WO2021006316A1 - がん細胞を特異的に攻撃しているｔ細胞を同定するための特異的マーカー - Google Patents

がん細胞を特異的に攻撃しているｔ細胞を同定するための特異的マーカー Download PDF

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WO2021006316A1
WO2021006316A1 PCT/JP2020/026897 JP2020026897W WO2021006316A1 WO 2021006316 A1 WO2021006316 A1 WO 2021006316A1 JP 2020026897 W JP2020026897 W JP 2020026897W WO 2021006316 A1 WO2021006316 A1 WO 2021006316A1
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cells
cell
tcr
cancer
cell population
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English (en)
French (fr)
Japanese (ja)
Inventor
庸介 冨樫
博嘉 西川
山下　和男
ニコラ クロード ポール サックス
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Kotai Biotechnologies Inc
National Cancer Center Japan
National Cancer Center Korea
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Kotai Biotechnologies Inc
National Cancer Center Japan
National Cancer Center Korea
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Priority to EP20837130.2A priority Critical patent/EP3998082A4/en
Priority to US17/625,442 priority patent/US20220257656A1/en
Priority to JP2021530728A priority patent/JP7640047B2/ja
Priority to CN202080049198.6A priority patent/CN114080231B/zh
Publication of WO2021006316A1 publication Critical patent/WO2021006316A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4254—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
    • 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
    • C12N2510/00—Genetically modified cells
    • C12N2510/02—Cells for production

Definitions

  • Cancer immunotherapy is attracting attention as a treatment for cancer.
  • immune checkpoint inhibitors such as nivolumab, an anti-PD-1 antibody
  • nivolumab an anti-PD-1 antibody
  • nivolumab an anti-PD-1 antibody
  • Immune cells such as T lymphocytes infiltrate cancer tissues and are thought to be involved in the defense response against cancer cells.
  • T lymphocytes infiltrate cancer tissues and are thought to be involved in the defense response against cancer cells.
  • it is known that not all infiltrating immune cells are attacking cancer cells.
  • the introduction of immune cells capable of attacking tumors is being studied as a treatment for cancer.
  • One embodiment of the present disclosure may relate to the treatment or prevention of cancer in a subject using a cell subpopulation included in a tumor tissue infiltrating CD106 + T cell population.
  • One embodiment of the present disclosure uses a subject using a T cell receptor (TCR) expressed by a cell subpopulation included in a tumor tissue infiltrating CD106 + T cell population or a cell expressing a TCR having the same antigen specificity. May be related to the treatment or prevention of cancer in.
  • TCR T cell receptor
  • Further embodiments of the present disclosure may relate to methods of making cytopharmaceuticals, comprising purifying the CD106 + T cell population from the T cell population. Also provided in the present disclosure is a method of using the amount of cell subpopulation contained in a subject's CD106 + T cell population as an indicator of a subject's responsiveness to cancer immunotherapy. In the present disclosure, a method for obtaining a sequence of tumor-specific TCR may also be provided.
  • (Item 1) A composition for treating or preventing cancer in a subject, comprising a cell subpopulation included in a tumor tissue infiltrating CD106 + T cell population.
  • (Item 2) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • the composition according to the above item which is further positive for.
  • (Item 3) The composition according to any one of the above items, wherein the cell subpopulation comprises T cells derived from the subject.
  • compositions according to any one of the above items, which is used in combination with cancer immunotherapy (Item 5) The composition according to any one of the above items, wherein the cell subpopulation expresses a tumor-specific TCR.
  • Item 6 A composition for treating or preventing cancer in a subject, comprising cells expressing a TCR expressed by a cell subpopulation included in a tumor tissue infiltrating CD106 + T cell population or a TCR having the same antigen specificity.
  • a cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • composition according to any one of the above items, which is further positive for. The composition according to any one of the above items, wherein the cells contain T cells derived from the subject.
  • the composition according to any one of the above items, which is used in combination with cancer immunotherapy. The composition according to any one of the above items, wherein the cells are included in the cell subpopulation and the TCR is endogenous.
  • iPSC induced pluripotent stem cells
  • ES cells embryonic stem cells
  • T cells T cells differentiated from any of them.
  • T cells T cells differentiated from any of them.
  • a pharmaceutically acceptable carrier Use of a subpopulation of cells contained within a tumor tissue infiltrating CD106 + T cell population in the manufacture of a medicament for the treatment or prevention of cancer in a subject.
  • (Item 15) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • (Item 16) The use according to any one of the above items, wherein the cell subpopulation comprises T cells derived from the subject.
  • (Item 17) The use according to any one of the above items, wherein the drug is used in combination with cancer immunotherapy.
  • (Item 18) The use according to any one of the above items, wherein the cell subpopulation expresses tumor-specific TCR.
  • (Item 19) Use of cells expressing the TCR expressed by the cell subpopulation contained in the tumor tissue infiltrating CD106 + T cell population or TCR having the same antigen specificity in the manufacture of a drug for the treatment or prevention of cancer in a subject. ..
  • (Item 20) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • (Item 21) The use according to any one of the above items, wherein the cells include T cells derived from the subject.
  • (Item 22) The use according to any one of the above items, wherein the drug is used in combination with cancer immunotherapy.
  • (Item 23) The use according to any one of the above items, wherein the cell is included in the cell subpopulation and the TCR is endogenous.
  • (Item 24) The use according to any one of the above items, wherein the TCR is externally introduced into the cell.
  • the cells include induced pluripotent stem cells (iPSCs), embryonic stem cells (ES cells), T cells, or T cells differentiated from any of them.
  • iPSCs induced pluripotent stem cells
  • ES cells embryonic stem cells
  • T cells or T cells differentiated from any of them.
  • the medicament further comprises a pharmaceutically acceptable carrier.
  • (Item 27) A method of treating or preventing cancer in a subject, comprising the step of administering to the subject an effective amount of a cell subpopulation contained in a tumor tissue infiltrating CD106 + T cell population.
  • (Item 28) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • the method according to any one of the above items, wherein the cell subpopulation comprises T cells derived from the subject.
  • (Item 30) The method according to any one of the above items, which is characterized in that it is used in combination with cancer immunotherapy.
  • (Item 31) The method according to any one of the above items, wherein the cell subpopulation expresses a tumor-specific TCR.
  • (Item 32) A method of treating or preventing cancer in a subject that expresses an effective amount of TCR expressed by a subpopulation of cells contained in a tumor tissue infiltrating CD106 + T cell population, or TCR having the same antigen specificity. A method comprising administering to the subject an effective amount of cells.
  • (Item 33) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • the method according to any one of the above items, wherein the cells include T cells derived from the subject.
  • (Item 36) The method according to any one of the above items, wherein the cells are included in the cell subpopulation and the TCR is endogenous.
  • (Item 37) The method according to any one of the above items, wherein the TCR is introduced into the cell from the outside.
  • the cells include induced pluripotent stem cells (iPSC), embryonic stem cells (ES cells), T cells, or T cells differentiated from any of them.
  • iPSC induced pluripotent stem cells
  • ES cells embryonic stem cells
  • T cells T cells differentiated from any of them.
  • Item 39) A subpopulation of cells included in a tumor tissue infiltrating CD106 + T cell population for the treatment or prevention of cancer in a subject.
  • the cell subpopulation is a cell marker selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • the TCR or cell according to any one of the above items, wherein the cell comprises a T cell derived from the subject.
  • (Item 48) The TCR or cell according to any one of the above items, wherein the cell is included in the cell subpopulation and the TCR is endogenous.
  • (Item 49) The TCR or cell according to any one of the above items, wherein the TCR is introduced into the cell from the outside.
  • (Item 50) The TCR or cell according to any one of the above items, wherein the cell comprises a induced pluripotent stem cell (iPSC), an embryonic stem cell (ES cell), a T cell, or a T cell differentiated from any of them. ..
  • iPSC induced pluripotent stem cell
  • ES cell embryonic stem cell
  • T cell or a T cell differentiated from any of them.
  • a method of producing a cell drug for the treatment or prevention of cancer in a subject comprising the step of purifying the CD106 + T cell population from the T cell population.
  • the T cell population is isolated from T cells that have invaded tumor tissue.
  • (Item 56) The method according to any one of the above items, further comprising the step of introducing into cells the TCR possessed by the purified T cell population or the TCR having the same antigen specificity.
  • the cells include T cells derived from the subject.
  • the cells include induced pluripotent stem cells (iPSC), embryonic stem cells (ES cells), T cells, or T cells differentiated from any of them.
  • iPSC induced pluripotent stem cells
  • ES cells embryonic stem cells
  • T cells or T cells differentiated from any of them.
  • a method in which the amount of cell subpopulation contained in a subject's CD106 + T cell population is used as an index of the subject's responsiveness to cancer immunotherapy.
  • (Item 60) The method according to any one of the above items, wherein the cancer immunotherapy comprises administration of an immune checkpoint inhibitor.
  • (Item 61) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • (Item 62) The method according to any one of the above items, wherein the cell subpopulation is a tumor infiltrating T cell subpopulation.
  • (Item 63) A method of diagnosing a subject's responsiveness to cancer immunotherapy, Step of obtaining CD106 + T cell population from the subject A step of measuring the amount of cell subpopulation contained in the subject's CD106 + T cell population, and based on the amount of the cell subpopulation, the subject's A method comprising diagnosing responsiveness to immunotherapy.
  • (Item 65) A cell marker whose cell subpopulation is selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, ITGAE (CD103), TIGIT, ENTPD1 (CD39), CTLA-4 and any combination thereof.
  • a method for obtaining the sequence of a tumor-specific T cell receptor (TCR). A method comprising the step of isolating a CD106 expression-positive T cell population from tumor-infiltrating T cells; and obtaining the TCR sequence of the T cells of the T cell population.
  • the method according to any one of the above items further comprising isolating a cell population that is further positive for the marker.
  • the step of obtaining the sequence of the TCR comprises sequencing the nucleic acid sequence of the T cell.
  • the step of obtaining a sequence of TCR having the same antigen specificity as the TCR of T cells of the T cell population isolating a cell population that is further positive for the marker.
  • a highly specific marker can be provided. Since CD106 is also a surface marker, it can be used for cell separation, and T cells that specifically attack tumors can be easily extracted. If such T cells can be efficiently increased or the T cell receptor sequence can be analyzed and artificially created, it will lead to highly effective tumor-specific cell therapy despite having very few side effects.
  • FIG. 1 is a diagram showing the expression of various markers in tumor infiltrating T cells.
  • cells positive for the expression of the markers described above are shown colored.
  • the cells are clustered according to the expression pattern, and the circled part corresponds to the tumor-damaging T cell.
  • FIG. 2 is a diagram showing the secretion of IFN ⁇ when autologous tumor stimulation is performed in a cell subpopulation sorted by marker expression.
  • the specificity is high because IFN ⁇ is emitted by stimulation in the CD106 positive fraction and IFN ⁇ is emitted by stimulation in other marker positive fractions but IFN ⁇ is emitted even in the negative fraction in other markers. It can be understood that it is inferior to CD106.
  • biomarker refers to a property that is objectively measured and evaluated as an indicator of a pharmacological response to a normal biological process, pathological process, or therapeutic intervention.
  • cancer or “cancer” is used interchangeably as a malignant tumor or a malignant tumor that is highly atypical, proliferates faster than normal cells, and can destructively infiltrate or metastasize surrounding tissues. A condition in which such a malignant tumor is present.
  • cancers include, but are not limited to, solid tumors and hematopoietic tumors.
  • cancer immunotherapy refers to a method of treating cancer by using a biological defense mechanism such as an immune system possessed by an organism.
  • cell subpopulation refers to any set of cells having some common characteristics in a cell population containing cells having various characteristics. Where a particular name is known in the art, such term can also be used to refer to a particular cell subpopulation, specifying any property (eg, expression of cell surface markers). It is also possible to refer to the cell subpopulation of.
  • the term “relative amount” for cells is used interchangeably with “percentage”.
  • the terms “relative amount” and “ratio” refer to the desired subpopulation of cells (eg, CD106 + CD8 + ) relative to the number of cells forming a particular cell population (eg, CD8 + T cell population). It means the number of cells forming a T cell subpopulation).
  • criteria refers to an amount to be compared to determine the amount or level of markers described herein.
  • a “criteria” may include the amount or level prior to the treatment.
  • Samples for cell fractionation / separation can be appropriately collected from the subject by a conventional method. For example, it can be performed from the peripheral blood, bone marrow, tumor tissue, hematopoietic tissue, spleen, normal tissue, lymph fluid, etc. of the subject. By isolating the immune cells that have invaded the tumor tissue and further selecting them as needed, it is considered that cells that attack the cancer can be obtained.
  • the composition of immune cells in a sample of a subject can be measured by one of ordinary skill in the art.
  • the number of cells positive for a marker (eg, CD4) that defines a target cell subpopulation in a sample can be measured using flow cytometry or the like.
  • Flow cytometry is generally used to measure the composition of cell populations, but in addition, immunostaining for samples containing cells, methods using antibody arrays, and protein expression analysis in samples containing cells ( For example, Western blotting, mass analysis, HPLC, etc.), mRNA expression analysis in a sample containing cells (eg, microarray, next-generation sequencing, etc.) may be used.
  • cells other than the subpopulation of each cell may be experimentally excluded from the total cells.
  • Cells can also be identified by examining the mRNA in individual cells by single-cell gene expression analysis and examining the presence or absence of mRNA encoding the protein molecule of interest.
  • single-cell gene expression analysis for example, 1) a method of performing next-generation sequencing using Quartz-Seq, and 2) isolating cells using Quantim C1 System or ICELL8 SIngle-Cell System and live on SMART-Seq v4 Examples thereof include a method of preparing a rally, 3) a method of separating cells with a cell sorter and measuring by quantitative PCR using an Ambion Single Cell-to-CT kit, and 4) CyTOF SYSTEM (Helios).
  • cell subpopulations with a particular marker expression pattern can be provided.
  • a cell subpopulation included within the CD106 + cell population can be provided.
  • Such cell subpopulations are cell markers selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, TIGIT, ITGAE (CD103), ENTPD1 (CD39), CTLA-4 and any combination thereof. Can be even more positive.
  • the cell subpopulations described in the present disclosure are, in the present disclosure, as cells used for adoptive cell transfer, as cells for obtaining tumor-specific TCR from the cells, as cells for using the amount as an index, and /. Or it can be used as a cell for making modifications to it.
  • a tumor tissue infiltrating cell population or a cell subpopulation contained therein can be used.
  • markers such as PD-1 and 4-1BB have been used as surface markers for T cells that specifically attack tumors, and in the most recent reports, CD103 and CD39 have been newly focused on. There is a report.
  • CD106 has the highest specificity as a surface marker, and it is useful in comparison with those markers even based on a comprehensive comparison of the reported markers. Conceivable.
  • the cell or cell population may be an immune cell or a progenitor cell thereof or a population thereof.
  • Immune cells include dendritic cells, macrophages, lymphocytes (eg, T cells (eg, killer T cells, helper T cells, regulatory T cells, ⁇ T cells, ⁇ T cells, natural killer T cells), B cells, NK. (Natural killer) cells), neutrophils, eosinophils, and basal spheres, and combinations thereof.
  • T cells eg, killer T cells, helper T cells, regulatory T cells, ⁇ T cells, ⁇ T cells, natural killer T cells
  • B cells e. (Natural killer) cells
  • neutrophils neutrophils
  • eosinophils eosinophils
  • basal spheres e.
  • the T cells in the present disclosure may be CD8-positive T cells.
  • Cytotoxic T cells are a type of lymphocyte T cells that recognize and destroy cells that are foreign to the host (such as cancer cells). CTLs differentiate from T cells expressing CD8 molecules on their surface.
  • a composition for treating or preventing cancer in a subject may be provided that comprises a cell subpopulation included in a tumor tissue infiltrating CD106 + T cell population.
  • a method for treating or preventing cancer in a subject may be provided that comprises the step of administering a cell subpopulation included in the tumor tissue infiltrating CD106 + T cell population.
  • the cell subpopulation is a cell marker selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, TIGIT, ITGAE (CD103), ENTPD1 (CD39), CTLA-4 and any combination thereof. On the other hand, it may be more positive.
  • the cell subpopulation may include T cells derived from a subject to be treated or prevented, or may include T cells derived from a subject different from the subject to be treated or prevented.
  • the cell subpopulation can be one that expresses tumor-specific TCR.
  • the markers provided in the present disclosure can identify cell subpopulations expressing tumor-specific TCR.
  • cell-containing compositions or adoptive cell transfer therapy can be combined with cancer immunotherapy.
  • cells can be provided that express a TCR expressed by a cell subpopulation included in a tumor tissue infiltrating CD106 + T cell population or a TCR having the same antigen specificity.
  • the cell may be the cell itself contained in the tumor tissue infiltrating CD106 + T cell population, or a different cell expressing TCR expressed by the cell subpopulation contained in the tumor tissue infiltrating CD106 + T cell population. You may.
  • Such cells can be obtained by introduction of TCR or by screening for TCR.
  • TCR can be introduced into cells from the outside.
  • cells to be introduced include artificial pluripotent stem cells (iPSC), embryonic stem cells (ES cells), peripheral T cells, naive T cells, memory T cells, central memory T cells (TCM), and T memory stem cells (TSCM), or T cells differentiated from either of them can be included.
  • iPSC artificial pluripotent stem cells
  • ES cells embryonic stem cells
  • TCM central memory T cells
  • TSCM T memory stem cells
  • TCR T cells differentiated from either of them can be included.
  • the introduction of TCR can be carried out by the methods described elsewhere in this disclosure and by methods known to those of skill in the art.
  • the CD3 molecule Since the CD3 molecule is present on the cell membrane and forms a complex with the TCR, it can be used as a marker for TCR expression. Endogenous antigens such as viral antigens that have proliferated intracellularly due to viral infection and cancer antigens derived from cancer cells are presented as antigen peptides on MHC class I molecules. In addition, antigens derived from foreign microorganisms are taken up by antigen-presenting cells by endocytosis, processed, and then presented on MHC class II molecules. These antigens are recognized by the TCR expressed by CD8 + T cells or CD4 + T cells, respectively. It is also known that co-stimulatory molecules such as CD28, ICOS, and OX40 molecules are important for stimulation via TCR molecules.
  • co-stimulatory molecules such as CD28, ICOS, and OX40 molecules are important for stimulation via TCR molecules.
  • the TCR gene has a large number of V regions (variable region, V), J region (joining region, J), D region (diversity region, D) and constant region C region (constant region) encoded in different regions on the genome. , C).
  • V variable region
  • J jointing region
  • D diversity region
  • C constant region C region
  • T cells produce one type of TCR with high specificity for a specific antigen. Due to the presence of a large number of antigen-specific T cells in a living body, a diverse TCR repertoire (repatoa) is formed and can effectively function as a defense mechanism against various pathogens.
  • a method of obtaining a tumor-specific T cell receptor (TCR) sequence may be provided.
  • this disclosure indicates that the cell subpopulations included in the CD106-positive T cell population specifically attack cancer, such cell subpopulations. It is considered that tumor-specific TCR can be isolated by isolating.
  • a method for obtaining the sequence of a tumor-specific T cell receptor (TCR) which is a step of isolating a CD106 expression-positive T cell population from tumor infiltrating T cells; and T of the T cell population.
  • a method may be provided that comprises the step of obtaining the TCR sequence of a cell.
  • the isolation step is any other marker disclosed herein (eg, LAG-3, PD-1, TIM3, 4-1BB, TIGIT, ITGAE (CD103), ENTPD1, CTLA-4 and theirs. It may further include isolating a cell population that is more positive for (cell markers selected from the group consisting of any combination of).
  • Obtaining the TCR sequence may include sequencing the nucleic acid sequence of the T cell.
  • the method for sequencing is not limited as long as the sequence of the nucleic acid sample can be determined, and any method known in the art can be used, but next-generation sequencing (NGS) can be used. preferable.
  • Next-generation sequencing includes, but is not limited to, pyrosequencing, synthetic sequencing (sequencing bisynthesis), ligation sequencing, and ionic semiconductor sequencing.
  • the TCR sequence can be obtained by amplicon sequence from intron-free mRNA.
  • the TCR sequence can be obtained by sequencing the genome sequence of T cells.
  • the TCR sequence may be obtained by directly determining the amino acid sequence of the TCR molecule, such as by mass spectrometry or Edman degradation. In the present specification, both an amino acid sequence and a nucleic acid sequence can be used as the "TCR sequence".
  • TCR cluster TCRs having the same antigen specificity as TCRs having tumor specificity can be used.
  • a TCR having the same antigen specificity as the TCR of the CD106 + T cell population can be used. "Having the same antigen specificity" can be determined by classifying the two TCRs into the same cluster by cluster analysis as shown below.
  • a TCR sequence having the same antigen specificity as the T cell TCR of an isolated T cell population such as CD106 + T cell population can be obtained. This can be achieved by subjecting one or more TCRs to the TCR of the T cells of the isolated T cell population and cluster analysis as shown below. Such an analysis method is described in detail in Japanese Patent No. 6500144, and the content thereof is incorporated herein by reference.
  • Cluster analysis of TCRs is (i) a step of providing features of at least two TCRs, except that the steps calculate features from a three-dimensional structural model of the at least two TCRs. (Ii) A step of machine learning the analysis of the antigen specificity or binding mode of the TCR without specifying the antigen specificity or binding mode based on the feature amount, and (iii) the antigen specificity or binding mode. It can be done by an analytical method that includes steps to make a classification or difference determination.
  • the set of TCRs is (aa) a step of extracting features for each of at least one paired sequence of members of the set of TCRs, the step forming the at least one pair. Except for calculating features from the three-dimensional structural model of the immune entity of the sequence, the steps and (bb) project the features into a higher dimensional vector space, where the spatial distance of the member is the member. Includes steps that reflect the functional similarity of, (cc) clustering the set of immune entities based on the distance, and (dd), if necessary, analyzing based on the classification by the clustering. Can be analyzed by the method.
  • the feature quantities include sequence information, CDR1-3 sequence length, sequence matching degree, sequence matching degree in the framework region, total charge / hydrophilic / hydrophobic / aromatic amino acid number of the molecule, each CDR, and framework.
  • Machine learning is performed by random forest or boosting with features as input, and clustering can be performed by a simple threshold based on bond length, hierarchical clustering, or non-hierarchical clustering method.
  • Machine learning can be selected from a group of machine learning algorithms such as recursive methods, neural network methods, support vector machines, and random forests.
  • a method for producing cells can be provided.
  • cells contained in the tumor CD106 + CD8 + T cell population express tumor-specific TCR can be used to obtain cells that attack the tumor. ..
  • Such cells may be useful for the treatment or prevention of cancer.
  • One embodiment of the present disclosure provides a method of producing a cytopharmaceutical for the treatment or prevention of cancer in a subject, comprising purifying the CD106 + T cell population from the T cell population. obtain.
  • the method is positive for cellular markers selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, TIGIT, ITGAE (CD103), ENTPD1, CTLA-4 and any combination thereof. It may further include the step of purifying the cell population.
  • the T cell population can be isolated from T cells that have infiltrated the tumor tissue.
  • T cell medicine containing a purified T cell population.
  • T cell populations are believed to have tumor-specific TCR and may be useful as cell medicines.
  • the purified T cell population can be cultivated and / or proliferated to provide medicinal.
  • the purified T cell population can be further modified as needed. Modifications of T cells include stimulation by integrins ⁇ 4 ⁇ 7 and ⁇ 4 ⁇ 1 (VLA-4) that interact with CD106, and CD3, IL-2, IL-4, and IL-7.
  • a method may be provided that comprises the step of introducing into cells the TCR of a purified T cell population or a TCR having the same antigen specificity. Acquisition and / or introduction of TCR can be performed by the methods described elsewhere herein, or by other methods known to those of skill in the art. Tumor-specific TCR may be introduced by modifying the acquired sequence, if necessary.
  • T cells derived from the subject to be treated or prevented may be used, or any other immune cells may be used.
  • Examples of cells to be introduced include artificial pluripotent stem cells (iPSC), embryonic stem cells (ES cells), peripheral T cells, central memory T cells (TCM), T memory stem cells (TSCM), naive T cells, and the like. It can include memory T cells, or T cells differentiated from any of them.
  • cancers covered in this disclosure include lung cancer, kidney (renal cell) cancer, prostate cancer, gastric cancer, testis cancer, liver (visceral) cancer, skin cancer, esophageal cancer, melanoma, and pancreas.
  • pancreatic cancer pancreatic cancer, bone tumor / osteosarcoma, colon cancer, bone soft tumor, biliary tract cancer, multiple myeloma, malignant lymphoma (hodgkin lymphoma, non-hodgkin lymphoma), urinary tract epithelial cancer, uterine cancer ( Body / neck), head and neck cancer, brain tumor, thoracic adenocarcinoma, thyroid cancer, mesenteric tumor, anal cancer, penis cancer, cancer of unknown primary origin, ovarian cancer, breast cancer, etc. It is not limited to.
  • cancer immunotherapy refers to a method of treating cancer using the immune function of an organism.
  • Cancer immunotherapy can be broadly divided into cancer immunotherapy by strengthening the immune function against cancer and cancer immunotherapy by inhibiting the immune evasion function of cancer.
  • cancer immunotherapy includes active immunotherapy that activates the immune function in the body and passive immunotherapy by returning the immune cells that have activated or proliferated the immune function in the body to the body. is there.
  • examples of cancer immunotherapy include non-specific immunostimulatory drugs, cytokine therapy, cancer vaccine therapy, dendritic cell therapy, adoptive immunotherapy, non-specific lymphocyte therapy, cancer antigen-specific T cell therapy, and antibodies. Examples include therapy, immune checkpoint inhibition therapy, CAR-T therapy and the like.
  • the present disclosure may provide a method of using the amount of cell subpopulation that specifically attacks a tumor as an indicator of a subject's responsiveness to cancer immunotherapy.
  • a method may be provided in which the amount of cell subpopulation contained in a subject's CD106 + T cell population is used as an indicator of the subject's responsiveness to cancer immunotherapy.
  • Cancer immunotherapy may include administration of immune checkpoint inhibitors.
  • cell markers selected from the group consisting of LAG-3, PD-1, TIM3, 4-1BB, TIGIT, ITGAE (CD103), ENTPD1, CTLA-4 and any combination thereof. Those that are positive can be used.
  • the amount at any site can be used, but preferably the amount of the cell subpopulation in the tumor infiltrating T cells can be used.
  • Immune checkpoint (inhibition) therapy using immune checkpoint inhibitors has received a great deal of attention in recent years (Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22; 12 (4): 252-64.). Cancer cells express various proteins on the surface, which leads to avoidance from attacks by immune cells such as T cells, so under normal conditions, cancer tissue is eliminated only by the immune function of the living body. It is believed that it is no longer possible. Immune checkpoint inhibitors are effective in cancer by the immune function of the living body by inhibiting the ligand-receptor interaction, etc., which controls the transmission of inhibitory signals from such cancer tissues to immune function. It enables exclusion.
  • One embodiment of the present disclosure uses the amount of cell subpopulation contained in the CD106 + T cell population as an indicator for predicting a subject's responsiveness to immune checkpoint inhibitors as described below.
  • the method Another embodiment of the present disclosure is a method of administering an immune checkpoint inhibitor as shown below to a (responsive) subject selected based on the amount of cell subpopulation contained in the CD106 + T cell population. Is.
  • a typical example of an immune checkpoint inhibitor is a PD-1 inhibitor.
  • the PD-1 inhibitors, anti-PD-1 antibody nivolumab (Nivolumab; sold as Obujibo TM) and Pemuburorizumabu (Pembrolizumab; sold as Kiitoruda TM) include, but are not limited to.
  • the anti-PD-1 antibody is considered to exert an anti-cancer effect by releasing the suppression of T cell activation by the PD-1 signal.
  • PD-1 programmeed death 1
  • SHP-2 a type of tyrosine dephosphorylating enzyme, is recruited into the cytoplasmic domain of PD-1 and a T cell receptor signal is signaled.
  • Inactivation of the transmissible protein ZAP70 is thought to suppress T cell activation (Okazaki, T., Chikuma, S., Iwai, Y. et al .: A rheostat for immune). responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol., 14, 1212-1218 (2013)).
  • PD-L1 is also thought to interact with CD80 and suppress T cell activation (Butte, MJ, Keir, ME, Phamduy, TB et al .: PD-L1 interacts specifically with B7-1 to inhibit T cell proliferation. Immunity, 27, 111-122 (2007)).
  • PD-1 is highly expressed in killer T cells and natural killer cells that infiltrate cancer tissues, and it is believed that PD-L1 on tumors attenuates the immune response.
  • the attenuation of the immune response by the PD-1 signal is inhibited by the anti-PD-1 antibody, the effect of enhancing the antitumor immune response can be obtained.
  • immune checkpoint inhibitors include PD-L1 inhibitors (eg, anti-PD-L1 antibodies such as avelumab, durvalumab or atezolizumab).
  • PD-L1 inhibitors eg, anti-PD-L1 antibodies such as avelumab, durvalumab or atezolizumab.
  • the PD-L1 inhibitor binds and inhibits the PD-1 pathway described above to the side of PD-L1 to generate an anti-tumor immune response.
  • immune checkpoint inhibitors include CTLA-4 inhibitors (eg, anti-CTLA-4 antibody ipilimumab or tremerylumab).
  • CTLA-4 inhibitors activate T cells by a different pathway than PD-1 inhibition, resulting in an anti-tumor immune response. T cells are activated by surface CD28 interacting with CD80 or CD86. However, even in once activated T cells, CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) expressed on the surface preferentially interacts with CD80 or CD86 with a higher affinity than CD20. However, it is believed that activation is suppressed.
  • CTLA-4 inhibitors result in an anti-tumor immune response by preventing the interaction of CD20 with CD80 or CD86 by inhibiting CTLA-4.
  • the immune checkpoint inhibitor may target an immune checkpoint protein such as TIM-3, LAG-3, B7-H3, B7-H4, B7-H5 (VISTA), or TIGIT.
  • an immune checkpoint protein such as TIM-3, LAG-3, B7-H3, B7-H4, B7-H5 (VISTA), or TIGIT.
  • the immune checkpoints described above are thought to suppress the immune response to self-tissues, but even when an antigen such as a virus is present in the body for a long period of time, the immune checkpoints increase in T cells. Since tumor tissue is also an antigen that exists in the living body for a long period of time, it is considered that antitumor immunity is avoided by these immune checkpoints, and the above-mentioned immune checkpoint inhibitors are described in this way. It has an antitumor effect by disabling the avoidance function.
  • CR complete response
  • PR partial response
  • PD progressive disease
  • SD stable
  • the term “responder” refers to a subject who has a complete or partial response to cancer treatment.
  • the term “non-responder” refers to a subject who is advanced or stable to cancer treatment.
  • the subject's responsiveness to cancer treatment includes that the subject is a "responding patient” or that the subject is a "non-responding patient”. Therefore, determining a subject's responsiveness to cancer treatment includes determining whether the subject is a responding patient or a non-responding patient.
  • the subject is a "responding patient” or that the subject is a "non-responding patient” using the amount of cell subpopulation contained in the CD106 + T cell population.
  • Predict or judge The timing of judgment is preferably predicted before the start of treatment, but may be after the start of treatment. It is also medically useful to determine whether the current treatment is appropriate.
  • the prognosis can be determined using the amount of cell subpopulation contained in the CD106 + T cell population of the present disclosure.
  • the amount of cell subpopulation contained in the CD106 + T cell population of the present disclosure can be used to predict that responding patients will be ineffective, that is, recurrence.
  • the timing of judgment it is possible to analyze the cell subpopulation composition over time after performing cancer immunotherapy (for example, after administration of an immune checkpoint inhibitor) to judge the prognosis.
  • the present disclosure comprises a composition comprising an immune checkpoint inhibitor for treating cancer in a subject having a high amount of cell subpopulation in the CD106 + T cell population.
  • the composition may be provided. It may be advantageous to administer such an immune checkpoint inhibitor to a subject with a large amount of cell subpopulation contained in the CD106 + T cell population, as many cells are considered to attack the tumor. Then, a subject having a low amount of cell subpopulation contained in the CD106 + T cell population can be determined to be a non-responding patient, and the immune checkpoint inhibitor is not administered, or the administration is discontinued or discontinued. Judgments can also be made.
  • the composition of the present disclosure is preferably a pharmaceutical composition, and examples of the immune checkpoint inhibitor contained as an active ingredient thereof include a PD-1 inhibitor.
  • PD-1 inhibitors include anti-PD-1 antibodies, nivolumab or pembrolizumab.
  • the composition can be formulated in any dosage form such as aerosols, solutions, extracts, elixirs, capsules, granules, pills, ointments, powders, tablets, solutions, suspensions, emulsions and the like.
  • the composition may contain any pharmaceutically acceptable additives and / or excipients known in the art.
  • the compositions of the present disclosure can be administered by any suitable route determined by one of ordinary skill in the art, including, but not limited to, intravenous injection, infusion, oral, parenteral, transdermal and the like. it can.
  • compositions containing immune checkpoint inhibitors or cells may be used in combination with other cancer treatments as appropriate.
  • Other cancer treatments include, but are not limited to, other cancer immunotherapy, radiation therapy, chemotherapy, hyperthermia, surgical procedures, and the like.
  • Compositions comprising immune checkpoint inhibitors or cells may be administered in combination with one or more additional agents.
  • the one or more additional agents may be any chemotherapeutic agent or may include a second immune checkpoint inhibitor.
  • compositions comprising an immune checkpoint inhibitor are provided.
  • Compositions comprising the immune checkpoint inhibitors of the present disclosure are usually administered systemically or topically, in oral or parenteral form.
  • Compositions comprising the immune checkpoint inhibitors of the present disclosure are markedly treated by administration by a method described herein to a subject who has been shown to have a large number of cells attacking a tumor. It is thought that the effect can be achieved.
  • the dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually, for example, from once a day to several times in the range of 0.1 mg to 100 mg per adult. Oral administration, or parenteral administration (preferably intravenous administration) once to several times daily in the range of 0.01 mg to 30 mg per adult, or daily. It is continuously administered intravenously in the range of 1 to 24 hours.
  • a dose smaller than the above dose may be sufficient, or it may be necessary beyond the range.
  • compositions containing immune checkpoint inhibitors or compositions containing cells may be administered as solids for oral administration, liquids for oral administration, and injections, external preparations, suppositories, etc. for parenteral administration.
  • Oral solids for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • compositions of the present disclosure are optionally intact with one or more active ingredients (eg, antibodies against cell or immune checkpoint proteins) or excipients (lactose, mannitol, glucose, microcrystalline cellulose, etc.). Starch, etc.), binder (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), disintegrant (calcium fibrin glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, solubilizer (solubilizer, etc.) It is mixed with glutamic acid, aspartic acid, etc.) and formulated according to a conventional method.
  • active ingredients eg, antibodies against cell or immune checkpoint proteins
  • excipients lactose, mannitol, glucose, microcrystalline cellulose, etc.
  • binder hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.
  • disintegrant calcium
  • a coating agent sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.
  • a coating agent sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.
  • capsules of absorbable substances such as gelatin.
  • this injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. ..
  • a stabilizer for example, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.
  • a suspending agent for example, a lyophilized product, which is sterilized or dissolved in sterile distilled water for injection or other solvent before use.
  • Tumor tissue was obtained from surgical specimens of anti-PD-1 antibody-effective melanoma patients prior to the start of anti-PD-1 antibody treatment. Tumor tissue was enzymatically treated with collagenase and DNase and stirred at 37 ° C. for 30 minutes to isolate cells. From a cell mixture of tumor tissue cells and tumor infiltrating immune cells, CD3-positive cells were sorted using BD FACSAria III to obtain TCR-expressing T cells.
  • a UMAP plot was created from the obtained fastq file using Python's umap library. The display of each gene was mapped on the obtained UMAP plot.
  • Example 2 Tumor aggression of CD106 positive cell population
  • Example 2 Tumor aggression of CD106 positive cell population
  • cells of tumor tissue were isolated, and CD3 positive cells were sorted from the mixture using BD FACSAria III to obtain TCR-expressing T cells as tumor infiltrating T cells.
  • Tumor-infiltrated T cells were co-cultured with a cell line established from an autologous tumor, and the secretion of IFN ⁇ was compared with that without stimulation. IFN ⁇ secretion was measured by intracellular staining with anti-IFN ⁇ antibody.
  • Cell staining was performed with anti-PD-1 antibody, anti-TIGIT antibody, anti-LAG3 antibody, and anti-CD106 antibody.
  • As a negative control an isotype control antibody against the anti-CD106 antibody was used.
  • Example 3 Creation of cells
  • the patient's tumor tissue is obtained and the cells are separated by enzyme treatment. Tumor infiltrating T cells are isolated as a CD3 positive fraction by flow cytometry. From the CD3 positive fraction, the CD106 positive and CD8 positive fractions are further isolated.
  • the cells of the isolated fraction are cultured and proliferated to be used as a cell medicine.
  • Sequence the nucleic acid sequence of the cells of the isolated fraction and obtain the TCR sequence.
  • a vector having the obtained TCR sequence is designed and introduced into other cells. The introduced cells are cultured and proliferated as needed to obtain a cell medicine.
  • Example 4 Prediction of effect of cancer immunotherapy
  • CD106 + T cell subpopulation in tumor-infiltrating T cells (CD106 + T cell subpopulation, CD106 + CD8 + T cell subpopulation, LAG-3 + CD106 + CD8 + T cell subpopulation, PD-1 + CD106 + CD8 + T cell subpopulation, TIM3 + CD106 + CD8 + T cell subpopulation, 4-1BB + CD106 + CD8 + T cell subpopulation, TIGIT + CD106 + CD8 + T cell subpopulation, ITGAE + CD106 + CD8 + Obtain the amount of T cell subpopulation, ENTPD1 + CD106 + CD8 + T cell subpopulation, CTLA-4 + CD106 + CD8 + T cell subpopulation).
  • a specific cell subpopulation amount can be an index.

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