1) A composition for treating or preventing a disease, disorder or symptom related to a subject's immune abnormality, wherein the composition is for a component different from the causative factor of the disease, disorder or symptom. , A composition comprising an antigenic component specific to the subject.
  • (Item 2) The composition according to the above item, wherein the disease, disorder or symptom includes cancer, preferably the antigen component is a non-tumor antigen component.
  • the antigen component is specific to the memory T cells of the subject.
  • the memory T cell is a memory type regulatory T cell (IL-2 producing).
  • the antigen component has an activity of biasing the abundance ratio of Th1 cells.
  • the IFN- ⁇ -producing T cell is a T-bet-positive Th1 cell.
  • the specific antigen component enhances at least one selected from the group consisting of IFN- ⁇ producing ability, IL-2 producing ability, and TNF- ⁇ producing ability in the sample derived from the subject.
  • the composition according to any of the above items, which has the ability to cause.
  • (ii) fluctuates memory-type regulatory T cells, (iii) fluctuates IFN- ⁇ production capacity, (iv) fluctuates IL-2 production capacity, and (V) A biomarker comprising at least one selected from the group consisting of varying TNF- ⁇ producing capacity.
  • (Item 14A) A method for determining whether a non-tumor antigen component has an anticancer effect on a subject, in which the antigen component is (i) antigen-dependent on memory CD4 + T cells. Whether it acts on (ii) memory-type regulatory T cells, (iii) IFN- ⁇ production capacity, (iv) IL-2 production capacity, and (v) TNF.
  • a composition or kit comprising an agent or means for detecting a biomarker for determining whether or not a non-tumor antigen component has an anticancer effect on a subject, the biomarker. (Ii) whether the non-tumor antigen component acts antigen-dependently on memory CD4-positive T cells, (ii) changes memory-type regulatory T cells, or (iii) changes IFN- ⁇ production ability.
  • a composition or kit comprising at least one selected from the group consisting of (iv) varying IL-2 production and (v) varying TNF- ⁇ production.
  • composition or kit for determining whether or not a non-tumor antigen component has an anticancer effect on a subject and the composition or kit is such that the non-tumor antigen component is (i). Whether it acts antigen-dependently on memory CD4-positive T cells, (ii) fluctuates memory-type regulatory T cells, (iii) fluctuates IFN- ⁇ production ability, or (iv) IL-2 production
  • a composition or kit comprising an agent or device for determining at least one selected from the group consisting of varying ability and (v) varying ability to produce TNF- ⁇ .
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • (Item 21) A method of producing or otherwise providing a composition for preventing or treating a subject's cancer, wherein the method is: A) A step of identifying a non-tumor antigen specific to the subject, and B) A step of identifying whether or not the non-tumor antigen has immune memory in the subject and selecting one having the immune memory. C) A method comprising the steps of producing or otherwise providing the selected non-tumor antigen. (Item 22) The method according to any one of the above items, which has one or more features according to any one of the above items in B).
  • a method for determining whether a subject's non-tumor antigen can prevent or treat the subject's cancer wherein the method is: B) A step of identifying whether the non-tumor antigen has immune memory in the subject. A method comprising the steps identified as being able to prevent or treat the subject's cancer if the immune memory is present.
  • (Item 25) a) A step of obtaining an antigen-responsive profile of a subject and b) In the step of identifying the antigen component or the combination of the antigen components from the antigen responsiveness profile, the antigen component or the combination of the antigen components is such that the subject is immune responsive to the antigen component or the antigen component. And the process identified based on the present or past presentation, c) Diseases associated with immune disorders, including the step of administering to the subject an antigen component or a combination of antigen components identified in step b) in an amount sufficient to elicit an immune response in the subject. , A method for the prevention or treatment of disorders or symptoms. (Item 26) The method according to any of the above items, wherein the disease, disorder or symptom includes cancer.
  • the antigen responsive profile is to confirm the subject's past physical condition and to confirm whether one or more antigen candidates are responsive in a sample derived from the subject, or The method according to any of the above items, comprising both of them.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to produce cytokines.
  • the method according to any one of the above items further comprising a step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • the above a) and b) are the following steps i) the step of obtaining the past physical condition of the subject, and ii) A step of collecting the blood of the subject, separating the peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to an antigen corresponding to the physical condition or measuring other biomarkers.
  • iii) The method according to any one of the above items, which is carried out by a step of identifying an appropriate antigen component or combination of antigen components from the results of ii).
  • the physical condition includes a history of infection and the cancer vaccine comprises an antigen component or a combination of antigen components for the infection.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • the physical condition includes a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to tubercle bacilli, and the antigen component or a combination of the antigen components includes a human tuberculosis bacterium hot water extract, any of the above items.
  • the method described. (Item 35) The method according to any one of the above items, wherein the physical condition includes a history of influenza vaccination, a history of influenza infection or antigen responsiveness to influenza virus, and the antigen component or a combination of antigen components includes influenza virus.
  • the administration includes subcutaneous administration or intradermal administration.
  • (Item 37) The method according to any one of the above items, wherein the subject is in a precancerous state, before the onset of cancer, after the onset of cancer, or in the early stage of onset of cancer or in a precancerous state.
  • the cancer normal carcinoma, relatively slow-growing carcinoma, those having low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • (Item 39) The method according to any one of the above items, wherein the subject exhibits immune resistance.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production, or a plurality of these cytokines at the same time.
  • the method described in. (Item 41) The method according to any one of the above items, wherein the antigen-responsive profile is obtained by pre-diagnosing a companion based on a medical history and a vaccination history.
  • the past physical condition and the antigen component or the combination of the antigen components are a history of tuberculosis infection and a human tuberculosis hot water extract.
  • the past physical condition and the components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, sputum, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, Water sputum, yellow fever, Ebola, Cytomegalovirus, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, mumps infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, decavirus , Herpesvirus type 1, EBV / Epstein-bar virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, diphtheria, one or more of the above items.
  • the subject is a patient having a history of BCG vaccination or a history of tuberculosis infection, or a subject whose antigen responsiveness can be confirmed.
  • the tubercle bacillus extract is administered prophylactically before the onset, prophylactically administered after treatment, or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract subcutaneously from tubercle bacillus by the conventional method.
  • the method according to any of the above items which comprises administration or intradermal administration.
  • the subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed.
  • the influenza vaccine may be administered prophylactically before the onset, prophylactically or in the early stage of cancer onset after treatment, and subcutaneously or intradermally administered with the influenza vaccine in the early stage or precancerous state of cancer.
  • the method according to any one of the above items, which is characteristic.
  • (Item 47) A method for preventing or treating cancer immunity based on any of the above items, which comprises re-inoculating the antigen component or a combination of the antigen components.
  • Item 48 A method for preventing or treating a subject's cancer with a non-tumor component, wherein the component is identified by interview and / or an antigen identified by referring to the subject's history and vaccination history.
  • the subject is a person with a history of infection or vaccination described in any of the above items
  • the component is a preventive measure against recurrence after treatment and prevention before the onset of the subject.
  • a method comprising a specific administration or administration in the early stage of cancer onset, and, if necessary, administration of the component in the early stage of cancer onset or in a precancerous state.
  • the cancer normal carcinoma, relatively slow-growing carcinoma, those having low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the method according to any of the above items selected from the group consisting of MHC class I negative carcinomas.
  • (Item 50) The method according to any one of the above items, wherein the subject is a patient exhibiting immune resistance.
  • the identification of the responsiveness includes a history of pre-infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines simultaneously produced.
  • the method according to any of the above items which comprises measuring the induction of cells.
  • the M. tuberculosis extract is a hot water extract of human M. tuberculosis or an extract from another M. tuberculosis (highly safe extract).
  • the physical condition of the subject of the vaccine preparation includes having a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tuberculosis bacteria, and the antigen includes a human tuberculosis hot water extract, any of the above items.
  • Vaccine preparation described in Crab. The vaccine preparation according to any one of the above items, wherein the adjuvant base contains a substance that promotes a Th1 type immune response.
  • (Item 25A) a) A step of obtaining an antigen-responsive profile of a subject and b) In the step of identifying the antigen component or the combination of the antigen components from the antigen responsiveness profile, the antigen component or the combination of the antigen components is such that the subject is immune responsive to the antigen component or the antigen component. And the process identified based on the present or past presentation, c) Diseases associated with immune disorders, including the step of administering to the subject an antigen component or a combination of antigen components identified in step b) in an amount sufficient to elicit an immune response in the subject.
  • composition To prevent or treat diseases, disorders or symptoms associated with immune disorders, including antigenic components or combinations of antigenic components for use in methods of preventing or treating disorders or symptoms, or combinations of antigenic components or antigenic components.
  • Composition (Item 26A) The antigen component or combination or composition of the antigen component according to any one of the above items, wherein the disease, disorder or symptom includes cancer.
  • the antigenic response profile comprises at least one selected from the group consisting of interviews, history based on maternal and child health handbooks or equivalents, vaccination history and combinations thereof, and / or.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to produce cytokines.
  • cytokines for example, cytokines
  • the antigen component or combination or combination of antigen components according to any one of the above items, further comprising the step of periodically inspecting the responsiveness of the antigen and confirming the maintenance of the responsiveness.
  • the above a) and b) are the following steps i) the step of obtaining the past physical condition of the subject, and ii) A step of collecting the blood of the subject, separating the peripheral blood cells, and then measuring whether the peripheral blood cells produce cytokines in response to an antigen corresponding to the physical condition or measuring other biomarkers.
  • iii The combination or composition of the antigen component or the antigen component according to any one of the above items, which is carried out by the step of identifying an appropriate antigen component or combination of antigen components from the results of ii).
  • the combination of antigenic components or antigenic components according to any one of the above items, wherein the physical condition includes a history of infection and the cancer vaccine comprises a combination of antigenic components or antigenic components for the infectious disease. , Or the composition.
  • the infectious diseases include tuberculosis, malaria, cytomegalovirus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, varicella, Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1 , EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, and any of the above items, including at least one selected from the group consisting of gifteria.
  • the antigen component or the combination of the antigen components described in the above, or the composition includes a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tuberculosis bacteria, and the antigen component or a combination of antigen components includes a human tuberculosis bacterium hot water extract, any of the above items.
  • the antigen component or combination of antigen components described, or a composition includes an influenza virus.
  • the subject is an antigen component or a combination of antigen components according to any one of the above items, or a composition, which is in the early stage of cancer onset or in a precancerous state after cancer onset, after cancer treatment, or in a precancerous state.
  • the cancer normal carcinoma, relatively slow-growing carcinoma, those having low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the step ii) is any of the above items, which comprises measuring the induction of cells producing IFN- ⁇ production, IL-2 production, TNF- ⁇ production or a plurality of these cytokines at the same time.
  • the antigen-responsive profile is obtained by pre-diagnosing a companion based on a medical history and vaccination history, and is the antigen component or a combination of antigen components according to any one of the above items, or Composition.
  • the past physical condition and the components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, sputum, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, Water sputum, yellow fever, Ebola, Cytomegalovirus, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, mumps infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, decavirus , Herpesvirus type 1, EBV / Epstein-bar virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease, diphtheria, one or more of the
  • the antigen component or combination of antigen components according to any one, or a composition (Item 45A)
  • the subject was a subject whose history of BCG vaccination, history of tuberculosis infection, or antigen responsiveness could be confirmed.
  • the tubercle bacillus extract is prophylactically administered before the onset or in the early stage of cancer onset, and in the early stage of cancer onset or in the precancerous state, the extract from M. tuberculosis is administered subcutaneously or intradermally by a conventional method.
  • the antigen component or combination of antigen components according to any one of the above items, or a composition which is characteristic.
  • the subject is a subject whose history of influenza vaccination, history of influenza infection, or antigen responsiveness has been confirmed.
  • the influenza vaccine may be administered prophylactically before the onset, prophylactically or in the early stage of cancer onset after treatment, and subcutaneously or intradermally administered with the influenza vaccine in the early stage of cancer onset or in the precancerous state.
  • the antigen component according to any one of the above items, or a combination of antigen components, or a composition.
  • (Item 48A) A non-tumor component for use in a subject's cancer prevention or treatment method, the component being identified by interview and / or with reference to the subject's history and vaccination history. An identified antigen or extract, the subject being a person with a history of infection or vaccination as described in any of the above items, the component being a subject to prevent recurrence after treatment.
  • a non-tumor component comprising prophylactic administration before the onset or administration in the early stage of cancer onset, and, if necessary, administration of the component in the early stage of cancer onset or in a precancerous state.
  • the cancers are normal carcinomas, relatively slow-growing carcinomas, those with low sensitivity to the immune system, oral squamous cell carcinoma, cervical cancer, and usually CD8-positive T cells are less effective.
  • the identification of responsiveness includes a history of infection, a history of vaccination, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood, or a plurality of these cytokines simultaneously produced.
  • the antigen or combination of antigens or non-tumor component according to any of the above items which comprises measuring the induction of cells.
  • the M. tuberculosis extract is a hot water extract of M. tuberculosis or an extract from another M. tuberculosis (highly safe extract).
  • Combination of antigens. (Item 53A) The antigen or combination of antigens according to any one of the above items, wherein the influenza virus is a human influenza virus or another influenza virus (a highly safe extract).
  • the present disclosure provides a technique capable of effectively preventing or treating an intractable disease such as cancer with the immune memory possessed by the host.
  • Treg cells Regulatory T cells
  • these drugs show useful effects, they also have a problem of strong side effects, and the number of patients who show the effects is limited, and there is no clear diagnostic agent that can select patients, so it is appropriate. Since side effects are also strong when proper selection is not possible, selection is necessary, but where it was almost impossible in the past, the present disclosure utilizes the mechanism of immunological memory to select patients and then. By selecting and administering appropriate drugs, appropriate treatment and prevention methods could be provided.
  • Treg cell non-tumor antigen-dependent regulatory T cell
  • Reg cell This is a non-tumor antigen-dependent regulatory T cell (Treg cell) that has been vaccinated in the past using a humanoid tuberculosis hot water extract (which has been confirmed to be safe in humans), which was used as a typical example. )
  • humanoid tuberculosis hot water extract which has been confirmed to be safe in humans
  • FIG. 1 is a diagram in which the correlation between Mycobacterium tuberculosis infection and memory T cells was verified. This is the result of conducting an experiment under the conditions described in Example 1.
  • the drawing is a diagram showing the correlation between PPD-induced producing cells and Extract A-induced producing cells for IFN- ⁇ , IL-2 and TNF- ⁇ from the upper left.
  • the middle row is a diagram showing the correlation between CMV-induced production cells and Extract A-induced production cells for IFN- ⁇ , IL-2 and TNF- ⁇ from the left.
  • the lower row is a diagram showing the correlation between the production cells induced by MHSP10 and the production cells induced by Extract A for IFN- ⁇ , IL-2 and TNF- ⁇ from the left.
  • FIG. 2 is a diagram in which the antitumor effect of Extract A was verified according to the difference in immune status. The contents are described in Example 2.
  • FIG. 2A shows the dosing schedule of BCG or Extract A + Freund Incomplete Adjuvant (E + FIA), tumor cells, and Extract A.
  • the upper part of FIG. 2B shows the results when B16BL6 was transplanted into (B) naive mouse and (C) BCG-infected mouse (D) Extract A emulsion-immune mouse from the left.
  • the lower row shows the results of transplantation of (E) naive mouse, (F) BCG-infected mouse, and (G) Extract A emulsion-immunized mouse from the left when B16F10 is transplanted.
  • FIGS. 3-1 and 3-2 show the experimental results of the effect of suppressing tumor growth when the model antigen is administered to an animal having a memory cell specific to the model antigen.
  • FIG. 3-1 shows the transition of tumor growth of B16BL6 when ovalbumin was administered to naive mice (A) and ovalbumin + FIA + Extract A immune mice (B) from the left.
  • FIG. 3-1 shows the transition of tumor growth of B16BL6 when ovalbumin was administered to naive mice (A) and ovalbumin + FIA + Extract A immune mice (B) from the left.
  • FIG. 3-2 shows B16BL6 when Ovalbumin-specific Th1 differentiated CD4T cells were transferred to Rag2-deficient mice (left) and IL2R ⁇ chain Rag2 double-deficient mice (right) from the left and administered with ovalbumin.
  • FIG. 4 shows the tumor weight of B16BL6 when Extract A was administered to mice immunized with a vaccine preparation containing various adjuvant bases. A detailed description is given in the fourth embodiment. From the left, the vaccine used for immunization 4 weeks and 2 weeks ago is shown.
  • FIG. 5 shows the results of flow cytometry evaluation of the effect of Extract A on tumor-infiltrating lymphocytes (TIL) in transplanted tumors.
  • TIL tumor-infiltrating lymphocytes
  • the contents are described in detail in Example 5.
  • the left panel shows T-bet positive Foxp3 negative, T-bet positive Foxp3 positive and T-bet negative Foxp3 positive TIL from the left.
  • the right panel shows typical flow cytometry results.
  • FIG. 6 shows the results of flow cytometry evaluation of the effect of Extract A on tumor-infiltrating lymphocytes (TIL) in transplanted tumors. Its contents are described in detail in Example 6.
  • FIG. 7 shows the results of a related experiment for identifying cells essential for the antitumor effect of Extract A. The contents are described in detail in Example 8.
  • FIG. 7A is a diagram showing an administration schedule of BCG, tumor cells, Extract A, anti-CD4 antibody and anti-IFN- ⁇ antibody to mice.
  • 7B-7D show the mice depleted of CD4 positive cells using anti-CD4 antibody after BCG infection (FIG. 7B), CD4 knockout mice (FIG. 7C), and MHC class II knockout mice (FIG.
  • FIG. 7D shows the change in the volume of subcutaneously transplanted B16BL6 when physiological saline (S) or Extract A (E) is administered after BCG infection.
  • FIG. 7E shows the results of administration of physiological saline or Extract A to BCG-infected mice, recovery of spleen cells, stimulation with Extract A, staining of intracellular cytokines, and FACS analysis.
  • FIG. 7F shows the tumor volume when physiological saline (S) or Extract A (E) was administered to mice depleted of IFN- ⁇ using an anti-IFN- ⁇ antibody after BCG infection.
  • FIG. 7G shows IFN- ⁇ produced when the spleen cells of BCG-infected wild-type mice (WT), CD4 knockout mice (CD4 KO), and MHC class II knockout mice (MHCII KO) are stimulated with Extract A. It is a figure which shows the amount of.
  • FIG. 7H is a diagram showing the amount of IFN- ⁇ produced when spleen cells of BCG-infected wild-type mice (WT) and CD1d1 knockout mice (CD1d1) are stimulated with Extract A.
  • FIG. 7I is a diagram showing the amount of IFN- ⁇ produced when spleen cells of a mouse depleted of CD4 or CD8 are stimulated with Extract A.
  • FIG. 8 shows the transition of the tumor volume of B16BL6 when Extract A was administered to BCG-infected mice.
  • the contents are described in detail in Example 9.
  • FIG. 8A is a diagram showing an experiment schedule.
  • 8B-G show Rag2-deficient mice (Fig. 8B), CD8-positive cell-depleted mice (Fig. 8C), CD1d1-deficient mice and FcR-deficient mice (Fig. 8D), and NK1.1-positive cell-depleted mice, respectively.
  • FIG. 8E shows IL12p40-deficient mice (FIG. 8F) and Battf3-deficient mice (FIG. 8G) are shown the tumor volume when BCG-infected mice are then administered with saline (S) or Extract A (E).
  • S saline
  • Extract A E
  • FIG. 9 shows the results of the antitumor effect when a non-tumor antigen was administered to BCG-infected mice. The contents are described in detail in Example 10.
  • FIG. 9A shows Extract A (Sub) in which spleen cells isolated from BCG-infected mice were treated with subtilicin, Extract A (HI-Sub) treated with heat-inactivated subtilicin, and Extract A treated with trypsin. The amount of IFN- ⁇ secreted when treated with Extract A (HI-Trp) treated with (Trp) or heat-inactivated tripsin is relative to the amount of IFN- ⁇ produced by Extract A stimulation as 100%. Shown by value.
  • FIG. 9A shows Extract A (Sub) in which spleen cells isolated from BCG-infected mice were treated with subtilicin, Extract A (HI-Sub) treated with heat-inactivated subtilicin, and Extract A treated with trypsin. The amount of IFN- ⁇ secreted when treated with Extract A (HI-Trp) treated with (
  • FIG. 10 is a diagram showing the analysis results of the tumor microenvironment after the administration of Extract A. The contents are described in detail in Example 11.
  • the left panel of FIG. 10A shows the number of TIL cells per 1 mg of tumor in a naive mouse treated with saline or Extract A, and the right panel shows the number of TIL cells per 1 mg of tumor in a BCG-infected mouse treated with saline or Extract A. Shows the number of TIL cells.
  • FIG. 10A shows the number of TIL cells per 1 mg of tumor in a naive mouse treated with saline or Extract A
  • the right panel shows the number of TIL cells per 1 mg of tumor in a BCG-infected mouse treated with saline or Extract A. Shows the number of TIL cells.
  • FIG. 10A shows the number of TIL cells per 1 mg of tumor in a naive mouse treated with saline or Extract A
  • the right panel shows the number of TIL cells per 1 mg of tumor in a
  • FIG. 10B shows the correlation between tumor weight and the number of TIL cells per mg of tumor.
  • FIG. 10C shows the number of CD3-positive TIL cells, the number of CD3-positive CD8-positive TIL cells, and the number of CD3-positive CD4-positive TIL cells per 1 mg of tumor in BCG-infected mice treated with saline or Extract A.
  • FIG. 10D shows typical results of flow cytometric analysis of T-bet and Foxp3 expression in TIL of naive mice treated with saline or Extract A.
  • 10E-G show T-bet-positive Foxp3-negative TIL cells (FIG. 10E), T-bet-positive Foxp3-positive TIL cells (FIG.
  • FIG. 11 is a diagram showing the correlation between the antitumor effect of Extract A and TIL that produces IFN- ⁇ . Its contents are described in detail in Example 12.
  • the left panel of FIG. 11A shows the experimental protocol and the right panel shows typical flow cytometry for the expression of IFN- ⁇ and T-bet in TIL in BCG-infected mice treated with saline or Extract A. It shows the result.
  • FIG. 11B shows the number of IFN- ⁇ positive TIL cells per 1 mg of tumor under non-stimulated conditions.
  • FIG. 11C shows the number of IFN- ⁇ -positive TIL cells per 1 mg of tumor under Extract A or LpqH stimulation conditions.
  • 11D-F show the number of IFN- ⁇ -positive TIL cells under non-stimulation conditions (FIG. 11D), the number of IFN- ⁇ -positive TIL cells under Extract A stimulation conditions (FIG. 11E), and IFN under LpqH stimulation conditions. -The correlation between the number of ⁇ -positive TIL cells and the tumor weight is shown.
  • FIG. 12 is a diagram in which the antitumor effect of the influenza vaccine based on the difference in immune status was verified. Its contents are described in detail in Example 13.
  • FIG. 12A shows the dosing schedule of influenza virus PR8, tumor cells, and influenza vaccine.
  • FIG. 12A shows the dosing schedule of influenza virus PR8, tumor cells, and influenza vaccine.
  • FIG. 12B shows the results of transplanting B16BL6 into naive mice and FIG. 12C shows PR8-infected mice.
  • the horizontal axis shows the number of days after tumor transplantation, and the vertical axis shows the transition of tumor volume. * Indicates that there is a statistically significant difference.
  • FIG. 13A is an example of a schematic diagram of the clinical protocol.
  • FIG. 13B is another example of a schematic diagram of the clinical protocol.
  • the term “specific” for any substance or component means that the substance or component has the property of eliciting a special reaction in that subject.
  • the term “specific” means that the subject has immune memory, especially in the field of treatment or prevention.
  • the term can mean specific to a subject's memory T cells.
  • whether or not a subject "has immunological memory” with respect to a certain component or substance is determined by (i) whether or not the component or substance in the subject or a biological component derived from the subject (for example, a cell). Whether to enhance cytokine production in an antigen-dependent manner for memory CD4-positive T cells or to have a growth-promoting effect, (ii) to alter the expression of surface antigens in memory-type regulatory T cells, or (iii).
  • IL- 2 Varying the production capacity and (vii) TNF- ⁇ production capacity, or (vii) measuring whether or not a component or substance in the blood has a specific antibody, and measuring these It can be evaluated by confirming that at least one produces a positive result.
  • the "antigen component” means a component capable of inducing an antigen-antibody reaction in a certain subject, and is sometimes referred to as an "antigen" in the present specification. It may be a single component (substance) or a complex.
  • the antigenic components may be provided in a plurality of different combinations, in which case it is referred to as "combination of antigenic components".
  • the antigenic component may be provided as an isolated product, a complex thereof, or an extract containing the same.
  • the "non-tumor antigen component” refers to an antigen component that is not a cancer antigen. Whether or not a component or substance in the present specification is a “non-tumor antigen component” can be confirmed, for example, by comprehensively identifying and comparing proteins or mRNAs at the tumor site and other sites. Mass spectrometry, microarrays, and next-generation sequencers are mainly used for this identification, and can be confirmed by examining sequence information and the like.
  • “Antibody” refers to a protein that has the role of recognizing and eliminating foreign substances. In this case, the foreign substance is called an "antigen".
  • the non-tumor antigen component
  • the non-tumor antigen component may have an immunostimulatory action (or adjuvant activity).
  • the antigen component used in the present disclosure may be an antigen related to a medical history and a vaccination history, or an antigen against an infectious disease.
  • the term "antigen related to history and vaccination history” refers to a history or an antigen component contained in a vaccine, and is a method called ELISA or an antigen-specific T that examines whether or not a person has a specific antibody. It can be confirmed by a method called FACS or ELISA to confirm whether or not it has cells.
  • the term "antigen against an infectious disease” refers to a component capable of inducing an immune response derived from an organism or virus that causes an infectious disease, and is a method called ELISA or antigen-specificity for examining whether or not a specific antibody is present. It can be confirmed by having a typical T cell.
  • infectious disease can be any infectious disease, such as tuberculosis, malaria, yellow fever virus, cytomegalovirus, varicella, measles / wind rash, polio, epidemic parotid inflammation (Otafuku) / MUMPS.
  • the infection is tuberculosis.
  • the subject preferably has a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness to M. tuberculosis.
  • antigen responsiveness has the same meaning as known in the art, and means that a subject induces an antigen-antibody reaction against a specific substance or the like.
  • the "antigen responsive profile” refers to a general term (profile) that summarizes the antigen responsiveness of a subject to various substances and the like when referring to a subject.
  • the antigen responsive profile can be obtained by various methods, for example, confirming the past physical condition such as medical history (for example, history of infectious disease) and vaccination history, or actually a panel of antigens. It can be obtained as a profile by confirming the antigen responsiveness using. These can be realized, for example, by conducting an interview, a medical history based on a maternal and child handbook or an equivalent thereof, a vaccination history, and a combination thereof.
  • body fluid for example, blood
  • peripheral blood cells are separated, and then the peripheral blood cells react with an antigen related to the antigen profile to perform a cytokine (IL-2). , IFN- ⁇ , TNF- ⁇ , and combinations of two or more thereof), or can be confirmed by measuring other biomarkers.
  • IL-2 cytokine
  • memory T cell refers to a cell that functions to maintain immunological memory by being present in the living body for a long period of time. In the body, 90% of effector T cells die after 1-2 weeks unless exposure to the same antigen persists. Some of the remaining T cells are then roughly divided into two cell populations, which are present in vivo for a long period of time and function to maintain immunological memory. It functions as a "memory cell”. Memory cells include be roughly categorized, central memory T cells (T CM) and effector memory T cells (T EM). The survival of these two types of memory T cells for a long period of time makes it possible to activate a rapid immune response when the same pathogen invades again. It is said that not only the memory T cells generated when the antigen is first encountered survive for a long time, but also a new pool of memory T cells is formed each time the same antigen is encountered again.
  • T CM central memory T cells
  • T EM effector memory T cells
  • T CM cells close to the naive T cells to cell surface markers specifically is one of CCR7 and adhesion factor which is one of chemokine receptor CD62L like is expressed
  • T cell areas of predominantly secondary lymphoid tissues Exists in. When exposed to the same antigen again, it produces IL-2 and proliferates rapidly, and part of it is said to differentiate into TEM cells.
  • T EM cells reduces the expression of adhesion factors such as CCR7 and CD62L, rather than the secondary lymphoid tissues, mostly present in local inflammation (e.g., lung, such as the liver and intestine), IL by the same antigen stimulation It is said to produce a large amount of cytokines such as -4, IFN- ⁇ , and IL-5.
  • the memory T cells targeted by the components of the present disclosure may be memory-type regulatory T cells (IL-2 production).
  • Regulatory T cells are a type of T cell that blocks an excessive immune response. Treg cells are roughly divided into two types: endogenous Treg (natural Treg; nTreg) cells that naturally occur in the thymus and inducible Treg (induced Treg; iTreg) cells that are generated by stimulation with cytokines in peripheral tissues. Will be done.
  • the “memory type regulatory T cell (IL-2 production)” is a cell having the characteristics of “memory T cell” and “regulatory T cell”.
  • the "immunity-activating action” refers to an action that non-specifically activates the immune function of a living body and enhances the reduced defense power. Whether or not a substance has an "immune-activating effect" is determined by conducting a test in which the activation of immune cells is evaluated using the production of cytokines, etc. as an index using a reporter gene assay of innate immune receptors, lymphocytes, etc. You can check.
  • activation refers to a state in which the functions of cells (for example, T cells), proteins, polypeptides, genes, etc. are increased.
  • Activation refers to a state in which changes or increases in cell function are observed, a state in which cell proliferation is enhanced, a state in which expression of proteins, polypeptides, genes, etc. is increased, or a pattern of expression changes. It includes a state in which cells are suppressed, a state in which cells having an inhibitory ability are suppressed, a state in which the suppressed function is released, and the like.
  • the present disclosure refers to the activation of regulatory T cells (Tregs).
  • Tregs regulatory T cells
  • conversion of regulatory T cells Tegs
  • activation of Treg is sometimes referred to as conversion of regulatory T cells (Tregs), but both are synonymous.
  • activation of Treg is sometimes referred to with respect to a certain target, in which case, it is accompanied by activation of Treg to the target, and exerts a preventive or therapeutic effect on a disease.
  • Targets in this case include, but are not limited to, cancer or cancer-derived factors. Whether or not the immune cells are "activated” can be confirmed by a test or the like described in "Immune activating effect".
  • Gene “activation” can be quantified using real-time PCR, RNA-Seq, Northern hybridization, or hybridization using a DNA array, and the expression level of the polypeptide recognizes the polypeptide. It can be quantified by using a staining compound having a binding property to an antibody or a polypeptide. Further, in addition to the quantification method described above, a conventional method used in the present technical field may be used.
  • non-target antigen component refers to a component other than that (for example, a non-tumor component when the target is cancer) when a certain target (for example, cancer) is assumed.
  • the term "adjuvant” refers to a substance used to enhance its effect (immunogenicity) when administered together with a drug such as a vaccine (antigen), and means "help” in Latin. It is a term that has the word'adjuvant'as its etymology. Whether a substance functions as an "adjuvant” against another substance (eg, an antigen) can be confirmed by performing a test of administering it to a mouse together with an antigen and evaluating antigen-specific antibody production.
  • the "antigen-dependent" "action" with respect to a certain component means that when a target such as a T cell is referred to, the component has an action on the target as a result of an antigen-antibody reaction. It can be confirmed by the fact that the action disappears when the antigen-antibody reaction is inhibited.
  • CD4 positive T cells refers to memory T cells that are CD4 positive.
  • CD4 positive is higher than the staining level with a non-specific antibody used as a negative control by an immunostaining method using an antibody specific to CD4 labeled with a fluorescent dye or the like. Staining at the level is considered positive.
  • the "Foxp3 positive Treg cell” refers to a Treg cell that is Foxp3 positive.
  • Foxp3 positivity is higher than the staining level with a non-specific antibody used as a negative control by an immunostaining method using an antibody specific to Foxp3 labeled with a fluorescent dye or the like. Staining at the level is considered positive.
  • IFN- ⁇ -producing T cell refers to a T cell having the ability to produce interferon gamma (IFN- ⁇ ).
  • IFN- ⁇ -producing T cells are stained with a non-specific antibody used as a negative control by an immunostaining method using an antibody specific to IFN- ⁇ labeled with a fluorescent dye or the like. It can be identified by being stained at a higher level compared to the level.
  • helper T cells are also referred to as “Th1 cells” and are a subgroup of CD4 positive T cells (so-called helper T cells) such as naive CD4 positive T cells matured in the thoracic gland, and rapidly. It is a type of cell that enters the bloodstream, moves to the site of infection, secretes cytokines such as IFN- ⁇ and IL-2, activates macrophages, and causes an inflammatory reaction. Th1 cells are a locally occurring immune response that is responsible for cell-mediated immunity, which is an immune response in which CTLs and macrophages directly attack cells.
  • Th2 cell type 2 helper T cell
  • CD4 positive T cells which secretes cytokines such as IL-4 and IL-5 and recognizes the same antigen in secondary lymphoid tissues.
  • cytokines such as IL-4 and IL-5
  • IL-4 and IL-5 cytokines
  • IL-5 cytokines
  • IL-4 and IL-5 cytokines
  • IL-5 cytokines
  • IL-4 and IL-5 Activates naive B cells.
  • Th2 cells are responsible for humoral immunity, which is an immune reaction centered on B cells and antibodies.
  • T-bet-positive Th1 cells refers to Th1 cells that are T-bet-positive.
  • T-bet positive is compared with the staining level with a non-specific antibody used as a negative control by an immunostaining method using an antibody specific to T-bet labeled with a fluorescent dye or the like. Then, it is positive if it is stained at a high level.
  • the transcription factor T-bet encoded by the Tbx21 gene in Th1 cells directly and positively regulates the production of interferon gamma as a phylogenetic transcription factor.
  • Interferon gamma is classified as type II interferon as one of the interferon family having antipathogenic and antitumor effects, induces the expression of T-bet, which is a transcription factor that regulates Th1 cells, and produces interferon gamma. It is known to be maintained by feed forward control.
  • IFN labeled with a label such as a fluorescent dye.
  • a label such as a fluorescent dye.
  • the amount of IFN- ⁇ and IL-2 produced and the number of cells produced by stimulation with antigens were compared with those of negative controls by immunostaining using antibodies specific for - ⁇ , IL-2, and TNF- ⁇ . It is judged that the increase is due to the significant increase.
  • the amount of cytokine produced can be measured by ELISA, and the number of cytokine-producing cells can be measured by FACS.
  • biomarker refers to a protein or the like that is measured in a biological sample such as blood, in which the presence or degree of progression of a specific physical condition such as a disease is reflected in its presence or absence, concentration or level. A substance or event. Therefore, in the present specification, as biomarkers, whether or not they act antigen-dependently on memory CD4 positive T cells, whether or not memory-type regulatory T cells are altered, or whether or not the ratio of Treg and Th1 is altered. Whether to induce IFN- ⁇ production from T-bet-positive Th1 cells, change IFN- ⁇ production ability, change IL-2 production ability, change TNF- ⁇ production ability, etc. It is understood that it also includes events.
  • Whether or not it acts antigen-dependently on memory CD4 positive T cells can be determined by FACS analysis with a statistically significant increase in the number of positive cells of the antibody used for staining.
  • Whether or not the memory-type regulatory T cells are changed can be determined by a statistically significant increase in the number of positive cells of the antibody used for staining by FACS analysis.
  • Whether to change the ratio of Treg and Th1 and whether to induce IFN- ⁇ production from T-bet-positive Th1 cells is measured by FACS after intracellular cytokine staining and transcription factor staining, and the produced cytokine is measured by ELISA. It can be judged by measuring with.
  • IL-2 production ability and TNF- ⁇ production ability should be measured by FACS after intracellular cytokine staining and transcription factor staining, or by measuring the produced cytokine by ELISA. Can be judged by.
  • the "bias" of the "presence ratio” of cells means that the ratio of a plurality of types of cells is statistically significantly different from the ratio existing in a normal state. Whether it is biased or not can be determined by reference to the cell analysis results obtained in any technique for analyzing cells (eg, FACS).
  • the "hot water extract of M. tuberculosis” is a substance typically produced from M. tuberculosis, and is a mixture containing arabinose, mannose, and a polysaccharide containing glucose as main components. Is. Although the anticancer effect of hot water extract of M. tuberculosis has been studied for a long time, the details of its mechanism of action have not always been clarified, and it has not been used as a preventive drug. .. In addition, trace components such as proteins, peptides, amino acids, nucleic acids, and lipids (glycolipids) may be appropriately contained.
  • the typical production method of hot water extract of Mycobacterium tuberculosis is as follows.
  • Human-type tubercle bacilli are cultured in a constant temperature bath at 37 ° C. for 3 to 7 weeks, and then the film-like cells formed on the medium are collected by filtration, and the wet cells removed by washing the medium components with water are used as the extraction raw material. To do.
  • the cells are suspended in distilled water in an amount of 15 to 40 times the wet weight, heated at 90 to 120 ° C. for 80 to 180 minutes for extraction, and the cell residues are removed with a sterilization filter to prepare the extract. After concentrating to 60% or less, add acetone, trichloroacetic acid, ammonium sulfate, sulfosalicylic acid, etc.
  • prevention is an act of administering the active ingredient of the present disclosure to a person who has not developed the target disease, for example, for the purpose of preventing the onset of the disease. is there.
  • treatment means, for example, the act of administering the active ingredient of the present disclosure to a person (subject, patient) diagnosed as developing a disease by a doctor or an equivalent practitioner.
  • the purpose is, for example, to alleviate the disease or symptom, not to increase the carcinoma, or to return to the state before the onset of the disease.
  • the purpose of administration is to prevent the exacerbation of diseases and symptoms or the growth of carcinoma, if the administration is to a patient, it is a therapeutic act.
  • immune abnormality refers to any disease, disorder or condition caused or suspected to be caused by, at least in part, an abnormality in the immune system.
  • Immune disorders include, but are not limited to, cancer, autoimmune diseases, and the like.
  • Prevention or treatment of immune disorders includes prevention of immune disorders, recovery from immune disorders, or prevention of immune disorders.
  • the present disclosure is based on the finding that a subject exerts a specific and effective therapeutic and preventive effect on malignant neoplasms such as cancer by using a non-tumor antigen component having immune memory. ..
  • the present disclosure provides a composition for preventing or treating a subject's disease, disorder or condition, or a treatment or prophylaxis using the same principles, generally based on an immune memory mechanism.
  • the composition comprises an antigen component specific to the subject or an antigen component to which the subject has immune memory, with respect to a component different from the causative factor of the disease, disorder or symptom.
  • the disclosure presents regulatory T cells (Tregs) that contain a non-target antigenic component and are suppressed in a subject and have immune memory to the non-target antigenic component against the target.
  • the present disclosure comprises administering to a subject an effective amount of a non-target antigenic component, a regulatory T cell (Treg) that is suppressed in the subject and has immune memory to the non-target antigenic component.
  • a method for activating (or converting or converting) to a target it has been found that activation of Treg imparts a killing ability to the target or an immunostimulatory effect to the target.
  • non-target component acts on antitarget immunity similar to or superior to the target (antigen), and this is also applied to other components.
  • broadly subject-specific (or subject has immune memory) non-target antigenic components can be used to treat or prevent targets (eg, cancer).
  • targets eg, cancer
  • BCG-infected animal used as a model that is, an animal that can be evaluated as having immunological memory for a component of M. tuberculosis as an antigen
  • an influenza virus-infected animal humanoid M.
  • tuberculosis hot water extraction containing the antigen is performed. It has been demonstrated that the substance or influenza virus antigen has a preventive effect as well as a therapeutic effect on the development of diseases other than tuberculosis or influenza (for example, cancer). In addition, for the therapeutic and / or preventive effect of the specific component (in the case of BCG, human type tuberculosis hot water extract) in a subject having immunological memory against the specific component such as a BCG-infected animal or an influenza virus-infected animal.
  • the specific component in the case of BCG, human type tuberculosis hot water extract
  • the disclosure comprises a composition for activating regulatory T cells (Tregs) that contain a non-tumor antigenic component and are suppressed in a subject and have immune memory to the non-tumor antigenic component.
  • Tregs regulatory T cells
  • the present disclosure activates regulatory T cells (Tregs) having immune memory in the non-tumor antigen component that are suppressed in the subject, including administering to the subject an effective amount of the non-tumor antigen component.
  • Tregs regulatory T cells
  • activation of Tregs may impart tumor killing ability or immunostimulatory effect on tumors.
  • the Treg is a memory T cell and / or is CD4 positive. We do not want to be bound by theory, as it has been found to have a relationship with immune memory and activity via CD4 positive cells.
  • the antigenic component comprises a protein, a portion thereof or a peptide.
  • the antigen component comprises an antigen selected from the group consisting of the pathogen of the infectious disease or a portion thereof, an antigen associated with a history and an antigen associated with a vaccination history.
  • the antigenic component comprises a human M. tuberculosis hot water extract or an influenza virus antigen.
  • it is investigated whether the antigen component has Treg immune memory in the subject, and if the subject has immune memory against the antigen component, the antigen component is the subject. It is characterized in that it is used in a method including administration to. It is understood that in the conversion techniques of the present disclosure, the various components can employ various embodiments of the same type of components described herein, and combinations thereof are also within the scope of the present disclosure. ..
  • the disclosure is a composition for preventing or treating a subject's cancer, wherein the composition has a non-tumor antigenic component specific to the subject, or the subject has immunological memory.
  • a composition comprising a non-tumor antigen component is provided.
  • the present disclosure identifies the subject's responsiveness to an ingredient effective as a cancer vaccine based on the subject's past physical condition, and the subject is responsive to the physical condition. It is intended to prevent or treat cancer when administered to.
  • the disclosure is a) a step of obtaining a subject's past physical condition and b) a step of identifying the subject's responsiveness to an ingredient effective as a cancer vaccine based on that physical condition. And c) a method for the prevention or treatment of cancer, comprising the step of administering the component, which is responsive to the physical condition, to the subject.
  • the active ingredient such as a non-tumor antigen component is specific to the memory T cell of the subject. Being specific for memory T cells means that the subject has immune memory for a particular antigen.
  • a specific example found in the present disclosure may be a cancer therapeutic agent, in which case the antitumor effect of a hot water extract of Mycobacterium tuberculosis was found in the present disclosure. Attention is paid. Conventionally, hot water extracts of human tuberculosis bacteria have been considered to have non-specific immunotherapy and the main mechanism of action is immunostimulatory action. However, as a result of diligent research, the present inventors have conducted non-specific immunotherapy. By finding that the contained components act on anti-tumor immunity similar to or superior to that of cancer antigens apart from the immune function, and confirming this with other components, it is widely and subject-specific (or).
  • non-tumor antigenic components can be used to treat or prevent cancer.
  • a humanoid M. tuberculosis hot water extract containing the antigen causes cancer development. It was proved that it shows a preventive effect as well as a therapeutic effect.
  • the therapeutic and / or preventive effect of the specific component in the case of BCG, human type tuberculosis hot water extract
  • the antigen responsiveness of the specific component is also important, and as the mechanism in the past It was newly found that the antigen response by the immune memory caused by the vaccine (antigen) inoculated into the vaccine was evoked, and the antigen response by the non-tumor antigen promoted the antitumor immune action.
  • the memory T cells associated with immune memory targeted by the present disclosure are memory-type regulatory T cells, and as an index thereof, for example, IL-2 production can be observed.
  • the index include IFN- ⁇ production, TNF- ⁇ production, and a combination of two or three of them, in addition to IL-2 production. That is, when it is judged that immune memory exists, the target antigen is added to a test system containing T cells, and then IL-2 production, IFN- ⁇ production, TNF- ⁇ production, and two of them are performed. Alternatively, by observing the enhancement of the combination of the three, it can be determined that there is immune memory for the antigen.
  • specific components such as the non-tumor antigen components of the present disclosure have immunostimulatory activity (eg, adjuvant activity).
  • immunostimulatory activity eg, adjuvant activity
  • the immunostimulatory effect can be confirmed by any method known in the art. For example, evaluation of the action on innate immune receptors, the ability to induce specific antibody production, and the like can be used.
  • specific components such as the non-tumor antigen components of the present disclosure act antigen-dependently on memory CD4 positive T cells. Whether or not it acts antigen-dependently on memory CD4 positive T cells can be confirmed by any method known in the art. For example, flow cytometric analysis using MHCII tetramer and a specific antigen peptide, or analysis of IFN- ⁇ -producing cells by flow cytometry after stimulation with a specific antigen can be used.
  • specific components such as the non-tumor antigen components of the present disclosure have the activity of biasing the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells.
  • the bias in the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells can be confirmed by any technique for analyzing cells (for example, FACS), and typically, for example, intracellular cytokine staining. And the technique of measuring by FACS after staining with transcription factors can be used.
  • the bias of the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells is to increase IFN- ⁇ -producing T cells as compared with Foxp3-positive Treg cells.
  • IFN- ⁇ -producing T cells may include type 1 helper T cells.
  • certain components such as the non-tumor antigen components of the present disclosure, have the activity of biasing the abundance ratio of Foxp3-positive Treg cells to type 1 helper T cells.
  • the mechanism of action is considered as an important aspect of the bias in the abundance ratio of Foxp3-positive Treg cells and IFN- ⁇ -producing T cells.
  • Specific components components that induce immune memory
  • such as hot water extracts of human tuberculosis act antigen-dependently on memory CD4-positive T cells, and Foxp3-positive Treg cells and type 1 helper T cells (Th1 cells) ), Etc., by biasing the abundance ratio with IFN- ⁇ -producing T cells, we can change it to antitumor immunity and increase IFN- ⁇ -producing T cells in the tumor. I have found it.
  • the disclosure includes those in which the antigenic component can elicit an immune response mediated by CD4 + T cells.
  • the disclosure confirms whether a subject can elicit an antitumor immune response mediated by CD4 + T cells, and the subject elicits an antitumor immune response mediated by CD4 + T cells. It is characterized in that the composition is administered where possible. In a further embodiment, the immune response is not mediated by CD8 positive T cells.
  • the targeted IFN- ⁇ -producing T cells may include type 1 helper T cells. Although not bound by theory, it acts antigen-dependently on memory CD4-positive T cells, altering them to anti-tumor immunity such as type 1 helper T cells (Th1 cells), and IFN in tumors. This is because the anticancer effect can be enhanced by increasing - ⁇ -producing T cells.
  • type 1 helper T cells Th1 cells
  • the IFN- ⁇ -producing T cells in the present disclosure are T-bet-positive Th1 cells.
  • interferon gamma induces expression of T-bet, a transcription factor that regulates Th1 cells, and maintains interferon gamma production by feedforward control. Because it is known.
  • T-bet in host defense, interferon gamma induces expression of T-bet, a transcription factor that regulates Th1 cells, and maintains interferon gamma production by feedforward control. Because it is known.
  • the novel role of T-bet in recognizing autoclined interferon by Th1 cells has also been studied, and in the absence of T-bet, interferon gamma causes an abnormal type I interferon response.
  • T-bet preferentially suppresses genes and pathways activated by the autocline of type I interferon and suppresses aberrant amplification of the type I interferon signaling system.
  • T-bet not only actively induces differentiation into Th1 cells, but also plays a role in suppressing the abnormal autocline of type I interferon and its downstream signal transduction system in Th1 cells (Harms). Pritchard, G., Hall, A.O., Christian, D.A. et al .: Diverse roles for T-bet in the effector responses required for resistance to infection. J. Immunol., 194, 1131-1140 (2015) ) Etc.).
  • the specific (or subject has immunological memory) non-tumor antigen component in the subject-derived sample, IFN- ⁇ producing ability and IL-2 producing ability and TNF. It is preferable to have the ability to enhance at least one selected from the group consisting of - ⁇ -producing ability.
  • IFN- ⁇ -producing ability, IL-2-producing ability, and TNF- ⁇ -producing ability are advantageous in anticancer activity.
  • the BCG infection model that can be used herein is an infection model similar to vaccination history and history, it has been established by past vaccination as a fact that can be derived based on the data demonstrated thereby. It is considered that dormant memory T cells are reactivated by being stimulated by a specific antigen, and the cells promote an antitumor immune response in a tumor antigen-independent manner. And this hypothesis could be substantiated by experimenting with other immune memory models. Therefore, it is understood that the treatment of diseases based on the immuno-memory model of the present disclosure can be applied not only to examples but also to any diseases. Similar effects can also be observed at the clinical trial level.
  • the mechanism of action of the present disclosure includes the importance of biasing the ratio of Th1 cells and Foxp3-positive Treg cells and the production of IFN- ⁇ in an animal model.
  • Identification of the present disclosure that, in peripheral blood-derived cells (such as humans), the initial response of the specific component of the present disclosure is memory-type regulatory T cells (IL-2 producing) based on the vaccination history and history. The component induces IFN- ⁇ production, and from day-to-day experiments, the ratio of Foxp3-positive regulatory T cells (Treg) to T-bet-positive Th1 cells can be changed, or IFN- from T-bet-positive Th1 cells. Inducing ⁇ production is also considered to play an important role as a functioning mechanism.
  • IL-2 producing memory-type regulatory T cells
  • IFN- ⁇ production, IL-2 production, and TNF- ⁇ production from memory-type regulatory T cells based on the subject's immune memory such as vaccination history and history are involved. It was found as a result of diligent research by the present inventors. Therefore, it can be said that the present disclosure demonstrates that IFN- ⁇ production, IL-2 production, and TNF- ⁇ production using peripheral blood-derived cells such as humans can be biomarkers for responder selection.
  • a mixture of a hot water extract of M. tuberculosis and an adjuvant base is administered to a normal animal in a vaccine-like manner, and then a hot water extract of M. tuberculosis by a conventional method is administered. After administration, cancer cells were transplanted and the antitumor effect was evaluated. As a result, the mixture of the hot water extract of M. tuberculosis and the adjuvant base is treated in advance (vaccine-like treatment) even under the condition that the hot water extract of M. tuberculosis alone or the adjuvant base alone is not effective. It was found that by keeping it, a strong antitumor effect different from the conventional one can be exhibited.
  • Antigen response ability in CD4-positive and CD44-positive cells derived from spleen cells by administering a tubercle bacillus extract at a time when the effect of BCG diminished after inoculating BCG to mice. 2 triple response was enhanced. Based on this result, we have found a useful treatment method that can maintain the vaccine effect against the increase in infectious diseases due to the diminished vaccine effect, which is currently a problem.
  • This disclosure can be expected to enhance the antitumor effect not only in tubercle bacillus infection but also in the relevant antigen treatment based on the history of infection against other infectious diseases and the history of vaccine. That is, the present disclosure provides an individualized cancer immunotherapy / prevention method that can predict the efficacy in advance based on the response of memory-type T cells, targeting persons with a history of infection and vaccination. These things have the advantage that immunotherapy can be selected with the relevant antigen vaccine based on the infection history and vaccination history of each individual, unlike conventional immunotherapy that cannot be used without identifying the cancer antigen. In addition, since it does not use a cancer antigen, it can be applied to healthy subjects, so that preventive measures can be taken.
  • the hot water extract of Mycobacterium tuberculosis which has been established to be safe in humans, is used as an active ingredient, and the formulation and administration method different from the conventional method are used. It is an object of the present invention to provide a therapeutic method and a prophylactic method that are effective even in cancer tumors that do not show a preventive effect and a therapeutic effect only by subcutaneous administration of the agent.
  • the disclosure provides a biomarker for determining whether a non-tumor antigen component has an anti-cancer effect on a subject.
  • the biomarkers in the present disclosure vary (ii) memory-type regulatory T cells, whether the (non-tumor) antigen component of the present disclosure acts antigen-dependently on (i) memory CD4-positive T cells. It can be an event such as whether to induce (iii) IFN- ⁇ production from T-bet-positive Th1 cells. Therefore, the present disclosure is a method for determining whether or not a non-tumor antigen component has an anticancer effect on a subject, in which the non-tumor antigen component is (i) for memory CD4 positive T cells.
  • a method comprising the step of determining at least one of varying TNF- ⁇ producing capacity.
  • the disclosure comprises a means for detecting a biomarker for determining whether a (non-tumor) antigenic component has an anti-cancer effect on a subject, or a composition or composition.
  • the means for detecting the biomarker is whether or not the non-tumor antigen component acts antigen-dependently on memory CD4-positive T cells, fluctuates memory-type regulatory T cells, or is derived from T-bet-positive Th1 cells. Any means can be used as long as it can be confirmed whether the IFN- ⁇ , IL-2 and TNF- ⁇ production ability is changed, and various known and commercially available kits can be used.
  • the present disclosure is a composition or kit for determining whether a non-tumor antigen component has an anticancer effect on a subject, and the composition or kit is such that the non-tumor antigen component is ( i) Whether it acts antigen-dependently on memory CD4-positive T cells, (ii) fluctuates memory-type regulatory T cells, (iii) fluctuates IFN- ⁇ production ability, or (iv) IL- Also provided are compositions or kits comprising agents or devices for determining at least one selected from the group consisting of 2 varying production capacity and (v) varying TNF- ⁇ production capacity.
  • peripheral mononuclear cells are isolated from a subject, memory CD4 positive cells contained therein are stimulated with various antigens, and intracellular cytokines or transcription factors are stained to obtain an antigen-responsive profile. You can get it.
  • any one or a combination of any of the features described in ⁇ Prevention and Treatment of Diseases Based on Immune Memory Mechanisms> can be applied.
  • the present disclosure provides, in another aspect, a method of producing or otherwise providing a composition for preventing or treating a subject's disease or disorder.
  • This method A) identifies an antigen that is specific to the subject but is non-specific to the disease or disorder, and B) whether the non-specific antigen has immune memory in the subject. Includes the steps of identifying and selecting the immune memory, and C) producing or otherwise providing the selected non-tumor antigen.
  • "or otherwise provide” refers to any method of provision other than the manufacture of a new subject, eg, isolated from a suitable source of that subject. It can be a method of purification or acquisition.
  • step C) a new non-tumor antigen may be produced, or may be provided by isolation from another source.
  • the present disclosure provides, in another aspect, a method of producing or otherwise providing a composition for preventing or treating a subject's cancer.
  • A) a step of identifying a non-tumor antigen specific to the subject, and B) identifying whether or not the non-tumor antigen has immune memory in the subject, and selecting one having the immune memory.
  • C) the step of producing the selected non-tumor antigen or providing it in another manner.
  • a new non-tumor antigen may be produced, or may be provided by isolation from another source.
  • any one or more features described in ⁇ prevention and treatment of diseases based on immune memory mechanism> can be appropriately applied.
  • the disclosure comprises a) obtaining an antigen responsive profile of a subject and b) identifying an antigen or combination of antigens responsive to the subject based on the antigen responsive profile.
  • the disclosure is a) a step of obtaining an antigen responsive profile of a subject and b) a step of identifying an antigen or a combination of antigens from the antigen responsive profile of the antigen or antigen.
  • the combination has been shown or is shown to exhibit immune responsiveness to the subject, step and c) the antigen or combination of antigens identified in step b) that gives the subject an immune response.
  • a method for the prevention or treatment of a disease, disorder or symptom associated with an immune disorder which comprises the step of administering to the subject in an amount sufficient to elicit.
  • the present disclosure comprises a) a step of obtaining an antigen-responsive profile of a subject and b) a step of identifying an antigen or a combination of antigens from the antigen-responsive profile, wherein the antigen or combination of antigens is the subject.
  • step and c) the antigen or combination of antigens identified in step b) that has been shown or is shown to exhibit immune responsiveness to the subject elicits an immune response in the subject.
  • the disclosure comprises a) obtaining an antigen responsive profile of a subject and b) identifying an antigen or combination of antigens responsive to the subject based on the antigen responsive profile.
  • the disclosure provides a method of determining whether a subject's non-tumor antigens can prevent or treat the subject's cancer.
  • This method is B) a step of identifying whether the non-tumor antigen has immune memory in the subject, and if so, it is identified that the subject's cancer can be prevented or treated. , Including the process.
  • any one or more features described in ⁇ Prevention and Treatment of Diseases Based on Immune Memory Mechanisms> can be appropriately adapted.
  • the present disclosure also provides a composition or pharmaceutical composition comprising an antigen or a combination of antigens that is responsive to a subject obtained based on such an antigen responsive profile.
  • the disclosure also provides antigens or combinations of antigens that are responsive to subjects obtained based on such antigen responsive profiles for treating or preventing a disease or disorder.
  • the disclosure also provides the use of antigens or combinations of antigens that are responsive to a subject obtained based on such an antigen responsive profile in a medicament for treating or preventing a disease or disorder.
  • the present disclosure provides a composition for preventing or treating a subject's disease, disorder or symptom using an ingredient as specified by the method described above.
  • the composition will contain an antigenic component specific to the subject (or the subject has an immune memory) for a component different from the causative factor of the disease, disorder or symptom.
  • the prophylactic or therapeutic methods of the present disclosure are a) a step of obtaining a subject's past physical condition and b) the subject's response to an ingredient effective as a cancer vaccine based on that physical condition. It may include a step of identifying sex and a step of c) administering the component, which is responsive to the physical condition, to the subject.
  • obtaining an antigen responsive profile in the present disclosure confirms a subject's past physical condition and confirms whether one or more antigen candidates are responsive in a sample derived from the subject. It can also be confirmed by doing so, or by a method that includes both of them.
  • the disclosure comprises a) obtaining the subject's past physical condition and b) identifying the subject's responsiveness to an ingredient effective as a cancer vaccine based on the physical condition.
  • past physical conditions that may be available include medical history and vaccination history.
  • the medical history and vaccination history can be obtained by referring to, for example, the Mother and Child Handbook or its equivalents, medical records, and other medical information (including electronically recorded information of the subject stored in the cloud or electronic chip). can do.
  • the MCH Handbook is a book that contains essential information maintained by the family and is intended to promote and maintain the health of mothers and children ((2009 International Committeeon MCH Handbook: ICMCHH).
  • the available physical conditions include a history of infection and the available cancer vaccines include antigens for the infection.
  • the types of infections that can be used can be of any choice, such as tuberculosis, malaria, yellow fever virus, cytomegalovirus, varicella, measles / wind rash, polio, mumps / MUMPS, Rotavirus infection, varicella, yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, mumps infection, salmonella infection, pathogenic Escherichia coli, Examples thereof include toxoplasma, dicavirus, herpesvirus type 1, EBV / Epstein-bar virus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza, MARS, mad dog disease and diphtheria.
  • infectious disease used in the present disclosure may be any infectious disease described herein. Therefore, in the context of describing the physical condition in the present specification, when "BCG vaccination history”, “tuberculosis infection history”, “antigen responsiveness to tuberculosis bacterium”, etc. are described, these physical conditions are referred to in the present specification. It may be replaced with any infectious disease described in. It has been described and demonstrated in Example 13 that the therapeutic, prophylactic and pharmaceutical methods of the present disclosure can be used as an example of any infectious disease, but not limited to, even if the patient has an "influenza infection history”. Has been done.
  • the infectious disease utilized is tuberculosis.
  • the physical condition includes a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness to M. tuberculosis.
  • the infection is tuberculosis, it may be advantageous to include a human tuberculosis hydrothermal extract as the antigenic component or cancer vaccine.
  • the present disclosure can be used therapeutically as well as prophylactically.
  • the antigen or cancer vaccine of the present disclosure may be provided in the dosage form of a pharmaceutical composition.
  • the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are present in the subject, eg, Extract A (Example). Can be converted to at least one compound (ie, prodrug).
  • the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are at least one (non-neoplastic) in the subject. ) Can be converted to antigenic components (ie, prodrugs).
  • a plurality of drugs When a plurality of drugs are included, they may be contained in a single composition (mixture) or in separate compositions.
  • the formulation can be formulated using forms known in the art, including those exemplified herein.
  • Multiple agents may be used with or in addition to the antigens (ingredients) or cancer vaccines of the present disclosure, along with one or more other agents (eg, anti-cancer agents such as surgery, chemotherapeutic agents, immune checkpoint inhibitors). It may be provided to realize a treatment method (for example, administration of an anticancer drug, radiation therapy, etc.).
  • the antigens (ingredients) or cancer vaccines of the present disclosure are combined with one or more other agents or therapies (eg, anti-cancer agents such as surgery, chemotherapeutic agents, radiation therapy, immune checkpoint inhibitors). Can be provided or administered.
  • one or more other agents or therapies are suitable after administration of the antigens or cancer vaccines of the present disclosure. It may be administered after a lapse of time. Two or more drugs may be provided as a kit when administered separately.
  • the anticancer agent is not limited, but is an immune checkpoint inhibitor (PD-1 inhibitor (eg, anti-PD-1 antibody), PD-L1 inhibitor (eg, anti-PD-L1 antibody), CTLA.
  • Inhibitors eg, anti-CTLA-4 antibody
  • metabolic antagonists chemotherapeutic agents such as alkylating agents, growth inhibitors, cytotoxic agents, agents used in radiotherapy, antiangiogenic agents , Anti-tubulin agents, anti-cancer antibiotics, microtubule agents, tyrosine kinase inhibitors, proteasome inhibitors, undifferentiated lymphoma kinase inhibitors, Janus kinase inhibitors, CDK inhibitors, MEK inhibitors, Raf kinase inhibitors, molecular-targeted therapeutic agents such as PARP inhibitors and antibody agents, platinum preparations, immunotherapy such as dendritic cell therapy, gene therapy, other small molecule drugs, other drugs for treating cancer, etc. Can be mentioned.
  • chemotherapeutic agents such as alkylating agents, growth inhibitors, cytotoxic agents, agents used in radiotherapy, antiangiogenic agents , Anti-tubulin agents, anti-cancer antibiotics, microtubule agents, t
  • the term “carrier” relates to, or enables, for example, transporting or transporting a pharmaceutical compound of interest from one organ or part of the body to another organ or part of the body.
  • a pharmaceutically acceptable substance, composition, or excipient such as a solid bulking agent, diluent, additive, solvent, or encapsulating agent.
  • “Pharmaceutically acceptable” means that it is compatible with other ingredients in the formulation and is 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, sodium carboxymethyl cellulose, ethyl cellulose, and.
  • Cellulose and derivatives thereof such as cellulose acetate, excipients such as powdered tragacanth, malt, gelatin, talc, cacao butter and suppository wax, peanut oil, cottonseed oil, benibana oil, sesame oil, olive oil, corn oil, and Of oils such as 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, magnesium hydroxide and aluminum hydroxide.
  • excipients such as powdered tragacanth, malt, gelatin, talc, cacao butter and suppository wax
  • peanut oil cottonseed oil
  • benibana oil sesame oil
  • olive oil corn oil
  • Of oils such as soybean oil
  • glycols such as propylene glycol
  • polyols such as glycer
  • buffers Includes such buffers, argicic acid, starch-free water, isotonic physiological saline, Ringer's solution, ethyl alcohol, phosphate buffer, 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 colorants, release agents, coating agents, sweeteners, flavors and flavors, preservatives, And antioxidants can also be included in the composition.
  • wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as colorants, release agents, coating agents, sweeteners, flavors and flavors, preservatives, And antioxidants can also be included in the composition.
  • parenteral administration refers to an administration form of any route other than oral administration, in a form and level effective for the treatment or prevention of a target disease such as cancer treatment or prevention. Any form of administration is adopted, and means of parenteral administration include administration by transdermal absorption or transmucosal absorption, including injection or injection, and combinations thereof.
  • a percutaneous absorption preparation such as a coating agent, a patch, or a spray agent is brought into contact with the skin or mucous membrane, and the drug in the preparation is transferred into the body through the skin or mucous membrane. Is effective.
  • Administration by injection or injection includes intravenous, intradermal, subcutaneous, intramuscular, and transintestinal (enema) administration, and may be bolus administration and / or continuous injection. They may use suspensions, solutions, emulsions, embeddings in oily or aqueous media, including other formulation substances such as suspending agents, stabilizers and / or dispersants.
  • transintestinal (enema) administration percutaneous endoscopic gastrostomy can be performed for continuous delivery to the proximal small intestine using a tube and a portable infusion pump. More preferably, it may be subcutaneously or intradermally administered.
  • Parenteral administration can also be performed with tapes / patches, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and the like.
  • Compositions suitable for parenteral administration are sterile isotonic or non-aqueous solutions, dispersions, suspensions, emulsions, implants, or sterile injectable solutions that are acceptable as at least one pharmaceutical product.
  • the dispersion can contain sterile powders that can be reconstituted.
  • compositions disclosed herein that are suitable for oral administration are capsules, cachets, pills, tablets, rhombic tablets (usually using flavor bases that are sucrose and acacia or tragant), powders, granules, aqueous or non-aqueous.
  • compositions disclosed herein can be administered as a bolus, lick, or paste.
  • the antigen or cancer vaccine of the present disclosure can be administered in any administration form, and any administration form can be used as long as the effect can be obtained by oral administration or parenteral administration. Parenteral administration is preferred.
  • Solid dosage forms for oral administration are one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or Fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, moisturizers such as glycerol.
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or Fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid
  • binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia
  • moisturizers such as glycerol.
  • Agents agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, disintegrants such as sodium carbonate and sodium glycolicate, dissolution retarders such as paraffin, absorption enhancers 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, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and these. It can be mixed with any of a lubricant such as a mixture, as well as a colorant.
  • a lubricant such as a mixture, as well as a colorant.
  • the pharmaceutical composition may also include a buffering agent.
  • Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules with additives such as lactose or lactose, and high molecular weight polyethylene glycol.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form can include inactive diluents used in the art, such as water or other solvents, solubilizers, emulsifiers, ethyl alcohol, isopropyl alcohol, etc.
  • oils especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil
  • glycerol Tetrahydrofuryl alcohol
  • polyethylene glycol fatty acid ester of sorbitan
  • cyclodextrins such as hydroxypropyl- ⁇ -cyclodextrin can be used to dissolve the compounds.
  • the ingredients of the present disclosure can include auxiliary agents such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents, and preservatives.
  • Suspensions can include suspending agents in addition to one or more compounds according to the present disclosure, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxydos, etc. Bentnite, agar, and tragacant, as well as mixtures thereof, and the like.
  • compositions disclosed herein can be suppositories for rectal or vaginal administration and include one or more compounds according to the present disclosure, such as cocoa butter, polyethylene glycol, suppository wax, salicylate, etc. It can be prepared by mixing with more than a variety of suitable non-irritating additives or carriers and is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity to release the compounds of the present disclosure.
  • Pharmaceutical compositions suitable for vaginal administration may also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the prior art.
  • Dosage forms for topical or transdermal administration of the compositions of the present disclosure can include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the pharmaceutical composition or tablet can be mixed under sterile conditions with a pharmaceutically acceptable carrier and possibly required preservatives, buffers, or high pressure gas.
  • Ointments, pastes, creams, and gels in addition to the compositions of the present disclosure, include animal and vegetable fats, oils, waxes, paraffins, starches, tragacants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc, and Additives such as zinc oxide or mixtures thereof can be included.
  • Powders and sprays include, in addition to the pharmaceutical compositions or tablets of the present disclosure, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Can be done.
  • the spray can include common high pressure gases such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.
  • Ophthalmic preparations are also construed as being within the scope of this disclosure.
  • compositions suitable for parenteral administration can be in sterile isotonic or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile injectable solutions or dispersions that are acceptable as at least one pharmaceutical product. It can contain sterile powders that can be reconstituted.
  • salt includes acids and / or base salts formed by inorganic and / or organic acids and bases.
  • pharmaceutically acceptable salt is used, within certain medical judgment, without undue toxicity, irritation, allergic reactions, and / or similar events. Means these salts, which are suitable for use in contact with the tissue of the subject and are balanced with a legitimate effect / risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , J. Pharmaceutical Sciences (1977) 66: 1-19 describes in detail pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts can be produced by inorganic or organic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid.
  • suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid.
  • suitable pharmaceutically acceptable salts include adipates, alginates, ascorbates, asparaginates, benzenesulfonates, besilates, benzoates, bisulfates, boroides.
  • the organic acids that can produce salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, lactic acid, trifluoracetic 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.
  • Salts can be prepared in-situ or separately during the separation and purification of the disclosed compounds, such as by reacting the compounds with appropriate bases or acids, respectively.
  • suitable alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • non-limiting examples of suitable pharmaceutically acceptable salts include, as required, non-toxic ammonium, quaternary ammonium, as well as halide ion, hydroxide ion, carboxylate ion, sulfate ion, phosphorus. Includes amine cations formed using counter ions such as acid ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.
  • Non-limiting examples of suitable organic bases that can give rise to salts include primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and isopropylamines, trimethylamines, diethylamines, Includes basic ion exchange resins such as triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the target subject may be a patient who is in the early stage of cancer onset or in a precancerous state after the onset of cancer, after treatment for cancer, and after treatment for cancer.
  • the subject of interest may be a healthy person. If the subject is a healthy person, it will be implemented as a preventive method.
  • the cancers covered in this disclosure are, but are not limited to, esophageal cancer, gastroesophageal junction cancer, renal cell cancer, lung cancer, gastrointestinal cancer, leukemia, lymphoma, myeloma, and brain.
  • Cancer pancreatic cancer, endometrial cancer, prostate cancer, liver cancer, bladder cancer, gastroesophageal adenocarcinoma, chondrosarcoma, colorectal adenocarcinoma, colorectal cancer, breast cancer, renal cells Cancer, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, sarcoma, urogenital cancer, gynecological cancer, and corticolytic cancer.
  • the cancer is a colorectal cancer. In certain embodiments, the cancer is a colorectal cancer. 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 can be unresectable. In certain embodiments, the cancer can be advanced. In certain embodiments, the cancer can be refractory. In certain embodiments, the cancer can be recurrent. In certain embodiments, the cancer can be metastatic.
  • the cancers of interest are normal carcinomas, relatively slow-growing carcinomas (eg, those that are less sensitive to the immune system), oral squamous cell carcinoma, cervical cancer, CD8 positive. It can include MHC class I-negative carcinomas, immune checkpoint inhibitor-resistant carcinomas, etc., for which T cells are less effective.
  • the cancer patient means a patient suffering from the above-mentioned "cancer".
  • the disease, disorder or symptom covered by the present disclosure comprises melanoma.
  • the subject subject to the present disclosure may be a subject exhibiting immune resistance.
  • Subjects with weak immune checkpoint inhibitors, subjects who are resistant to treatment with chimeric antigen receptor-expressing cells, subjects who are ineffective with treatment with monoclonal antibodies, and the like may also be the subject of this disclosure.
  • a step of identifying an antigen or a combination of antigens that is responsive to the subject is performed based on the antigen responsive profile.
  • the responsiveness to the subject may be any one related to disease treatment or prevention, and in particular, any one suggesting an association with immune memory. Therefore, for example, the responsiveness is IFN. It may include responsiveness to any of - ⁇ production, IL-2 production, TNF- ⁇ production or responsiveness to any two or three.
  • the disclosure provides a companion diagnostic agent or method for the prevention or treatment of cancer and a therapeutic or preventive method or drug based thereto.
  • the confirmation of responsiveness is characterized in that a companion diagnosis is made in advance based on a medical history and a vaccination history, and it is possible to make such a companion diagnosis.
  • a companion diagnosis is made in advance based on a medical history and a vaccination history, and it is possible to make such a companion diagnosis.
  • preliminary companion diagnostics based on medical history and vaccination history can be carried out as follows. -Acquisition of antigen response profile based on medical history or vaccination history using non-invasive methods, interviews, maternal and child health handbooks or equivalents. -Confirmation of actual responsiveness using the antigen panel and peripheral mononuclear cells isolated from the subject-Judge the antigen or combination thereof that responded above as a prophylactic or therapeutic agent
  • a human tuberculosis hot water extract can be used as an antigen component by utilizing the history of tuberculosis infection. Can be done. I do not want to be bound by theory, but as an example, a subject who can prevent cancer etc. using human tuberculosis hot water extract by judging by using the history of tuberculosis infection as a past physical condition Can be identified, which can lead to cancer prevention. Alternatively, as an example, by making a judgment using the history of tuberculosis infection as a past physical condition, it is possible to identify a subject who can prevent cancer etc. using a human tuberculosis hot water extract. Treatment of cancer can be realized.
  • the past physical condition and the components include tuberculosis, malaria, yellow fever virus, cytomegalovirus, seed poultry, measles / wind eczema, polio, mumps / MUMPS, rotavirus infection, and varicella.
  • herpesvirus 1 Yellow fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus 1 It can be one or more selected from type, EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza virus, MARS, mad dog disease, and diphtheria.
  • the subject of the present disclosure is a patient with a history of BCG vaccination or tuberculosis infection or a healthy person with confirmed antigen responsiveness
  • the method of the present disclosure is an individualized therapeutic method.
  • the target subject may be a person who has a history of vaccination, a history of infection, a person who has a history of tubercle bacillus infection, or a person who has a history of BCG vaccination.
  • tubercle bacillus extract that can be used in the present disclosure is administered prophylactically before the onset, prophylactically administered after treatment or in the early stage of cancer onset, and is described herein in the early stage of cancer onset or in the precancerous state.
  • the extract from Mycobacterium tuberculosis obtained by an improved method thereof is also administered subcutaneously or intradermally.
  • the disclosure is a method of preventing or treating cancer immunity by pre-diagnosing a companion based on a history, vaccination history, comprising re-inoculating the antigen. , Provide a method. It has been described and demonstrated in Example 2 that cancer immunity can be prevented or treated by pre-diagnosing companion based on medical history and vaccination history.
  • the disclosure provides a method of preventing or treating a subject's cancer with a non-tumor component.
  • the component used herein is an antigen or extract identified by interview and / or with reference to the subject's history and vaccination history, the subject being a history and vaccine.
  • a method using a non-tumor component which comprises administering the component as needed in the early stage of onset of cancer or in a precancerous state.
  • the present disclosure is also a non-tumor component for use in a subject's cancer prevention or treatment method, the component being identified by interview and / or referring to the subject's history and vaccination history.
  • the subject is a person with a history of infection or a history of vaccination described in the present disclosure, and the component is used to prevent recurrence of the subject after treatment and before the onset of the disease.
  • non-tumor components characterized by prophylactic administration or administration in the early stage of onset of cancer, and administration of the component in the early stage of onset of cancer or in a precancerous state as needed.
  • the present disclosure provides a vaccine formulation comprising any one of the antigens of the present disclosure and an adjuvant base.
  • the vaccine formulation is used for personalized medicine.
  • vaccines can be appropriately provided for individual patients or subjects based on companion medicine as provided in the present disclosure.
  • the cancers covered by the disclosure include normal carcinomas, relatively slow-growing carcinomas (less sensitive to the immune system), oral squamous cell carcinomas, cervical cancers, and the like. And, usually, it may be MHC class I negative carcinoma or the like in which CD8 positive T cells are hard to show the effect.
  • the subject of the present disclosure is a patient exhibiting immune resistance.
  • subject responsiveness identification includes pre-infection history, vaccination history, and IFN- ⁇ production, IL-2 production, TNF- ⁇ production using peripheral blood. Alternatively, it can be done using either responsiveness to any two or three. "Response to IFN- ⁇ production, IL-2 production, TNF- ⁇ production or any two or three using peripheral blood" can be carried out as follows. -Separate peripheral blood mononuclear cells from the subject's blood.
  • peripheral blood mononuclear cells in the presence of the substance or a stimulant such as PPD (purified protein derivative, purified tuberculin), tuberculosis antigen, and a protein transport inhibitor such as Breferdin A and monencin.
  • PPD purified protein derivative, purified tuberculin
  • tuberculosis antigen tuberculosis antigen
  • a protein transport inhibitor such as Breferdin A and monencin.
  • peripheral blood mononuclear cells are collected, stained with a cell surface marker and an intracellular cytokine-specific fluorescently labeled antibody, and the stained cells are analyzed using a flow cytometer.
  • -In memory CD4 T cells CD3 positive CD4 positive CD45RA negative
  • Extract A is exemplified and described in detail in Example 1 and the like.
  • the M. tuberculosis extract used in the present disclosure is a hot water extract of M. tuberculosis or an extract from another M. tuberculosis (highly safe extract). Compositions used for tuberculin and the like are also preferable.
  • the disclosure provides a vaccine formulation comprising the antigen provided in the present disclosure and an adjuvant base (eg, a substance that promotes a Th1 type immune response).
  • the vaccine formulation is used for personalized medicine.
  • an appropriate vaccine is prepared for each patient or subject based on the companion medicine as provided in the present disclosure.
  • the pharmaceutical or antigenic component provided in the present disclosure is a human M. tuberculosis hot water extract or an extract from another M. tuberculosis (highly safe extract) or an extract component, or an antigen. It may be provided as a vaccine formulation, including an adjuvant base.
  • a method for producing such a vaccine preparation can be produced by mixing each material substance at an arbitrary concentration, and the result is exemplified in Example 4.
  • the vaccine formulation is intended for use in personalized medical methods.
  • -Innate immune receptor-activated adjuvant substrate for example, bacterial membrane-derived substance that is a TLR agonist, DNA, RNA, dinucleotide, NOD1, NOD2 agonist
  • -Aluminum-containing adjuvant base material such as aluminum hydroxide-Adjuvant base material capable of forming emulsions such as ISA51 and ISA720.
  • the adjuvant base comprises a substance that promotes a Th1 type immune response (eg, a nucleic acid-based base such as CpG).
  • the disclosure is a composition for treating or preventing a disease, disorder or symptom associated with a subject's immune disorder, the composition being the cause of the disease, disorder or symptom.
  • the subject contains a specific antigen component for a component different from the factor, the disease, disorder or symptom contains melanoma, the antigen component also contains a protein or a part thereof, a peptide, etc., and is CD4 positive. Those that can elicit a T cell-mediated immune response, including those that can be treated or prevented by a CD4-positive T cell-mediated immune response.
  • compositions characterized in that the composition is administered.
  • the disclosure also provides prophylactic and therapeutic methods associated with this composition.
  • the immune response is not mediated by CD8 positive T cells.
  • the disclosure is a composition for treating or preventing a cancer or tumor in a subject, wherein the composition comprises a non-tumor antigen component, the non-tumor antigen component is the subject.
  • Tregs regulatory T cells
  • the disclosure also provides prophylactic and therapeutic methods associated with this composition.
  • the present disclosure is a composition for treating or preventing a disease, disorder or symptom associated with a subject's immunological disorder, which is different from the causative factor of the disease, disorder or symptom.
  • the subject contains a specific antigen component (the antigen component may be isolated, an extract containing the antigen component or another form), and at an appropriate usage and dosage.
  • the compositions are provided that are administered (eg, once daily (1st week) and about once a week (after the 2nd week) subcutaneously or intratumorally).
  • the disclosure also provides prophylactic and therapeutic methods associated with this composition.
  • the antigen component is contained in an amount of about 0.001 ⁇ g or more per unit formulation.
  • the disclosure is a method for treating or preventing a cancer or tumor in a subject, a) identifying a non-tumor antigen specific to the subject based on an antigenic response profile. And b) a step of identifying whether or not the subject has an immune memory against the non-tumor antigen and identifying a subject having the immune memory, and c) the subject identified as having the immune memory.
  • a method comprising the step of administering the non-tumor antigen.
  • the disclosure may include prophylactic and therapeutic methods, pharmaceutical compositions, antigenic components and the like associated with this method.
  • the antigenic response profile comprises a history of vaccination and / or a history of infection.
  • the step of identifying a subject with immune memory stimulates infiltrating immune cells isolated from peripheral blood mononuclear cells (PBMCs) or tumor masses isolated from the subject with the non-tumor antigen. Then, the production of cytokines is measured, and a subject whose cytokine production amount is increased by a predetermined multiple from that before stimulation can be identified as a subject having the immune memory (also referred to as a responder).
  • the non-tumor antigen is administered once daily, three times a week, twice a week, once a week, once every two weeks, or once a month. ..
  • the dose may be increased or decreased as appropriate, such as once a day for the first time and once a week for the second and subsequent times.
  • the non-tumor antigens in the present disclosure are administered at a dose of about 0.1 pg / dose to about 1 mg / dose.
  • the disclosure provides a composition comprising mHSP10 and / or MTB12 and / or the lipoprotein LpqH for treating or preventing a disease, disorder or condition associated with a subject's immune disorder.
  • the disclosure also provides prophylactic and therapeutic methods associated with this composition.
  • Extract A used in this example was manufactured as follows. Mycobacterium tuberculosis strain Aoyama B, which has been cryopreserved (-20 ° C.), is seed-cultured in Soichiton potato medium (1) at 37 ⁇ 1 ° C. This seed culture was transplanted into the production medium (2) , and the cells obtained by culturing (main culture) at 37 ⁇ 1 ° C. for 5 to 7 weeks were washed with water for injection, and then the wet cell weight was increased. Add 20 times the amount of water for injection and heat at 100 ° C. for 120 minutes to obtain an extract.
  • This extract is filtered through a 0.45 ⁇ m membrane filter and then concentrated under reduced pressure so that the sugar content (in terms of D-arabinose by the phenol-sulfuric acid method) is 4.0 to 6.0 mg / mL to obtain a concentrated solution. Then, for the purpose of removing protein, 1 W / V% sulfosalicylic acid was added to this concentrated solution, left at 10 ° C. or lower for 15 to 20 minutes, and then the precipitate was removed by centrifugation (10 ° C. or lower, 1150 ⁇ G, 10 minutes). Then, collect the supernatant. The protein concentration of this supernatant is 0.30 mg / mL (Lowry method, tyrosine equivalent) or less.
  • the sulfosalicylic acid is removed from the supernatant until it reaches the detection limit or less (l0 ppm or less, ferric chloride solution method).
  • This solution is concentrated under reduced pressure so that the sugar content is 1.8 to 2.2 mg / mL, and sodium chloride (0.9 W / V%) and cold ethanol having the same volume as the concentrate are added thereto.
  • the precipitate polysaccharide in the polymer region
  • the precipitate is centrifuged (10 ° C. or lower, 2040 ⁇ G, 10 minutes).
  • 4 times the amount of cold ethanol is added to the supernatant, and the mixture is left at 10 ° C.
  • Sawton potato medium Soak washed potato pieces in Sawton medium, sterilize at 115 ° C. for 15 minutes, and then use as Sawton potato medium.
  • Sawton medium L-asparagine (monohydrate) 4.0 g Citric acid (monohydrate) 2.0 g
  • Magnesium sulfate (hepatohydrate) 0.5 g
  • Phosphoric acid-potassium hydrogen (anhydrous) 0.5g Ammonium ferric citrate 0.05g Glycerin 60mL Dissolve the above in water to make 1000 mL. The pH is adjusted to 7.0 to 7.3 with a sodium hydroxide solution.
  • 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 an amino acid) in lyophilized products (4) Nucleic acid content 0.1% by weight in lyophilized products (5) Main Composition of Polysaccharide Monosaccharide Mannose 43.4% by weight, arabinose 18.2% by weight, glucose 10.4% by weight. (Hydrolyzed at 100 ° C. for 2 hours with 2N trifluoroacetic acid, and then liquid chromatographing with a 2-cyanoacetamide fluorescent derivative (S. Honda, et al, Anal. Chem., 52, 1079 (1980)).
  • Extract A prepared by the method described in the above production example can be appropriately diluted before use, and in the following examples, diluted 1 to 50,000 times and adjusted to an appropriate concentration. And used.
  • Example 1 Verification of correlation between tubercle bacillus infection and memory T cells
  • a patient with a history of BCG vaccination or tuberculosis infection or a healthy person with confirmed antigen responsiveness is targeted for personalized treatment by stimulating with an antigen and analyzing the response of memory T cells. Validated for effectiveness.
  • PBMC peripheral blood mononuclear cells
  • Extract A 100 ⁇ g / mL
  • PPD 3 ⁇ g / mL
  • CMV pp65 overlapping peptides 3 ⁇ g / mL
  • TB recombinant tuberculosis
  • the PBMCs were then stained with Live / Dead fixed blue stain kit (Life technologies) and blocked with Human TruStain FcX (Biolegend) to block the following fluorescently labeled antibodies: anti-CD4 (OKT4), anti-CD8 (RP8), anti-CD8 (RP8).
  • the surface was stained using CD45RA (HI100) anti-CCR7 (G043H).
  • fixation and permeation treatment were performed by BD Cytofix / Cytoperm (BD Biosciences) to perform anti-CD3 (SK7), anti-CD154 (24-31), anti-IL-2 (MQ1-17H12), anti-TNF- ⁇ (MAb11).
  • Anti-IFN- ⁇ (4SB3) Stained cells were subjected to flow cytometric analysis using LSRII and FlowJo software (BD Biosciences).
  • Extract A promoted the secretion of Th1 cytokines (IFN- ⁇ , IL-2 and TNF- ⁇ ) from memory T cells of human PBMCs.
  • the secretion of IFN- ⁇ was also induced by stimulation with PPD.
  • PPD cytokines
  • MHSP10 which is one of the antigens contained in Extract A, induced the production of IFN- ⁇ and showed a positive correlation with Extract A.
  • IL-2 and TNF- ⁇ a correlation was also observed between Extract A and PPD, and between Extract A and MHSP10.
  • Example 2 Difference in immune status against the antitumor effect of Extract A
  • the antitumor effect of Extract A was verified using mice with different immune status.
  • BCG infection model 12 mg of dry BCG vaccine was suspended in 12 mL of physiological saline to prepare a 1 mg / mL BCG vaccine solution.
  • a BCG infection model was created by infecting mice twice 5 and 2 weeks prior to tumor cell transplantation by subcutaneous administration of the ridge with 100 ⁇ L of vaccine solution.
  • Extract A and Freund Incomplete Adjuvant are mixed in a volume ratio of 1: 1 to prepare an Extract A emulsion using a GP syringe connector (BrightPath Bio) and a lure lock syringe (HENKE SASS WOLF).
  • An Extract A emulsion immune model was created by intradermally administering 100 ⁇ L of Extract A emulsion to the ridge of a mouse using a 1 mL syringe with a 25 G needle twice, 4 weeks and 2 weeks before tumor cell transplantation. did.
  • B16BL6 cells and B16F10 cells were used as tumor cells, and these cells fell asleep about 1 week before transplantation and were passaged twice or more.
  • B16BL6 cells were diluted to 3 ⁇ 10 6 cells / mL with PBS and transplanted into anesthetized naive mice, BCG-infected mice and Extract A emulsion immunomodels at a cell count of 3.0 ⁇ 10 5 cells / mouse.
  • Extract A was diluted 10-fold with physiological saline, and 100 ⁇ L per mouse was administered subcutaneously to the right inguinal region using a 1 mL syringe with a 26 G needle. Control animals were administered an equal dose of saline. Extract A was administered subcutaneously every other day from 8 days before transplantation to dissection.
  • Extract A When Extract A was administered to naive mice, no antitumor effect was observed on either B16BL6 cells or B16F10 cells (FIGS. 2B and 2E). On the other hand, in the mice inoculated with BCG, the antitumor effect of Extract A was observed (FIGS. 2C and F). Furthermore, in Extract A emulsion-immunized mice, administration of Extract A also showed an antitumor effect on both B16BL6 cells and B16F10 cells (FIGS. 2D and G).
  • Example 3 Antitumor effect when the model antigen is administered to an animal having a memory cell specific to the model antigen
  • the inhibitory effect of the model antigen on tumor growth after immunization was verified.
  • CD4 T cells from OT-II mice (much expressing MHCclassII-binding specific TCR to ovoalbumin) or OT-II rag1 knockout (KO) mice, CD11c-positive cells from wild-type mice , CD4 T cell isolation kit (Miltenyi Biotec) or CD11c beads (Miltenyi Biotec), respectively, and separated using Auto MACS according to their respective instructions.
  • CD11c positive cells 10 7 pieces of CD4 T cells per 1 mL, CD11c positive cells were prepared to be 1 ⁇ 2 ⁇ 10 6 cells, 10 [mu] g / mL anti-IL-4 antibodies of, 7.5 ng / mL of IL-12p70,10ng / IL-2 in mL, 10 ⁇ g / mL of OVA 323-339 peptide was added and cultured. The medium was changed 3 to 4 days after culturing, and each cell was collected 6 to 7 days later. Dead cells were removed by centrifugation using Lymphorite (Sedalane).
  • CD4 T cells derived from OT-II mice differentiated into Th1 cells in vitro were transferred to Rag2KO mice or Rag2, IL-2 receptor ⁇ chain double KO mice, and ovalbumin was transferred every other day until the day of dissection. Or it was administered 15 times.
  • B16BL6 cells were transplanted 8 or 16 days after transplantation of OT-II mouse-derived cells, and changes in tumor volume were measured over time.
  • Example 4 Antitumor effect by a vaccine preparation containing various adjuvant bases
  • Example 4 Antitumor effect by a vaccine preparation containing various adjuvant bases
  • mice were immunized by administration of FIA, K3-SPG, K3-cGAMP and K3-Alum adjuvants formulated with Extract A.
  • Control mice received PBS, FIA, K3-SPG and K3-cGAMP adjuvant alone in combination with saline.
  • each adjuvant was prepared so that K3 contained 10 ⁇ g as the final dose, K3-SPG contained 5 ⁇ g as the final dose, and 2,3 cGAMP contained 10 ⁇ g as the final dose.
  • the dosage solutions were prepared to be 50% or 25% in 100 ⁇ L of each solution.
  • Extract A was diluted to 1 mg / mL with PBS and 100 ⁇ L was administered intradermally in the ridge (id). Then, tumor cells were transplanted by the same method as in Example 2 (Extract A emulsion immunomodel) and (Tumor cell transplantation), and the weight of the tumor in the mouse on the day of dissection was measured.
  • Example 5 Evaluation by flow cytometry of the effect on tumor infiltrating lymphocytes (TIL)
  • TIL tumor infiltrating lymphocytes
  • mice were infected with BCG, and 5 weeks after BCG infection, 2 ⁇ 10 5 B16BL6 cells were subcutaneously transplanted into the mice.
  • Subcutaneous administration of Extract A or physiological saline was performed every other day from 8 days before tumor cell transplantation. Mice were euthanized 14 days after tumor cell transplantation to remove the tumor.
  • Tumors were dispersed using a Tumor dissection kit (Miltenyi Biotec), and then density gradient centrifugation was performed to separate tumor cells and lymphocytes. After washing the isolated lymphocytes, dead cells were stained and Fc receptors were blocked. After staining the cell surface with various fluorescently labeled antibodies, the cells were fixed, permeabilized, and intracellularly stained with the fluorescently labeled antibody.
  • Example 6 Evaluation by flow cytometry of the effect on tumor-infiltrating lymphocytes (TIL)
  • TIL tumor-infiltrating lymphocytes
  • Companion treatment / diagnosis can be carried out as follows. -Acquisition of antigen response profile based on medical history or vaccination history using non-invasive methods, interviews, maternal and child health handbooks or equivalents. -Confirmation of whether or not the cells actually have responsiveness using the antigen panel and peripheral mononuclear cells isolated from the subject.-The antigen or a combination thereof that responded above is judged as a prophylactic or therapeutic drug and administered.
  • Example 8 Identification of cells essential for antitumor effect by Extract A
  • cells essential for the antitumor effect of Extract A were identified.
  • FIG. 7A The administration schedule of BCG, B16BL6 cells, Extract A, anti-CD4 antibody, and anti-IFN- ⁇ antibody is shown in FIG. 7A.
  • BCG was injected into mice 35 and 14 days prior to tumor inoculation, followed by 3.0 ⁇ 10 5 B16BL6 melanoma cells.
  • Extract A was subcutaneously administered every other day from 8 days before tumor inoculation.
  • 200 ⁇ g of anti-CD4 antibody was injected intraperitoneally 1 day, 3 days, 7 days and 11 days after tumor inoculation.
  • mice were infected with BCG and then saline or Extract A was administered every other day starting 8 days prior to sacrifice. Spleens were isolated from mice, ground and centrifuged to obtain cell pellets. The cell pellet was suspended in Pharma lysis buffer (BD) for 15 minutes, after which the cell suspension was centrifuged and suspended in R10. Cell number was counted by Z1 particle counter (Beckman Coulter), and adjusted to 2 ⁇ 10 7 cells / mL by R10. 100 ⁇ L of cell suspension was dispensed into 96 well round bottom microplates (Asahi Technograss) and these cells were stimulated with 100 ⁇ L of R10 containing Extract A.
  • Pharma lysis buffer BD
  • Z1 particle counter Beckman Coulter
  • Example 9 Experiment in a subcutaneous injection experimental model
  • Example 9 Experiment in a subcutaneous injection experimental model
  • FIG. 8A The schedule of the intratumoral injection experiment is shown in FIG. 8A. Specifically, Rag2-deficient mice, CD1d1-deficient mice, FcR-deficient mice, IL12p40-deficient mice and Battf3-deficient mice were subjected to BCG 35 days and 14 days before tumor cell inoculation, and Extract A was performed every other day from 8 days before tumor inoculation. Was administered subcutaneously.
  • the anti-CD8 antibody was administered 3 days, 2 days, 1 day, 3 days, 7 days and 11 days after tumor inoculation.
  • the anti-NK1.1 antibody was administered 1 day, 3 days, 7 days and 11 days after tumor inoculation. Then, the tumor volume was measured according to the method described in Example 2.
  • CD1d1-deficient mice were also evaluated, and the antitumor effect of Extract A was also observed in these mice (Fig. 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 essential for the antitumor effect.
  • Example 10 Experiment in which a tumor-unrelated protein was injected into a pre-immunized mouse
  • the antitumor effect when the tumor-unrelated protein contained in Extract A is administered to BCG-infected mice is shown.
  • proteases Protease treatment of Extract A
  • EDTA-0.5% trypsin solution Nacalai Tesque
  • subtilisin P5380
  • the proteases were heat-inactivated (HI) treated by incubation at 96 ° C. for 15 minutes.
  • the HI-treated protease or the HI-treated protease was mixed with Extract A and incubated for 16 hours. These solutions were then incubated at 96 ° C. for 15 minutes to inactivate the active enzyme.
  • Extract A In BCG-infected mice, saline, Extract A, Subtilicin-treated Extract A (Sub), heat-inactivated subtilicin-treated Extract A (HI-Sub), trypsin-treated Extract A (Trp) or fever. Extract A (HI-Trp) treated with inactivated trypsin induced the secretion of IFN- ⁇ from spleen cells. Each protease was used in 4 different concentrations. The amount of IFN- ⁇ from each stimulus was divided by the amount of IFN- ⁇ secreted by the stimulus from Extract A.
  • BCG-infected mice were subcutaneously administered with Extract A every other day from 8 days before tumor cell transplantation. Mice were euthanized 14 days after tumor cell transplantation to remove the tumor. Tumor pieces were digested using a Tumor dissociation kit (Miltenyi Biotec). After digestion, tumor fragments were disrupted using a 70 ⁇ m mesh. Tumor cells, erythrocytes and dead cells were removed by density gradient centrifugation using Lympholite-M (Sedalane). The intermediate layer after centrifugation was recovered and used as TIL.
  • Naive mice and BCG-infected mice were subcutaneously administered with saline, 0.1 ⁇ g LpqH, or 1 ⁇ g LpqH every other day from 8 days before tumor inoculation. Then, the tumor volume was measured using an electronic caliper according to the method described in Example 2 and the like.
  • Example 11 Analysis of correlation between the antitumor effect of Extract A and tumor-infiltrating lymphocytes
  • the tumor microenvironment after administration of Extract A was investigated, and the correlation with tumor-infiltrating lymphocytes was analyzed.
  • TIL tumor infiltrating lymphocytes
  • TIL is stained with anti-CD45 antibody (30-F11, BD), anti-CD62L antibody (MEL-14, BD), anti-FOXP3 antibody (FJK-16S, ebioscience), and anti-T-bet antibody (4B10, BioLegend). did. Antibodies to FOXP3 and T-bet were stained after permeabilization with BD Harmingen Transcription Factor buffer (BD). Stained cells were analyzed by LSRII (BD) and FlowJo software.
  • BD BD Harmingen Transcription Factor buffer
  • Example 12 Analysis of correlation between the antitumor effect of Extract A and TIL that produces IFN- ⁇
  • the correlation between the antitumor effect of Extract A and TIL that produces IFN- ⁇ was analyzed.
  • Intracellular IFN- ⁇ was measured with or without stimulation by Extract A according to the experimental procedure described in FIG. 11A.
  • the isolated TIL was seeded on culture plates and antigen and protein transport inhibitors were added. After culturing overnight, TIL was collected and analyzed by FACS.
  • CD4-positive memory T cells that produce IFN- ⁇ were detected under non-stimulation and were also shown to be induced independently of the Extract A antigen (FIGS. 11B and 11D). Under these experimental conditions, tumor-derived cells and debris thereof are preferably contained in the medium, so that a T cell response to the tumor antigen may be detected. Furthermore, it was revealed that CD4-positive T cells capable of producing IFN- ⁇ in response to Extract A and LpqH are present in the tumor tissues of BCG-infected mice and Extract A-immune mice (FIGS. 11C, 11E). And 11F).
  • Example 13 Antitumor effect of influenza vaccine
  • the antitumor effect of influenza vaccine was verified by the difference in immune status.
  • Influenza virus PR8 was suspended in PBS to prepare a virus solution at 10 pfu / mL. Mice were infected by nasal administration of 30 ⁇ L of virus solution to prepare a PR8 infection model. Virus infection was performed under anesthesia.
  • influenza vaccine administered to 1 ⁇ g / mL with physiological saline, and 100 ⁇ L was subcutaneously administered to the right inguinal region of the mouse.
  • Example 14 Cancer prevention, recurrence prevention, and treatment
  • clinical trials of cancer prevention, recurrence prevention, and / or treatment are performed.
  • PBMCs Peripheral blood mononuclear cells
  • Vaccination history and infection history include tuberculosis, malaria, yellow fever virus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, yellow Fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1, It may include, but is not limited to, EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza (virus), MARS, mad dog disease, diphtheria, and the like.
  • the isolated PBMC (for example, 1.0 ⁇ 10 4 to 1.0 ⁇ 10 6 cells) is mixed with the non-tumor antigen (0.01 ⁇ g / mL to 1 mg / mL) or the non-tumor antigen (0.01 ⁇ g / mL). Stimulate with an extract containing ⁇ 1 mg / mL) for about 6-24 hours and use cytokines (eg, IFN- ⁇ , IL) by detection methods commonly used in the art (eg, ELISA, qPCR and / or FACS, etc.). -2 and / or TNF- ⁇ , etc.) production is measured. Subjects whose cytokine production after stimulation is at least twice the cytokine production before stimulation are selected as Responders.
  • cytokines eg, IFN- ⁇ , IL
  • non-tumor antigens are administered according to the dosing regimen below and evaluated for clinical efficacy.
  • -Group composition Placebo or non-tumor antigen (about 0.001 ⁇ g / single dose to about 1 mg / single dose) or extract containing non-tumor antigen (about 0.001 ⁇ g / single dose to about non-tumor antigen equivalent) 2 doses (1 mg / single dose) ⁇
  • Number of subjects Approximately 100 ⁇ Route of administration: SC (subcutaneous administration) or IT (intratumor administration) -Number of administrations: Approximately once a day (1st week) and approximately once a week (after the 2nd week)
  • administering period Approximately 3 months to approximately 1 year-Primary endpoints: Progression-free survival (PFS) and overall survival (OS) -Secondary endpoints: duration of response, disease control rate, and safety.
  • PFS progression-free survival
  • OS overall survival
  • Example 15 Prevention of cancer recurrence
  • a clinical trial for preventing cancer recurrence in cancer patients is performed.
  • Method (Identification of non-tumor antigens) See Figure 13B for the protocol. Isolate tumor mass from postoperative cancer patients. In this example, the antigen response profile is identified by confirming the vaccination history and / or infection history of the cancer patient with the immune cells infiltrated into the tumor mass.
  • the vaccination history and infection history are tuberculosis, malaria, yellow fever virus, cytomegalovirus, seed poultry, measles / wind rash, polio, mumps / MUMPS, rotavirus infection, varicella, yellow Fever, Ebola, West Nile fever, hib infection, pneumoniae infection, pertussis, Japanese encephalitis, meningitis infection, salmonella infection, pathogenic Escherichia coli, toxoplasma, dicavirus, herpesvirus type 1, It may include, but is not limited to, EBV / Epstein-Barvirus (herpesvirus type 4), CMV / cytomegalovirus (herpesvirus type 5), influenza (virus), MARS, mad dog disease, diphtheria, and the like.
  • the tumor-infiltrating immune cells (1.0 ⁇ 10 4 ⁇ 1.0 ⁇ 10 6 cells / sample), the non-tumor antigens (0.01 ⁇ g / mL ⁇ 1mg / mL ) or non-tumor antigens (0.01 [mu] g / mL ⁇ Stimulate with an extract containing (1 mg / mL) for about 6-24 hours and use cytokines (eg, IFN- ⁇ , IL-, etc.) by detection methods commonly used in the art (eg, ELISA, qPCR and / or FACS, etc.). 2 and / or TNF- ⁇ , etc.) production is measured. Subjects whose cytokine production after stimulation is at least twice the cytokine production before stimulation are selected as Responders.
  • cytokines eg, IFN- ⁇ , IL-, etc.
  • non-tumor antigens are administered according to the dosing regimen below and evaluated for clinical efficacy.
  • -Group composition Placebo or non-tumor antigen (about 0.001 ⁇ g / single dose to about 1 mg / single dose) or extract containing non-tumor antigen (about 0.001 ⁇ g / single dose to about non-tumor antigen equivalent) 2 doses (1 mg / single dose) ⁇
  • Number of subjects Approximately 100 ⁇ Route of administration: SC (subcutaneous administration) or IT (intratumor administration) -Number of administrations: Approximately once a day (1st week) and approximately once a week (after the 2nd week)
  • administering period Approximately 3 months to approximately 1 year-Primary endpoints: Progression-free survival (PFS) and overall survival (OS) -Secondary endpoints: duration of response, disease control rate, and safety.
  • PFS progression-free survival
  • OS overall survival
  • the present disclosure provides a method of prevention and treatment based on an unprecedented mechanism for diseases such as cancer.

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