Biomarkers for determining efficacy of immune checkpoint inhibitors

Abstract

The present invention addresses the problem of providing: a method for identifying patients having malignant tumors and more likely to benefit from the effects of immune checkpoint inhibitors; and an agent that is for inhibiting the progress and recurrence of malignant tumors, and / or treating malignant tumors, and that is characterized by being prescribed on the basis of the method.　The present invention provides an agent that is for inhibiting the progress and recurrence of malignant tumors, and / or treating malignant tumors, and that is characterized by: involving identification of patients having malignant tumors and more likely to benefit from immune checkpoint inhibitors, by use of a plurality of combinations of two sets of assessment items and specific conditions specified by the respective two-set combinations; and being prescribed on the basis of the identification.

Description

[Technical field]

[0001] The present invention relates to a method for identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors (hereinafter sometimes abbreviated as the "patient identification method of the present invention"), and to a drug for inhibiting the progression and recurrence of and / or treating malignant tumors, characterized by a prescription based on the method. [Background technology]

[0002] Cancer immunotherapy, unlike conventional treatments such as surgery, radiation therapy, and chemotherapy with anticancer drugs or molecular targeted drugs, is a therapy that suppresses or treats the progression of malignant tumors by acting on the immune surveillance mechanism inherent in the malignant tumor patient himself / herself and strengthening the immunity against malignant tumors. Recent research on tumor immunity has revealed that the progression of malignant tumors is related to an immunosuppressive environment centered on the tumor local area, and that tumors themselves use a system to evade the immune surveillance mechanism. Molecules used in such evasion systems include so-called immune checkpoint molecules such as PD-1 and its ligand PD-L1, and these inhibitors have already achieved some success in clinical trials.

[0003] However, it is still true that there are malignant tumor patients for whom these immune checkpoint inhibitors do not provide sufficient therapeutic benefit, and there is an urgent need to identify efficacy markers that can identify patients who may benefit from these drugs.

[0004] To date, CD8 + Although there is a report suggesting that the ratio of T cell counts to Treg cell counts may correlate with the prognosis of patients with malignant tumors (Non-Patent Document 1), there has been no reported treatment that can predict the effectiveness of an immune checkpoint inhibitor before administration by evaluating a combination of at least two items according to the present invention and prescribe the immune checkpoint inhibitor to patients identified based on the biomarkers. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Journal of Clinical Oncology 34, no. 8 (March 2016) 833-842. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a method for identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors, and a prescription based on the method for inhibiting the progression and recurrence of and / or treating malignant tumors. [Means for solving the problem]

[0007] As a result of intensive research, the inventors of the present invention discovered that specific conditions defined by the evaluation items described in this specification or combinations of each pair of them can serve as biomarkers that can predict the effectiveness of immune checkpoint inhibitors, and thus completed the present invention. That is, the present invention is as follows. [1] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells express the following formula:

[0008]

number

[0009] [In the formula, Y 1 The CD8 + The percentage of CCR7-expressing T cells (%) is shown. 1-1 represents a number of about -637, and X 1 Foxp3 +The mean fluorescence intensity (MFI) of PD-1 expression in T cells relative to the CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells, and Y 1-1 represents any numerical value from about 784 to about 914.], or (2) (i) the following formula:

[0010]

number

[0011] [In the formula, Y 1-2 represents any number between about 39.0 and about 50.9, and a 1-2 represents a numerical value of approximately -24.0, and the other symbols have the same meanings as above.] and (ii) the following formula:

[0012]

number

[0013] [In the formula, a 1-3 represents the value of approximately 666, and Y 1-3 represents any numerical value from about -652 to about -522, and the other symbols have the same meanings as above.] (Herein, the combination of conditions represented by formulas (1) and (2)(i) and (2)(ii) may be abbreviated as "biomarker 1". In addition, in this specification, the "agent for inhibiting progression, inhibiting recurrence and / or treating malignant tumors comprising an immune checkpoint inhibitor as an active ingredient" of the present invention may be collectively abbreviated as "the agent for inhibiting progression, inhibiting recurrence and / or treating malignant tumors comprising an immune checkpoint inhibitor as an active ingredient" of the present invention may be abbreviated as "the agent for inhibiting progression, inhibiting recurrence and / or treating malignant tumors comprising an immune checkpoint inhibitor as an active ingredient".) [2] Y 1-1 represents any numerical value from about 853 to about 914. [3] Y 1-2 The agent according to the preceding item [1] or [2], wherein represents any numerical value between about 39.0 and about 44.6. [4] Y 1-3 The agent according to any one of the preceding items [1] to [3], wherein represents any numerical value from about -652 to about -591. [5] Y 1-1 The agent according to the preceding item [1], [3] or [4], wherein represents any numerical value from about 784 to about 853. [6] Y 1-2 The agent according to the preceding item [1], [2], [4] or [5], wherein represents any numerical value between about 44.6 and about 50.9. [7] Y 1-3 The agent according to any one of the preceding items [1] to [3], [5] and [6], wherein represents any numerical value from about -591 to about -522. [8] Y 1-1 The agent according to the preceding item [1], [3], [4], [6] or [7], wherein the MnI is about 853. [9] Y 1-2 The agent according to the preceding item [1], [2], [4], [5], [7] or [8], wherein the MgCl2 content is about 44.6.

[10] Y 1-3 The agent according to any one of the preceding items [1] to [3], [5], [6], [8] and [9], wherein the MgO concentration is about -591.

[11] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells express the following formula:

[0014]

number

[0015] [wherein all symbols have the same meanings as in the preceding paragraph [1].], or (2)(i) the following formula:

[0016]

number

[0017] [wherein all symbols have the same meaning as in the preceding paragraph [1].] and (ii) the following formula:

[0018]

number

[0019] [wherein all symbols have the same meaning as in the preceding paragraph [1].], wherein the agent is administered to a patient with a malignant tumor who satisfies the two conditions represented by the formula:

[12] Treg cells (Fr.III) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0020]

number

[0021] [In the formula, Y 2 represents the percentage (%) of PD-1 expressing cells in the Treg cells (Fr.III), and a 2-1 represents a value of approximately 0.765, and X 2 The CD8 + The percentage of PD-1 expressing T cells is shown. 2-1 represents any numerical value between about 50.6 and about 59.2.], or (2) the condition represented by the following formula:

[0022]

number

[0023] [In the formula, a 2-2 represents a value of approximately 1.56, and Y 2-2 represents any numerical value from about -44.1 to about -14.5, and the other symbols have the same meanings as above.], wherein the agent for inhibiting progression and inhibiting recurrence and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the conditions represented by the formulas (1) and (2) (hereinafter, the combination of conditions represented by the formulas (1) and (2) may be abbreviated as "biomarker 2").

[13] Y 2-1 represents any numerical value from about 54.1 to about 59.2.

[14] Y 2-2 represents any numerical value from about -44.1 to about -26.6.

[15] Y 2-1 The agent according to the preceding item

[12] or

[14] , wherein represents any numerical value from about 50.6 to about 54.1.

[16] Y 2-2 represents any numerical value from about -26.6 to about -14.5.

[17] Y 2-1 The agent according to the preceding item

[12] ,

[14] or

[16] , wherein the MgCl2 content is about 54.1.

[18] Y 2-2 The agent according to the preceding item

[12] ,

[13] ,

[15] or

[17] , wherein the MgCl2 concentration is about -26.6.

[19] Treg cells (Fr.III) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0024]

number

[0025] [wherein all symbols have the same meanings as in the preceding paragraph

[12] .], or (2) the following formula:

[0026]

number

[0027] [wherein all symbols have the same meanings as in the preceding paragraph

[12] .], wherein the agent for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[20] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 +(1)(i) a formula comprising:

[0028]

number

[0029] [In the formula, Y 3 The CD8 + The number of PD-1 expressing T cells is shown. 3-1 represents a value of approximately -1.59, and X 3 Foxp3 + MFI of PD-1 expression on T cells versus CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells, and Y 3-1 represents any number between about 4.09 and about 4.89; or (ii) the following formula:

[0030]

number

[0031] [wherein all symbols have the same meanings as above], or (2)(i) the following formula:

[0032]

number

[0033] [In the formula, a 3-2 represents a value of approximately -9.05, and Y 3-2 represents any numerical value from about 10.7 to about 13.3, and the other symbols have the same meanings as above.] or (ii) a formula:

[0034]

number

[0035] [wherein all symbols have the same meaning as above], an agent for suppressing progression, suppressing recurrence and / or treating a malignant tumor, comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered to a patient with a malignant tumor who satisfies the conditions represented by the formula (1) and (2) here (hereinafter, the combination of conditions represented by the formulas (1) and (2) may be abbreviated as "biomarker 3").

[21] Y 3-1 represents any numerical value from about 4.42 to about 4.89.

[22] Y 3-2 The agent according to the preceding item

[20] or

[21] , wherein represents any numerical value from about 11.7 to about 13.3.

[23] Y 3-1 The agent according to the preceding item

[20] or

[22] , wherein represents any numerical value from about 4.09 to about 4.42.

[24] Y 3-2 The agent according to the preceding item

[20] ,

[21] or

[23] , wherein represents any numerical value from about 10.7 to about 11.7.

[25] Y 3-1 The agent according to the preceding item

[20] ,

[22] or

[24] , wherein the MnI is about 4.42.

[26] Y 3-2 The agent according to the preceding item

[20] ,

[21] ,

[23] or

[25] , wherein the MgCl2 content is about 11.7.

[27] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + (1)(i) a formula comprising:

[0036]

number

[0037] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .] or (ii) the following formula:

[0038]

number

[0039] [wherein all symbols have the same meanings as in the preceding paragraph

[20] ], or (2)(i) The following formula:

[0040]

number

[0041] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .] or (ii) the following formula:

[0042]

number

[0043] [wherein all symbols have the same meanings as in the preceding paragraph

[20] .], wherein the agent is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[28] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells express the following formula:

[0044]

number

[0045] [In the formula, Y 4 Foxp3 + MFI of PD-1 expression on T cells versus CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells; a 4-1 represents a number of approximately -0.00273, and X 4 The CD8 + The percentage of PD-1 expressing T cells is shown. 4-1 represents any number between about 0.905 and 1.46.], or (2) the following formula:

[0046]

number

[0047] [In the formula, a 4-2 represents a value of approximately -0.0294, and Y 4-2 represents any numerical value from about 2.18 to about 3.31, and the other symbols have the same meanings as above.], wherein the agent for inhibiting progression and inhibiting recurrence and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the conditions represented by the formulas (1) and (2) (hereinafter, the combination of conditions represented by the formulas (1) and (2) may be abbreviated as "biomarker 4").

[29] Y 4-1 represents any numerical value from about 1.18 to about 1.46.

[30] Y 4-2 The agent according to the preceding item

[28] or

[29] , wherein represents any numerical value from about 2.74 to about 3.31.

[31] Y 4-1 The agent according to the preceding item

[28] or

[30] , wherein represents any numerical value from about 0.905 to about 1.18.

[32] Y 4-2 The agent according to the preceding item

[28] ,

[29] or

[31] , wherein represents any numerical value from about 2.18 to about 2.74.

[33] Y 4-1 The agent according to the preceding item

[28] ,

[30] or

[32] , wherein the MnI is about 1.18.

[34] Y 4-2 The agent according to the preceding item

[28] ,

[29] ,

[31] or

[33] , wherein the MgCl2 content is about 2.74.

[35] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells express the following formula:

[0048]

number

[0049] [wherein all symbols have the same meanings as in the preceding paragraph

[28] .], or (2) the following formula:

[0050]

number

[0051] [wherein all symbols have the same meanings as in the preceding paragraph

[28] .], wherein the agent for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[36] Foxp3 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0052]

number

[0053] [In the formula, Y 5 Foxp3 + The percentage of PD-1 expressing T cells (%) is shown. 5 represents a value of approximately 2.34, and X 5 The CD8 + The percentage of PD-1 expressing T cells is shown. 5-1 represents any numerical value from about -117 to about 131.] (hereinafter, the condition represented by the above formula may be abbreviated as "biomarker 5"), wherein the agent for inhibiting progression and inhibiting recurrence of a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the above formula.

[37] Y 5-1 represents any numerical value from about -117 to about -54.4.

[38] Y 5-1 represents any numerical value from about -54.4 to about 131.

[39] Y 5-1is about -54.4.

[40] Foxp3 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0054]

number

[0055] [wherein all symbols have the same meaning as in the preceding paragraph

[36] .], wherein the agent is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[41] Treg cells (Fr. II) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0056]

number

[0057] [In the formula, Y 6 represents the percentage (%) of PD-1 expressing cells in the Treg cells (Fr. II), and a 6-1 represents a value of approximately 1.69, and X 6 The CD8 + The percentage of PD-1 expressing T cells is shown. 6-1 represents any numerical value from about 21.4 to about 44.1.], or (2) the condition represented by the following formula:

[0058]

number

[0059] [In the formula, a 6-2 represents a value of approximately 1.78, and Y 6-2represents any numerical value from about -80.6 to about -21.0, and the other symbols have the same meanings as above.], wherein the agent for inhibiting progression and inhibiting recurrence and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the conditions represented by the formulas (1) and (2) (hereinafter, the combination of conditions represented by the formulas (1) and (2) may be abbreviated as "biomarker 6").

[42] Y 6-1 represents any numerical value from about 31.8 to about 44.1.

[43] Y 6-2 represents any numerical value from about -80.6 to about -48.2.

[44] Y 6-1 The agent according to the preceding item

[41] or

[43] , wherein represents any numerical value from about 21.4 to about 31.8.

[45] Y 6-2 The agent according to the preceding item

[41] ,

[42] or

[44] , wherein represents any numerical value from about -48.2 to about -21.0.

[46] Y 6-1 The agent according to the preceding item

[41] ,

[43] or

[45] , wherein the MgCl2 content is about 31.8.

[47] Y 6-2 The agent according to the preceding item

[41] ,

[42] ,

[44] or

[46] , wherein the MgCl2 concentration is about -48.2.

[48] ​​Treg cells (Fr. II) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0060]

number

[0061] [wherein all symbols have the same meanings as in the preceding paragraph

[41] .], or (2) the following formula:

[0062]

number

[0063] [wherein all symbols have the same meanings as in the preceding paragraph

[41] .], wherein the agent for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[49] CD4 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0064]

number

[0065] [In the formula, Y 7 The CD4 + The percentage of PD-1 expressing T cells (%) is shown. 7-1 represents a value of approximately 0.227, and X 7 The CD8 + The percentage of PD-1 expressing T cells is shown. 7-1 represents any number between approximately -13.9 and 4.03.], or (2) the following formula:

[0066]

number

[0067] [In the formula, a 7-2 represents a value of approximately 3.32, and Y 7-2 represents any numerical value from about -199 to 58.2, and the other symbols have the same meanings as above.], wherein the agent for inhibiting progression and inhibiting recurrence and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the conditions represented by the formulas (1) and (2) (hereinafter, the combination of conditions represented by the formulas (1) and (2) may be abbreviated as "biomarker 7").

[50] Y 7-1 represents any numerical value from about -13.9 to about -6.56.

[51] Y 7-2represents any numerical value from about -199 to about -93.5.

[52] Y 7-1 represents any numerical value from about -6.56 to about 4.03.

[53] Y 7-2 The agent according to the preceding item

[49] ,

[50] or

[52] , wherein represents any numerical value from about -93.5 to about 58.2.

[54] Y 7-1 The agent according to the preceding item

[49] ,

[51] or

[53] , wherein the MnI value is about -6.56.

[55] Y 7-2 The agent according to the preceding item

[49] ,

[50] ,

[52] or

[54] , wherein the MgCl2 content is about -93.5.

[56] CD4 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0068]

number

[0069] [wherein all symbols have the same meanings as in the preceding paragraph

[49] .], or (2) the following formula:

[0070]

number

[0071] [wherein all symbols have the same meanings as in the preceding paragraph

[49] .], wherein the agent is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[57] CD3 in tumor tissue or blood of patients with malignant tumors + cells, Treg cells (Fr. II) and CD4 + T cells express the following formula:

[0072]

number

[0073] [In the formula, Y 8 is the ratio of the MFI of PD-1 expression to the CD3 + represents the square root of the ratio of MFI of PD-1 expression in cells, a 8-1 represents a value of approximately -0.00338, and X 8 The CD4 + The percentage of PD-1 expressing T cells is shown. 8-1 represents any number between about 0.939 and about 1.37, 8-2 represents a value of approximately 0.270, and Y 8-2 represents any numerical value from about -6.98 to about -0.654.] (Hereinafter, the combination of conditions represented by the above formula may be abbreviated as "biomarker 8"), and the agent for suppressing progression and / or suppressing recurrence of a malignant tumor, comprising an immune checkpoint inhibitor as an active ingredient, characterized in that the agent is administered to a patient with a malignant tumor who satisfies the condition represented by the above formula.

[58] Y 8-1 represents any numerical value from about 1.17 to about 1.37.

[59] Y 8-2 represents any numerical value from about -6.98 to about -4.10.

[60] Y 8-1 The agent according to the preceding item

[57] or

[59] , wherein represents any numerical value from about 0.939 to about 1.17.

[61] Y 8-2 The agent according to the preceding item

[57] ,

[58] or

[60] , wherein represents any numerical value from about -4.10 to about -0.654.

[62] Y 8-1 The agent according to the preceding item

[57] ,

[59] or

[61] , wherein the MnI is about 1.17.

[63] Y 8-2 The agent according to the preceding item

[57] ,

[58] ,

[60] or

[62] , wherein the MnI value is about -4.10.

[64] CD3 in tumor tissue or blood of patients with malignant tumors +cells, Treg cells (Fr. II) and CD4 + T cells express the following formula:

[0074]

number

[0075] [wherein all symbols have the same meaning as in the preceding paragraph

[57] .], wherein the agent for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the formula:

[65] Foxp3 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0076]

number

[0077] [In the formula, Y 9-1 Foxp3 + represents the MFI of PD-1 expression in T cells, 9-2 The CD8 + represents the MFI of PD-1 expression in T cells; 9 represents any numerical value from about -716 to about 166.], wherein the agent for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the formula (hereinbelow, the condition represented by the above formula may be abbreviated as "biomarker 9").

[66] a 9 The agent according to the preceding item

[65] , wherein represents any numerical value from about -462 to about 166.

[67] a 9 The agent according to the preceding item

[65] , wherein represents any numerical value from about -716 to about -3.96.

[68] a 9 The agent according to the preceding item

[65] , wherein represents any numerical value from about -462 to about -3.96.

[69] a9 The agent according to the preceding item

[65] , wherein the pH is about -208.

[70] Treg cells (Fr. II) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0078]

number

[0079] [In the formula, Y 10-1 represents the MFI of PD-1 expression in the Treg cells (Fr. II), and Y 10-2 The CD8 + represents the MFI of PD-1 expression in T cells; 10 represents any numerical value from about -842 to about 133.], wherein the agent for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor who satisfies the condition represented by the formula (hereinbelow, the condition represented by the above formula may be abbreviated as "biomarker 10").

[71] a 10 The agent according to the preceding item

[70] , wherein represents any numerical value from about -505 to about 133.

[72] a 10 The agent according to the preceding item

[70] , wherein represents any numerical value from about -842 to about -2.40.

[73] a 10 The agent according to the preceding item

[70] , wherein represents any numerical value from about -505 to about -2.40.

[74] a 10 The agent according to the preceding item

[70] , wherein the pH is about -131.

[75] The agent according to any one of the preceding items [1] to

[74] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, a PD-L1 / VISTA antagonist, a PD-L1 / TIM3 antagonist, an anti-PD-L2 antibody, a PD-L1 fusion protein, a PD-L2 fusion protein, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, a LAG-3 fusion protein, an anti-Tim3 antibody, an anti-KIR antibody, an anti-BTLA antibody, an anti-TIGIT antibody, an anti-VISTA antibody, an anti-CSF-1R antibody, or a CSF-1R inhibitor.

[76] The anti-PD-1 antibody is Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lod apolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Penpulimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK103, BI The agent according to the preceding item

[75] , which is 754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 or CX-188.

[77] The agent described in the preceding paragraph

[75] , wherein the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 or JS003.

[78] The agent described in the preceding paragraph

[75] , wherein the anti-CTLA-4 antibody is Ipilimumab, Zalifrelimab, Nurulimab or Tremelimumab.

[79] The agent according to any one of the preceding items [1] to

[78] , wherein the malignant tumor is a solid cancer or a blood cancer.

[80] The solid cancer is melanoma (e.g., melanoma of the skin, oral mucosa epithelium, or orbit, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian clear cell adenocarcinoma), nasopharyngeal cancer, uterine cancer (e.g., cervical cancer, endometrial cancer, and uterine body cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (e.g., Microsatellite instability-high (hereinafter abbreviated as "MSI-H") and / or mismatch repair deficient (hereinafter abbreviated as "dMMR") positive colorectal cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial carcinoma (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer , within The agent according to the preceding item

[79] , wherein the cancer is one or more selected from endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, brain tumor (e.g., glioma (e.g., glioblastoma and gliosarcoma) and meningioma), squamous cell carcinoma, bone and soft tissue sarcoma (e.g., Ewing's sarcoma, childhood rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma and congenital fibrosarcoma), and Kaposi's sarcoma.

[81] The blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma) , bacteriaThe agent described in the preceding item

[79] , wherein the cancer is one or more selected from the group consisting of mythos fungoides, Sézary syndrome, chronic or acute lymphocytic leukemia, peripheral T-cell lymphoma, extranodal NK / T-cell lymphoma, adult T-cell leukemia, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, and lymphoplasmacytic lymphoma) and Hodgkin lymphoma (e.g., classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma)), leukemia (e.g., acute myeloid leukemia and chronic myeloid leukemia), primary central nervous system malignant lymphoma, myelodysplastic syndrome, and myeloproliferative syndrome.

[82] The agent described in the preceding item

[79] , wherein the malignant tumor is non-small cell lung cancer or gastric cancer.

[83] The agent according to any one of the preceding items [1] to

[79] , wherein the malignant tumor is childhood cancer or cancer of unknown primary origin.

[84] The agent according to any one of the preceding items [1] to

[83] , wherein the malignant tumor is a malignant tumor for which the therapeutic effect of other anti-malignant tumor drugs is insufficient or not sufficient.

[85] The agent according to any one of the preceding items [1] to

[84] , wherein the malignant tumor is a malignant tumor that has worsened after treatment with another anti-malignant tumor drug.

[86] The agent according to any one of the preceding items [1] to

[83] , wherein the malignant tumor patient has no history of treatment with other anti-malignant tumor drugs.

[87] The agent according to any one of the preceding items [1] to

[86] , which is prescribed for postoperative adjuvant therapy or neoadjuvant therapy.

[88] The agent according to any one of the preceding items [1] to

[87] , wherein the malignant tumor is incurable or inresectable, metastatic, recurrent, refractory, and / or distant metastatic.

[89] The agent according to any one of the preceding items [1] to

[88] , wherein the proportion of tumor cells expressing PD-L1 among tumor cells in tumor tissue (hereinafter abbreviated as "TPS"), or the number of PD-L1 positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells and multiplied by 100 (hereinafter abbreviated as "CPS"), is 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more.

[90] The agent according to any one of the preceding items [1] to

[88] , wherein TPS or CPS is less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%.

[91] The agent according to any one of the preceding items [1] to

[90] , wherein the malignant tumor has MSI-H and / or dMMR.

[92] The agent described in any one of the preceding items [1] to

[90] , wherein the malignant tumor does not have MSI-H and / or dMMR, or has low-frequency microsatellite instability (hereinafter abbreviated as "MSI-L").

[93] The agent according to any one of the preceding items

[80] to

[92] , wherein the malignant melanoma or non-small cell lung cancer is BRAF V600E mutation-positive.

[94] The agent according to any one of the preceding items

[80] to

[92] , wherein the malignant melanoma or non-small cell lung cancer is BRAF V600 wild-type.

[95] The agent according to any one of the preceding items

[80] to

[94] , wherein the non-small cell lung cancer is EGFR gene mutation-positive and / or ALK fusion gene-positive.

[96] The agent according to any one of the preceding items

[80] to

[94] , wherein the non-small cell lung cancer is EGFR gene mutation-negative and / or ALK fusion gene-negative.

[97] The tumor mutation burden (TMB) of the malignant tumor is high (10 6 The agent according to any one of the preceding items [1] to

[96] , wherein the number of mutations per base is 10 or more.

[98] The malignant tumor has a low TMB frequency (10 6 The agent according to any one of the preceding items [1] to

[96] , wherein the number of mutations per base is less than 10.

[99] The agent according to any one of the preceding items [1] to

[98] , which is further used in combination with another anticancer drug.

[0100] The agent according to any one of the preceding paragraphs

[84] to

[86] and

[99] , wherein the other antineoplastic drug is one or more drugs selected from alkylating agents, platinum preparations, metabolic antagonists (e.g., folate metabolic antagonists, pyridine metabolic inhibitors, purine metabolic inhibitors), ribonucleotide reductase inhibitors, nucleotide analogues, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormones, molecular targeted drugs, and cancer immunotherapy drugs.

[0101] The agent according to any one of the preceding items [1] to

[0100] , wherein the malignant tumor patient is a patient prior to administration of a drug containing the immune checkpoint inhibitor as an active ingredient.

[0102] The agent according to any one of the preceding items [1] to

[0101] , wherein the tumor tissue is tissue including at least the tumor mass itself, the invasive periphery of the tumor, or a lymph node adjacent to the tumor. [1-1] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells express the following formula:

[0080]

number

[0081] [wherein all symbols have the same meanings as in the preceding paragraph [1].], or (2)(i) the following formula:

[0082]

number

[0083] [wherein all symbols have the same meaning as in the preceding paragraph [1].] and (ii) the following formula:

[0084]

number

[0085] [wherein all symbols have the same meaning as in the preceding paragraph [1].], the present invention relates to a method for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor, the method comprising administering an effective amount of an immune checkpoint inhibitor to a patient with a malignant tumor who satisfies (or has been confirmed to satisfy) the two conditions represented by the formula: [1-2] Treg cells (Fr.III) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0086]

number

[0087] [wherein all symbols have the same meanings as in the preceding paragraph

[12] .], or (2) the following formula:

[0088]

number

[0089] [wherein all symbols have the same meaning as in the preceding paragraph

[12] .], the method for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to a patient with a malignant tumor who satisfies the condition represented by the formula (or who has been confirmed to satisfy the condition). [1-3] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells are classified according to the following formula:

[0090]

number

[0091] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .] or (ii) the following formula:

[0092]

number

[0093] [wherein all symbols have the same meanings as in the preceding paragraph

[20] .], or (2)(i) the following formula:

[0094]

number

[0095] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .] or (ii) the following formula:

[0096]

number

[0097] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .], the method for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to a patient with a malignant tumor who satisfies the condition represented by the formula (or who has been confirmed to satisfy the condition). [1-4] CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells express the following formula:

[0098]

number

[0099] [wherein all symbols have the same meanings as in the preceding paragraph

[28] .], or (2) the following formula:

[0100]

number

[0101] [wherein all symbols have the same meaning as in the preceding paragraph

[28] .], the malignant tumor patient satisfies the condition (or has been confirmed to satisfy the condition) represented by the formula

[28] , the malignant tumor progression inhibition, recurrence inhibition, and / or treatment method, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient. [1-5] Foxp3 in tumor tissues and blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0102]

number

[0103] [wherein all symbols have the same meaning as in the previous section

[36] ] A method for inhibiting the progression, inhibiting recurrence, and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to a patient with a malignant tumor (or a patient who has been confirmed to meet the said conditions). [1-6] Treg cells (Fr.II) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0104]

number

[0105] [wherein all symbols have the same meanings as in the preceding paragraph

[41] .], or (2) the following formula:

[0106]

number

[0107] [wherein all symbols have the same meaning as in the preceding paragraph

[41] .], the malignant tumor patient satisfies the condition (or has been confirmed to satisfy the condition) represented by the formula

[41] , the malignant tumor progression inhibition, recurrence inhibition, and / or treatment method, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient. [1-7] CD4 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0108]

number

[0109] [wherein all symbols have the same meanings as in the preceding paragraph

[49] .], or (2) the following formula:

[0110]

number

[0111] [wherein all symbols have the same meaning as in the preceding paragraph

[49] .], the malignant tumor patient satisfies the condition (or has been confirmed to satisfy the condition) represented by the formula

[49] , the malignant tumor progression inhibition, recurrence inhibition, and / or treatment method, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient. [1-8] CD3 in tumor tissue or blood of patients with malignant tumors + cells, Treg cells (Fr. II) and CD4 + T cells express the following formula:

[0112]

number

[0113] [wherein all symbols have the same meaning as in the preceding paragraph

[57] .], the method for inhibiting progression, inhibiting recurrence, and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to a patient with a malignant tumor who satisfies the condition represented by the formula (confirmed to satisfy the condition). [1-9] Foxp3 in tumor tissues and blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula:

[0114]

number

[0115] [wherein all symbols have the same meaning as in the preceding paragraph

[65] .], the malignant tumor patient satisfies the condition (or has been confirmed to satisfy the condition) represented by the formula

[65] , the malignant tumor progression inhibition, recurrence inhibition, and / or treatment method, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient. [1-10] Treg cells (Fr.II) and CD8 in tumor tissue or blood of patients with malignant tumors + T cells express the following formula:

[0116]

number

[0117] [wherein all symbols have the same meaning as in the preceding paragraph

[70] .], the malignant tumor patient satisfies the condition (or has been confirmed to satisfy the condition) represented by the formula

[70] , the malignant tumor progression inhibition, recurrence inhibition, and / or treatment method, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient. Each of the treatment methods in the above [1-1] to [1-10] may include a process of identifying a malignant tumor patient to be treated based on each biomarker. [2-1] Using flow cytometry or immunohistochemistry, (1) CD8 in samples derived from tumor tissue or blood of patients with malignant tumors + (1) Number of T cells and number of CCR7 expressing cells among them, and (2) the CD8 + Foxp3 in T cells and their samples + (1a) measuring PD-1 expression in each of the CD8 T cells; + (2a) Percentage of CCR7-expressing T cells and the Foxp3 + MFI of PD-1 expression on T cells versus CD8 +A method for identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors, or malignant tumor patients who are not likely to benefit from immune checkpoint inhibitors, by determining the MFI ratio of PD-1 expression in T cells, and based on a combination of said percentages and said ratios or the square root value of said ratios. [2-2] As patients with malignant tumors for whom immune checkpoint inhibitors are more likely to be effective, + T cells and Foxp3 + T cells express the following formula:

[0118]

number

[0119] [wherein all symbols have the same meanings as in the preceding paragraph [1].], or (2)(i) the following formula:

[0120]

number

[0121] [wherein all symbols have the same meaning as in the preceding paragraph [1].] and (ii) the following formula:

[0122]

number

[0123] [wherein all symbols have the same meanings as in the preceding item [1].], wherein a patient who satisfies the two conditions represented by the formula: [2-3] Y 1-1 represents any numerical value from about 853 to about 914. [2-4] Y 1-2 represents any numerical value from about 39.0 to about 44.6. [2-5] Y 1-3represents any numerical value from about -652 to about -591. [2-6] Y 1-1 The method according to the preceding item [2-2], [2-4] or [2-5], wherein represents any numerical value from about 784 to about 853. [2-7] Y 1-2 The method according to the preceding item [2-2], [2-3], [2-5] or [2-6], wherein represents any numerical value between about 44.6 and about 50.9. [2-8] Y 1-3 represents any numerical value from about -591 to about -522. [2-9] Y 1-1 The method according to the preceding paragraph [2-2], [2-4], [2-5], [2-7] or [2-8], wherein the .alpha.-amino acid sequence is about 853. [2-10] Y 1-2 The method according to the preceding paragraph [2-2], [2-3], [2-5], [2-6], [2-8] or [2-9], wherein the β- [2-11] Y 1-3 The method according to any one of the preceding items [2-2] to [2-4], [2-6], [2-7], [2-9] and [2-10], wherein the pH is about -591. [2-12] Flow cytometry or immunohistochemistry was used to detect Treg cells (Fr.III) and CD8 in samples derived from tumor tissue or blood of patients with malignant tumors. + The number of T cells and the number of PD-1 expressing cells among them were measured, and the Treg cells (Fr.III) and the CD8 + A method for determining the percentage (%) of PD-1 expressing cells in each T cell, and identifying malignant tumor patients in whom immune checkpoint inhibitors are likely to be effective or in whom immune checkpoint inhibitors are unlikely to be effective based on the combination of these two percentages (%). [2-13] In patients with malignant tumors, the effects of immune checkpoint inhibitors are more likely to be seen in those with Treg cells (Fr.III) and CD8 + T cells express the following formula:

[0124]

number

[0125] [wherein all symbols have the same meanings as in the preceding paragraph

[12] .], or (2) the following formula:

[0126]

number

[0127] [wherein all symbols have the same meanings as in the preceding item

[12] ].], the method according to the preceding item [2-12], wherein a patient satisfying the condition represented by the formula is identified. [2-14] Y 2-1 The method described in the above item [2-13], wherein represents any numerical value from about 54.1 to about 59.2. [2-15] Y 2-2 The method according to the above item [2-13] or [2-14], wherein represents any numerical value from about -44.1 to about -26.6. [2-16] Y 2-1 The method according to the preceding item [2-13] or [2-15], wherein represents any numerical value from about 50.6 to about 54.1. [2-17] Y 2-2 The method according to the preceding item [2-13], [2-14] or [2-16], wherein represents any numerical value from about -26.6 to about -14.5. [2-18] Y 2-1 The method according to the preceding paragraph [2-13], [2-15] or [2-17], wherein the β- [2-19] Y 2-2 The method according to the preceding paragraph [2-13], [2-14], [2-16] or [2-18], wherein the β- [2-20] Using flow cytometry or immunohistochemistry, (1) CD8 + (2) the number of PD-1 expressing T cells and the corresponding CD8 + Foxp3 in T cells and their samples +PD-1 expression was measured on each T cell, and the Foxp3 + MFI of PD-1 expression on T cells versus CD8 + A method for identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors, or malignant tumor patients who are not likely to benefit from immune checkpoint inhibitors, by determining the MFI ratio of PD-1 expression in T cells, and based on a combination of (i) the number of PD-1 expressing cells, the common logarithm of the number of cells, or the common logarithm of the number of cells plus 1, and (ii) the ratio or the square root of the ratio. [2-21] The CD8 + T cells and Foxp3 + (1)(i) a formula comprising:

[0128]

number

[0129] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .] or (ii) the following formula:

[0130]

number

[0131] [wherein all symbols have the same meanings as in the preceding paragraph

[20] .], or (2)(i) the following formula:

[0132]

number

[0133] [wherein all symbols have the same meaning as in the preceding paragraph

[20] .] or (ii) the following formula:

[0134]

number

[0135] [wherein all symbols have the same meanings as in the preceding paragraph

[20] .], wherein a patient satisfying the condition represented by the formula is identified. [2-22] Y 3-1 The method according to the preceding item [2-21], wherein represents any numerical value from about 4.42 to about 4.89. [2-23] Y 3-2 The method according to the preceding item [2-21] or [2-22], wherein represents any numerical value from about 111.7 to about 13.3. [2-24] Y 3-1 The method according to the preceding item [2-21] or [2-23], wherein represents any numerical value from about 4.09 to about 4.42. [2-25] Y 3-2 The method according to the preceding item [2-21], [2-22] or [2-24], wherein represents any numerical value between about 10.7 and about 11.7. [2-26] Y 3-1 The method according to the preceding paragraph [2-21], [2-23] or [2-25], wherein the β- [2-27] Y 3-2 The method according to the preceding paragraph [2-21], [2-22], [2-24] or [2-26], wherein the β- [2-28] Using flow cytometry or immunohistochemistry, (1) CD8 + T cells and Foxp3 + (2) PD-1 expression on each T cell and the corresponding CD8 + (1a) measuring the number of T cells and the number of PD-1-expressing cells among them, + MFI of PD-1 expression on T cells versus CD8 + (2a) the ratio of MFI of PD-1 expression on T cells and the corresponding CD8 + A method for determining the percentage (%) of PD-1 expressing cells in T cells, and identifying malignant tumor patients in whom immune checkpoint inhibitors are more likely to be effective, or malignant tumor patients in whom immune checkpoint inhibitors are not likely to be effective, based on said percentage or a combination of said percentage (%) and the square root of said percentage. [2-29] The CD8 + T cells and Foxp3 + T cells express the following formula:

[0136]

number

[0137] [wherein all symbols have the same meanings as in the preceding paragraph

[28] .], or (2) the following formula:

[0138]

number

[0139] [wherein all symbols have the same meanings as in the preceding paragraph

[28] ], wherein a patient satisfying the condition represented by the formula is identified. [2-30] Y 4-1 The method according to the above item [2-29], wherein represents any numerical value from about 1.18 to about 1.46. [2-31] Y 4-2 The method according to the preceding item [2-29] or [2-30], wherein represents any numerical value between about 2.74 and about 3.31. [2-32] Y 4-1 The method according to the preceding item [2-29] or [2-31], wherein represents any numerical value from about 0.905 to about 1.18. [2-33] Y 4-2 The method according to the preceding item [2-29], [2-30] or [2-32], wherein represents any numerical value between about 2.18 and about 2.74. [2-34] Y 4-1 The method according to the preceding paragraphs [2-29], [2-31] or [2-33], wherein the β- [2-35] Y 4-2 The method according to the preceding paragraph [2-29], [2-30], [2-32] or [2-34], wherein the β- [2-36] Using flow cytometry or immunostaining, Foxp3 was detected in samples derived from tumor tissue or blood of patients with malignant tumors. + T cells and CD8 + The number of T cells and the number of PD-1 expressing cells were measured, and the Foxp3 + T cells and the relevant CD8 + A method for determining the percentage (%) of PD-1 expressing cells in each T cell, and identifying malignant tumor patients in whom immune checkpoint inhibitors are likely to be effective or in whom immune checkpoint inhibitors are unlikely to be effective based on the combination of these two percentages (%). [2-37] The Foxp3 gene is a promising candidate for malignant tumor patients who may benefit from immune checkpoint inhibitors. + T cells and CD8 + T cells express the following formula:

[0140]

number

[0141] [wherein all symbols have the same meanings as in the preceding paragraph

[36] .], wherein a patient satisfying the condition represented by the formula is identified. [2-38] Y 5-1 The method according to the above item [2-37], wherein represents any numerical value from about -117 to about -54.4. [2-39] Y 5-1 represents any numerical value from about -54.4 to about 131. [2-40] Y 5-1 The method according to the preceding paragraph [2-37], wherein the ΔΨ is about -54.4. [2-41] Flow cytometry or immunohistochemistry was used to detect Treg cells (Fr. II) and CD8 + The number of T cells and the number of PD-1 expressing cells were measured, and the Treg cells (Fr. II) and the CD8 +A method for determining the percentage (%) of PD-1 expressing cells in each T cell, and identifying malignant tumor patients in whom immune checkpoint inhibitors are likely to be effective or in whom immune checkpoint inhibitors are unlikely to be effective based on the combination of these two percentages (%). [2-42] Treg cells (Fr.II) and CD8 + T cells express the following formula:

[0142]

number

[0143] [wherein all symbols have the same meanings as in the preceding paragraph

[41] .], or (2) the following formula:

[0144]

number

[0145] [wherein all symbols have the same meanings as in the preceding paragraph

[41] .], wherein a patient satisfying the condition represented by the formula is identified. [2-43] Y 6-1 The method described in the preceding item [2-42], wherein represents any numerical value from about 31.8 to about 44.1. [2-44] Y 6-2 The method according to the preceding item [2-42] or [2-43], wherein represents any numerical value from about -80.6 to about -48.2. [2-45] Y 6-1 The method according to the preceding item [2-42] or [2-44], wherein represents any numerical value between about 21.4 and about 31.8. [2-46] Y 6-2 The method according to the preceding item [2-42], [2-43] or [2-45], wherein represents any numerical value from about -48.2 to about -21.0. [2-47] Y 6-1 The method according to the preceding paragraphs [2-42], [2-44] or [2-46], wherein the β- [2-48] Y 6-2 The method according to the preceding paragraphs [2-42], [2-43], [2-45] or [2-47], wherein the ΔN is about -48.2. [2-49] Flow cytometry or immunohistochemistry showed that CD4 + T cells and CD8 + The number of T cells and the number of PD-1 expressing cells were measured, and the CD4 + T cells and the relevant CD8 + A method for determining the percentage (%) of PD-1 expressing cells in each T cell, and identifying malignant tumor patients in whom immune checkpoint inhibitors are likely to be effective or in whom immune checkpoint inhibitors are unlikely to be effective based on the combination of these two percentages (%). [2-50] The CD4 + T cells and CD8 + T cells express the following formula:

[0146]

number

[0147] [wherein all symbols have the same meanings as in the preceding paragraph

[49] .], or (2) the following formula:

[0148]

number

[0149] The method according to the above [2-49], further comprising identifying a patient who satisfies the condition represented by the formula [wherein all symbols have the same meaning as in the above

[49] ]. [2-51] Y 7-1 The method according to the above item [2-50], wherein represents any numerical value from about -13.9 to about -6.56. [2-52] Y 7-2The method according to the preceding item [2-50] or [2-51], wherein represents any numerical value from about -199 to about -93.5. [2-53] Y 7-1 The method according to the preceding item [2-50] or [2-52], wherein represents any numerical value from about -6.56 to about 4.03. [2-54] Y 7-2 The method according to the preceding item [2-50], [2-51] or [2-53], wherein represents any numerical value from about -93.5 to about 58.2. [2-55] Y 7-1 The method according to the preceding paragraph [2-50], [2-52] or [2-54], wherein the β- [2-56] Y 7-2 The method according to the preceding paragraph [2-50], [2-51], [2-53] or [2-55], wherein the pH is about -93.5. [2-57] Using flow cytometry or immunohistochemistry, (1) CD3 in samples derived from tumor tissue or blood of patients with malignant tumors + (1) PD-1 expression in the cells and the Treg cells (Fr. II), and (2) CD4 + The number of T cells and the number of PD-1 expressing cells were measured, and (1a) the ratio of the MFI of PD-1 expression in the Treg cells (Fr. II) to the CD3 + (2a) the ratio of MFI of PD-1 expression in cells and the corresponding CD4 + A method for determining the percentage (%) of PD-1 expressing cells in T cells, and identifying malignant tumor patients in whom immune checkpoint inhibitors are more likely to be effective, or malignant tumor patients in whom immune checkpoint inhibitors are not likely to be effective, based on said percentage or a combination of said percentage (%) and the square root of said percentage. [2-58] CD3+ is a promising candidate for malignant tumor patients who may benefit from immune checkpoint inhibitors. + cells, Foxp3 + T cells and CD4 + T cells express the following formula:

[0150]

number

[0151] [wherein all symbols have the same meanings as in the preceding item

[57] ].] The method according to the above [2-57], further comprising identifying a patient who satisfies the condition represented by the formula

[57] . [2-59] Y 8-1 The method according to the above item [2-58], wherein represents any numerical value from about 1.17 to about 1.37. [2-60] Y 8-2 The method according to the preceding item [2-58] or [2-59], wherein represents any numerical value from about -6.98 to about -4.10. [2-61] Y 8-1 The method according to the preceding item [2-58] or [2-60], wherein represents any numerical value from about 0.939 to about 1.17. [2-62] Y 8-2 The method according to the preceding item [2-58], [2-59] or [2-61], wherein represents any numerical value from about -4.10 to about -0.654. [2-63] Y 8-1 The method according to the preceding paragraphs [2-59], [2-61] or [2-62], wherein the β- [2-64] Y 8-2 The method according to the preceding paragraphs [2-58], [2-59], [2-61] or [2-63], wherein the β- [2-65] Using flow cytometry or immunostaining, Foxp3 was detected in samples derived from tumor tissue or blood of patients with malignant tumors. + T cells and CD8 + PD-1 expression in each T cell was measured, and the Foxp3 + The MFI of PD-1 expression on T cells was used to determine the CD8 + A method for determining a value obtained by subtracting the MFI of PD-1 expression in T cells, and based on that value, identifying malignant tumor patients in whom immune checkpoint inhibitors are more likely to be effective, or malignant tumor patients in whom immune checkpoint inhibitors are not likely to be effective. [2-66] As a malignant tumor patient who is more likely to benefit from immune checkpoint inhibitors, the Foxp3 + T cells and CD8 +T cells express the following formula:

[0152]

number

[0153] The method according to the above [2-65], further comprising identifying a patient who satisfies the condition represented by the formula [wherein all symbols have the same meaning as in the previous item

[65] ]. [2-67] a 9 represents any numerical value from about -462 to about 166, method . [2-68] a 9 represents any numerical value from about -716 to about -3.96, method . [2-69] a 9 represents any numerical value from about -462 to about -3.96, method . [2-70] a 9 is about -208, method . [2-71] Flow cytometry or immunohistochemistry was used to detect Treg cells (Fr.II) and CD8 + PD-1 expression in each T cell was measured, and the MFI of PD-1 expression in the Treg cells (Fr. II) was used to calculate the CD8 + A method for determining a value obtained by subtracting the MFI of PD-1 expression in T cells, and based on that value, identifying malignant tumor patients in whom immune checkpoint inhibitors are more likely to be effective, or malignant tumor patients in whom immune checkpoint inhibitors are not likely to be effective. [2-72] In patients with malignant tumors for whom immune checkpoint inhibitors are more likely to be effective, the Treg cells (Fr.II) and CD8 + T cells express the following formula:

[0154]

number

[0155] The method according to the above [2-71], further comprising identifying a patient who satisfies the condition represented by the formula [wherein all symbols have the same meaning as in the above

[70] ]. [2-73] a 10 represents any numerical value from about -505 to about 133, method . [2-74] a 10 represents any numerical value from about -842 to about -2.40, method . [2-75] a 10 represents any numerical value from about -505 to about -2.40, method . [2-76] a 10 is about -131, method . [2-77] The method described in any one of the preceding items [2-1] to [2-76], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, a PD-L1 / VISTA antagonist, a PD-L1 / TIM3 antagonist, an anti-PD-L2 antibody, a PD-L1 fusion protein, a PD-L2 fusion protein, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, a LAG-3 fusion protein, an anti-Tim3 antibody, an anti-KIR antibody, an anti-BTLA antibody, an anti-TIGIT antibody, an anti-VISTA antibody, an anti-CSF-1R antibody or a CSF-1R inhibitor. [2-78] The anti-PD-1 antibody is Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lod apolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Penpulimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK103, BI The method described in the preceding paragraph [2-77], wherein the antibody is 754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 or CX-188. [2-79] The method described in the preceding paragraph [2-77], wherein the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 or JS003. [2-80] The method described in the preceding paragraph [2-77], wherein the anti-CTLA-4 antibody is Ipilimumab, Zalifrelimab, Nurulimab or Tremelimumab. [2-81] The method described in any one of the preceding items [2-1] to [2-80], wherein the malignant tumor is a solid cancer or a blood cancer. [2-82] The solid cancer is melanoma (e.g., melanoma of the skin, oral mucosa epithelium, or orbit, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian clear cell adenocarcinoma), nasopharyngeal carcinoma, uterine cancer (e.g., cervical cancer, endometrial cancer, and uterine body cancer), anal cancer ( anal canal cancer), colon cancer (colorectal cancer) (e.g., MSI-H and / or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial carcinoma (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer , within The method described in the preceding paragraph [2-81], wherein the cancer is one or more selected from endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, brain tumor (e.g., glioma (e.g., glioblastoma and gliosarcoma) and meningioma), squamous cell carcinoma, bone and soft tissue sarcoma (e.g., Ewing's sarcoma, childhood rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma and congenital fibrosarcoma) and Kaposi's sarcoma. [2-83] The blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma) , bacteria The method according to the preceding paragraph [2-81], wherein the cancer is one or more cancers selected from the group consisting of mycosis fungoides, Sezary syndrome, chronic or acute lymphocytic leukemia, peripheral T-cell lymphoma, extranodal NK / T-cell lymphoma, adult T-cell leukemia, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia and lymphoplasmacytic lymphoma) and Hodgkin's lymphoma (e.g., classical Hodgkin's lymphoma and nodular lymphocyte-predominant Hodgkin's lymphoma)), leukemia (e.g., acute myeloid leukemia and chronic myeloid leukemia), primary central nervous system malignant lymphoma, myelodysplastic syndrome and myeloproliferative syndrome. [2-84] The method described in the preceding paragraph [2-81], wherein the malignant tumor is non-small cell lung cancer or gastric cancer. [2-85] The method described in any one of the preceding paragraphs [2-1] to [2-81], wherein the malignant tumor is childhood cancer or cancer of unknown primary origin. [2-86] The method according to any one of the preceding items [2-1] to [2-85], wherein the malignant tumor is a cancer for which the therapeutic effect of other anti-malignant tumor drugs is insufficient or not sufficient. [2-87] The method according to any one of the preceding items [2-1] to [2-86], wherein the malignant tumor is a cancer that has worsened after treatment with another anti-malignant tumor drug. [2-88] The method according to any one of the preceding paragraphs [2-1] to [2-85], wherein the malignant tumor patient has no history of treatment with other anti-malignant tumor drugs. [2-89] The method according to any one of items [2-1] to [2-88], which is prescribed as postoperative adjuvant therapy or neoadjuvant therapy. [2-90] The method described in any one of the preceding items [2-1] to [2-89], wherein the malignant tumor is incurable or inoperable, metastatic, recurrent, refractory, and / or distant metastatic. [2-91] The method according to any one of the preceding paragraphs [2-1] to [2-90], wherein TPS or CPS is 50% or more, 25% or more, 5% or more, or 1% or more. [2-92] The method according to any one of the preceding paragraphs [2-1] to [2-90], wherein TPS or CPS is less than 50%, less than 25%, less than 5%, or less than 1%. [2-93] The method described in any one of the preceding items [2-1] to [2-92], wherein the malignant tumor has MSI-H and / or dMMR. [2-94] The method described in any one of the preceding items [2-1] to [2-92], wherein the malignant tumor does not have MSI-H and / or dMMR, or has MSI-L. [2-95] The method according to any one of the preceding paragraphs [2-82] to [2-94], wherein the malignant melanoma or non-small cell lung cancer is BRAF V600E mutation-positive. [2-96] The method according to any one of the preceding paragraphs [2-82] to [2-94], wherein the malignant melanoma or non-small cell lung cancer is BRAF V600 wild-type. [2-97] The method described in any one of the preceding items [2-82] to [2-96], wherein the non-small cell lung cancer is EGFR gene mutation-positive and / or ALK fusion gene-positive. [2-98] The method described in any one of the preceding items [2-82] to [2-96], wherein the non-small cell lung cancer is EGFR gene mutation-negative and / or ALK fusion gene-negative. [2-99] The method described in any one of the preceding items [2-1] to [2-98], wherein the malignant tumor has a high frequency of TMB. [2-100] The method described in any one of the preceding items [2-1] to [2-98], wherein the malignant tumor has a low frequency of TMB. [2-101] The method described in any one of the preceding items [2-1] to [2-100], wherein the malignant tumor patient is a patient prior to administration of the immune checkpoint inhibitor. [2-102] The method according to any one of the preceding items [2-1] to [2-101], wherein the tumor tissue is tissue including at least the tumor mass itself, the invasive periphery of the tumor, or a lymph node adjacent to the tumor. [3-0] (1) CD8 in tumor tissue or blood of patients with malignant tumors + Percentage of CCR7 expressing T cells (%) (2) The CD8 + The number of PD-1 expressing T cells, the common logarithm of the number of expressing cells or the common logarithm of the number of expressing cells plus 1, (3) Foxp3 from the same source + MFI of PD-1 expression on T cells versus CD8 + The ratio of MFI of PD-1 expression in T cells or the square root of the ratio; (4) Percentage of PD-1 expressing cells in Treg cells (Fr.III) derived from the same mouse model (5) The Foxp3 + Percentage of PD-1 expressing T cells (%) (6) Percentage of PD-1 expressing cells in Treg cells (Fr. II) derived from the same mouse model (7) CD4 derived from the same source + Percentage of PD-1 expressing T cells (%) (8) The CD8 + Percentage of PD-1 expressing T cells (%) (9) MFI of PD-1 expression in Treg cells (Fr. II) versus CD3 + the ratio of MFI of PD-1 expression in cells or the square root of said ratio; (10) The CD4 + Percentage of PD-1 expressing T cells (%) (11) The Foxp3 + The MFI of PD-1 expression on T cells was used to determine the CD8 + MFI subtraction of PD-1 expression on T cells, and (12) The MFI of PD-1 expression in the Treg cells (Fr. II) + Use of an evaluation item including any one selected from the above, preferably a combination of any two evaluation items, as a biomarker for predicting the effectiveness of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors. [3-1] (1)(i) CD8 in the tumor tissue or blood of the patient with the malignant tumor + Percentage of T cells expressing CCR7, or (ii) The CD8 + The number of PD-1 expressing T cells, the common logarithm of the number of expressing cells or the common logarithm of the number of expressing cells plus 1, and (2) Foxp3 from the same source + MFI of PD-1 expression on T cells versus CD8 + Use of the ratio of MFI of PD-1 expression in T cells or a combination of the square root values ​​of said ratios as a biomarker described in the preceding paragraph [3-0]. [3-2] (1)(i) The percentage (%) of PD-1 expressing Treg cells (Fr.III) in the tumor tissue or blood of the patient with the malignant tumor, (ii) Foxp3 from the same source +MFI of PD-1 expression on T cells versus CD8 + The ratio of MFI of PD-1 expression in T cells or the square root of the ratio; (iii) the Foxp3 + Percentage of PD-1 expressing T cells (%) (iv) Percentage (%) of PD-1 expressing cells in Treg cells (Fr. II) derived from the same mouse model; (v) CD4 from the same source + any one selected from the percentage (%) of PD-1 expressing cells in T cells, and (2) The CD8 + Use of the combination of the percentage (%) of PD-1 expressing cells in T cells as a biomarker as described in the preceding section [3-0]. [3-3] (1) The CD8 + (2) the percentage of CCR7-expressing T cells and the Foxp3 + MFI of PD-1 expression on T cells versus CD8 + Use of the ratio of MFI of PD-1 expression in T cells or a combination of the square root values ​​of said ratios as a biomarker as described in the preceding paragraph [3-1]. [3-4] Treg cells (Fr.III) and CD8 + Use of the combination of the percentages (%) of PD-1 expressing cells in each of the T cells as a biomarker as described in the previous section [3-2]. [3-5] (1) The CD8 + (2) the number of PD-1-expressing T cells, the common logarithm of the number of said cells or the common logarithm of the value obtained by adding 1 to the number of said cells, and + MFI of PD-1 expression on T cells versus CD8 + Use of the ratio of MFI of PD-1 expression in T cells or a combination of the square root values ​​of said ratios as a biomarker as described in the preceding paragraph [3-1]. [3-6] (1) Foxp3 + MFI of PD-1 expression on T cells versus CD8 + (2) the ratio of MFI of PD-1 expression on T cells or the square root of the ratio and the CD8 +Use of the combination of the percentage (%) of PD-1 expressing cells in T cells as a biomarker as described in the preceding section [3-2]. [3-7] Foxp3 + T cells and CD8 + Use of the combination of the percentages (%) of PD-1 expressing cells in each of the T cells as a biomarker as described in the previous section [3-2]. [3-8] Treg cells (Fr.II) and CD8 + Use of the combination of the percentages (%) of PD-1 expressing cells in each of the T cells as a biomarker as described in the previous section [3-2]. [3-9] CD4 + T cells and CD8 + Use of the combination of the percentages (%) of PD-1 expressing cells in each of the T cells as a biomarker as described in the previous section [3-2]. [3-10] (1) MFI of PD-1 expression on the Treg cells (Fr. II) versus the CD3 + (2) the ratio of MFI of PD-1 expression in the cells or the square root of the ratio and the CD4 + Use of the combination of the percentage (%) of PD-1 expressing cells in T cells as a biomarker as described in the preceding section [3-0]. [3-11] Foxp3 in tumor tissues and blood of patients with malignant tumors + MFI of PD-1 expression on T cells from the same source CD8 + Use of the MFI-subtracted value of PD-1 expression in T cells as a biomarker for predicting efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors. [3-12] The MFI of PD-1 expression on Treg cells (Fr.II) in tumor tissue or blood of patients with malignant tumors was compared with that of CD8 + Use of the MFI-subtracted value of PD-1 expression in T cells as a biomarker for predicting efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors. [3-13] The use according to any one of the preceding paragraphs [3-0] to [3-12], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, a PD-L1 / VISTA antagonist, a PD-L1 / TIM3 antagonist, an anti-PD-L2 antibody, a PD-L1 fusion protein, a PD-L2 fusion protein, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, a LAG-3 fusion protein, an anti-Tim3 antibody, an anti-KIR antibody, an anti-BTLA antibody, an anti-TIGIT antibody, an anti-VISTA antibody, an anti-CSF-1R antibody, or a CSF-1R inhibitor. [3-14] The anti-PD-1 antibody is Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lod apolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Penpulimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK103, BI The use according to the preceding paragraph [3-13], wherein the compound is 754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 or CX-188. [3-15] The use described in the preceding paragraph [3-13], wherein the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 or JS003. [3-16] The use described in the preceding paragraph [3-13], wherein the anti-CTLA-4 antibody is Ipilimumab, Zalifrelimab, Nurulimab or Tremelimumab. [3-17] The use according to any one of the preceding items [3-0] to [3-16], wherein the malignant tumor is a solid cancer or a blood cancer. [3-18] The solid cancer is malignant melanoma (e.g., malignant melanoma in the skin, oral mucosal epithelium, or orbit, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian clear cell adenocarcinoma), nasopharyngeal carcinoma, uterine cancer (e.g., cervical cancer, endometrial cancer, and uterine body cancer), anal cancer ( anal canal cancer), colon cancer (colorectal cancer) (e.g., MSI-H and / or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial carcinoma (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer , within The use according to the preceding item [3-17], wherein the cancer is one or more selected from endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, brain tumor (e.g., glioma (e.g., glioblastoma and gliosarcoma) and meningioma), squamous cell carcinoma, bone and soft tissue sarcoma (e.g., Ewing's sarcoma, childhood rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma and congenital fibrosarcoma) and Kaposi's sarcoma. [3-19] The blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma) , bacteriaThe use according to the preceding item [3-17], wherein the cancer is one or more selected from the group consisting of mycosis fungoides, Sézary syndrome, chronic or acute lymphocytic leukemia, peripheral T-cell lymphoma, extranodal NK / T-cell lymphoma, adult T-cell leukemia, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia and lymphoplasmacytic lymphoma) and Hodgkin's lymphoma (e.g., classical Hodgkin's lymphoma and nodular lymphocyte-predominant Hodgkin's lymphoma)), leukemia (e.g., acute myeloid leukemia and chronic myeloid leukemia), primary central nervous system malignant lymphoma, myelodysplastic syndrome and myeloproliferative syndrome. [3-20] The use according to any one of the preceding paragraphs [3-0] to [3-16], wherein the malignant tumor is childhood cancer or cancer of unknown primary origin. [3-21] The use according to any one of the preceding paragraphs [3-0] to [3-20], wherein the malignant tumor patient is a patient prior to administration of the immune checkpoint inhibitor. [3-22] The use according to any one of the preceding items [3-0] to [3-21], wherein the tumor tissue is tissue including at least the tumor mass itself, the invasive periphery of the tumor, or a lymph node adjacent to the tumor. Effect of the Invention

[0156] By measuring the biomarkers of the present invention, it is possible to identify malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors. [Brief description of the drawings]

[0157] [Figure 1]The graph shows the results of plotting the percentage (%) of CCR7-expressing cells in CD8+ T cells in the tumor tissue of each patient before Nivolumab administration on the vertical axis and the square root value of the ratio of the MFI of PD-1 expression in the CD8+ T cells to the MFI of PD-1 expression in the Foxp3+ T cells derived from the same patient on the horizontal axis for the responder group (black circle in the figure) and non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (16 cases) treated with Nivolumab administration. The three solid lines in the figure represent the piecewise linear (discrimination boundary) derived by machine learning so that the value of fα is maximized when the α value is 0.5, using the weighted f-measure (fα) as an index, and the shaded area on the right side of the figure indicates that the effect of Nivolumab can be expected in the cancer patients plotted in that area. [Diagram 2] The results are shown for the responder group (black circle in the figure) and the non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) who received Nivolumab treatment. The vertical axis shows the percentage (%) of PD-1 expressing cells in Treg cells (Fr.III) in the tumor tissue of each patient before Nivolumab administration, and the horizontal axis shows the percentage (%) of PD-1 expressing cells in CD8+ T cells. The two solid lines in the figure represent piecewise straight lines derived by machine learning similar to that described above, and the shaded areas on the upper left and lower right of the figure represent the expected effects of Nivolumab in the cancer patients plotted in those areas. [Diagram 3]The graph shows the results of plotting the common logarithm of the value obtained by adding 1 to the number of PD-1 expressing cells in CD8+T cells in the tumor tissue of each patient before Nivolumab administration for the responder group (black circle in the figure) and the non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) treated with Nivolumab administration on a graph with the square root of the ratio of the MFI of PD-1 expression in the CD8+T cells to the MFI of PD-1 expression in the same origin Foxp3+T cells on the horizontal axis. The two solid lines in the figure represent piecewise straight lines derived by machine learning similar to that described above, and the shaded area excluding the lower left side of the figure indicates that the effect of Nivolumab can be expected in the cancer patients plotted in that area. [Figure 4] For gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) treated with Nivolumab, the square root of the ratio of the MFI of PD-1 expression in Foxp3+ T cells in the tumor tissue of each patient before Nivolumab administration to the MFI of PD-1 expression in CD8+ T cells derived from the same is plotted on the vertical axis, and the percentage (%) of PD-1 expressing cells in the CD8+ T cells is plotted on the horizontal axis. The two solid lines in the figure represent piecewise straight lines derived by machine learning similar to that described above, and the shaded area excluding the lower left side of the figure indicates that the effect of Nivolumab can be expected in the cancer patients plotted in that area. [Diagram 5]The results are shown for the responder group (black circle in the figure) and the non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) who received Nivolumab treatment. The vertical axis shows the percentage of PD-1 expressing cells in Foxp3+ T cells in the tumor tissue of each patient before Nivolumab administration, and the horizontal axis shows the percentage of PD-1 expressing cells in the CD8+ cells derived from the same. The solid line in the figure represents a piecewise straight line derived by machine learning similar to that described above, and the shaded area on the right side of the figure indicates that the effect of Nivolumab can be expected in the cancer patients plotted in that area. [Figure 6] The results are shown for the responder group (black circle in the figure) and the non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) who received Nivolumab treatment. The percentage (%) of PD-1 expressing cells in Treg cells (Fr. II) in the tumor tissue of each patient before Nivolumab administration is plotted on the vertical axis, and the percentage (%) of PD-1 expressing cells in CD8+ cells derived from the same is plotted on the horizontal axis. The two solid lines in the figure represent piecewise straight lines derived by machine learning similar to that described above, and the shaded areas on the upper left and lower right of the figure represent the expected effects of Nivolumab in the cancer patients plotted in those areas. [Figure 7] The results are shown for the responder group (black circle in the figure) and the non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) who received Nivolumab treatment. The vertical axis shows the percentage of PD-1 expressing cells in CD4+ cells in the tumor tissue of each patient before Nivolumab administration, and the horizontal axis shows the percentage of PD-1 expressing cells in CD8+ cells derived from the same. The two solid lines in the figure represent piecewise straight lines derived by machine learning similar to that described above, and the shaded area excluding the upper left area in the figure indicates that the effect of Nivolumab can be expected in the cancer patients plotted in that area. [Figure 8]The graph shows the results of plotting the square root of the ratio of the MFI of PD-1 expression in CD3+ cells derived from the same patient to the MFI of PD-1 expression in Treg cells (Fr.II) in the tumor tissue of each patient before Nivolumab administration for the responder group (black circle in the figure) and the non-responder group (x in the figure) of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) treated with Nivolumab administration on the vertical axis and the percentage (%) of PD-1 expressing cells in CD4+ T cells derived from the same patient on the horizontal axis. The two solid lines in the figure represent piecewise straight lines derived by machine learning similar to that described above, and the shaded area on the upper left side of the figure indicates that the effect of Nivolumab can be expected in the cancer patients plotted in that area. [Figure 9] The vertical axis shows the results of plotting the MFI of PD-1 expression in Foxp3+ T cells in tumor tissue of each patient before Nivolumab administration minus the MFI of PD-1 expression in CD8+ T cells derived from the same tumor tissue for the responder and non-responder groups of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) treated with Nivolumab. The dotted line in the figure shows the dividing line derived by ROC analysis (Receiver Operating Characteristic analysis), and cancer patients showing values ​​below the dividing line are expected to be effective with Nivolumab. [Figure 10] The vertical axis shows the results of subtracting the MFI of PD-1 expression in CD8+ T cells derived from Treg cells (Fr. II) in the tumor tissue of each patient before Nivolumab administration from the MFI of PD-1 expression in the same derived CD8+ T cells for the responder and non-responder groups of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) treated with Nivolumab administration. The dotted line in the figure represents the dividing line derived by ROC analysis, and cancer patients showing values ​​below the dividing line are expected to be effective with Nivolumab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0158] As used herein, the term "immune checkpoint inhibitor" refers to, for example, an anti-PD-1 antibody (e.g., Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Penpulimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK103, BI 754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 or CX-188, etc.), anti-PD-L1 antibodies (e.g., Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 and JS003, etc.), PD-1 antagonists (e.g., AUNP-12, BMS- Each of the compounds BMS-M1 to BMS-M10 (WO2014 / 151634, WO2016 / 039749, WO2016 / 057624, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 149351, WO2017 / 151830 and WO20 17 / 176608), BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001, BMS-1166 (see WO2015 / 034820, WO2015 / 160641, WO2017 / 066227 and Oncotarget. 2017 Sep 22; 8(42): 72167-72181.see WO2017 / 118762), Incyte-1 to Incyte-6 compounds (see WO2017 / 070089, WO2017 / 087777, WO2017 / 106634, WO2017 / 112730, WO2017 / 192961 and WO2017 / 205464), CAMC-1 to CAMC-4 compounds (see WO2017 / 202273, WO2017 / 202274, WO2017 / 202275 and WO2017 / 202276), RG_1 (see WO2017 / 118762) and DPPA-1 (Angew. Chem. Int. Ed.2015, 54, 11760-11764), PD-L1 / VISTA antagonists (e.g., CA-170), PD-L1 / TIM3 antagonists (e.g., CA-327), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-CTLA-4 antibodies (e.g., Ipilimumab, Zalifrelimab, Nurulimab, and Tremelimumab), anti-LAG-3 antibodies (e.g., Relatlimab, Ieramilimab, Fianlimab, Encelimab, and Mavezelimab), LAG-3 fusion proteins (e.g., IMP321), anti-Tim3 antibodies (e.g., M BG453 and Cobolimab, etc.), anti-KIR antibodies (e.g., Lirilumab, IPH2101, LY3321367 and MK-4280, etc.), anti-BTLA antibodies, anti-TIGIT antibodies (e.g., Tiragolumab, Etigilimab, Vibostolimab and BMS-986207, etc.), anti-VISTA antibodies (e.g., Onvatilimab, etc.), anti-CSF-1R antibodies or CSF-1R inhibitors (e.g., Cabiralizumab, Emactuzumab, LY3022855, MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945 and ARRY-382, etc.). In the present specification, drugs containing these substances as active ingredients are referred to as "immune checkpoint inhibitors". Nivolumab can be produced according to the method described in WO2006 / 121168, Pembrolizumab can be produced according to the method described in WO2008 / 156712, BMS-936559 can be produced according to the method described in WO2007 / 005874, and Ipilimumab can be produced according to the method described in WO2001 / 014424.

[0159] Preferred "immune checkpoint inhibitors" in the present invention are anti-PD-1 antibodies and anti-PD-L1 antibodies, and particularly preferred anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab and Penpulimab, and anti-PD-L1 antibodies include Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab and BMS-936559.

[0160] The "evaluation items" in the biomarker of the present invention are the following (1) to (12), namely: (1) CD8 in tumor tissue or blood of patients with malignant tumors + Percentage of CCR7 expressing T cells (%) (2) The CD8 + The number of PD-1 expressing T cells, the common logarithm of the number of expressing cells or the common logarithm of the number of expressing cells plus 1, (3) Foxp3 from the same source + MFI of PD-1 expression on T cells versus CD8 + The ratio of MFI of PD-1 expression in T cells or the square root of the ratio; (4) Percentage of PD-1 expressing cells in Treg cells (Fr.III) derived from the same mouse model (5) The Foxp3 + Percentage of PD-1 expressing T cells (%) (6) Percentage of PD-1 expressing cells in Treg cells (Fr. II) derived from the same mouse model (7) CD4 derived from the same source +Percentage of PD-1 expressing T cells (%) (8) The CD8 + Percentage of PD-1 expressing T cells (%) (9) MFI of PD-1 expression in Treg cells (Fr. II) versus CD3 + the ratio of MFI of PD-1 expression in cells or the square root of said ratio; (10) The CD4 + Percentage of PD-1 expressing T cells (%) (11) The Foxp3 + The MFI of PD-1 expression on T cells was used to determine the CD8 + subtracted MFI of PD-1 expression on T cells, and (12) The MFI of PD-1 expression in the Treg cells (Fr. II) + The values ​​shown are those obtained by subtracting the MFI of PD-1 expression in T cells.

[0161] As used herein, CD8 + The T cell refers to a T cell that is positive for the surface antigen CD8, and can be identified as, for example, CD3 positive, CD4 negative and CD8 positive cells. As used herein, CD4 + The T cells refer to CD4 positive T cells. As used herein, CD3 + By cells is meant cells that are CD3 positive. As used herein, Foxp3 + The T cells refer to T cells that are positive for Foxp3.

[0162] In the present specification, Treg cells can be identified as, for example, CD3 positive, CD4 positive, CD8 negative and Foxp3 positive cells, and in the present specification, "Treg cells (Fr. II)" (synonymous with "Fraction II Treg cells" or "eTreg cells") are effector Treg cells that have a particularly strong immunosuppressive effect among Treg cells and are responsible for immunosuppressive activity, and can be identified as, for example, CD45RA negative, CD25 positive and strongly Foxp3 positive Treg cells (see Immunity, Volume 30, Issue 6, 2009, pp. 899-911 and International Immunology, Volume 28, No. 8, 2016, pp. 401-409). In addition, in the present specification, "Treg cells (Fr. III)" (synonymous with "Fraction III Treg cells") can be identified as, for example, CD45RA negative, CD25 positive and weakly Foxp3 positive Treg cells. In this specification, "positive" means that a certain marker molecule is expressed on the cell surface and specific binding of an antibody to the marker molecule can be confirmed with a certain intensity, and "negative" means that specific binding of an antibody to the marker molecule cannot be confirmed with a certain intensity.

[0163] In the present invention, the "tumor tissue" from which the immune cells constituting each evaluation item are collected includes, for example, tissues including at least the tumor mass itself, the invasive periphery of the tumor, or lymph nodes adjacent to the tumor, and can be collected by known methods, such as forceps biopsy, puncture aspiration, needle biopsy, surgical biopsy, or surgical operation for tumor removal. In the present invention, the "blood" from which the immune cells constituting each evaluation item are collected includes, for example, peripheral blood. The sample derived from the tumor tissue may be extracted after mechanically crushing the tumor tissue by a known method, and may further be obtained by isolating and further purifying the immune cells constituting each evaluation item, if necessary. The destruction of the tumor tissue may be performed by enzyme treatment. On the other hand, the sample derived from the blood may be the blood itself, and may further be obtained by isolating and further purifying the immune cells constituting each evaluation item, if necessary, by specific gravity centrifugation or the like.

[0164] In the present invention, CD8 + T cell count, CD4 + T cell number, Foxp3 + The number of T cells, Treg cells (Fr. II) and Treg cells (Fr. III), as well as the number of PD-1 expressing cells and CCR7 expressing CD8 + The number of T cells can be measured and calculated by a measurement method such as flow cytometry or immunostaining. Specifically, mononuclear cells isolated from tumor tissues and peripheral blood are stained with a fluorescent dye-labeled antibody. Here, the fluorescent dye-labeled antibody includes staining with an unlabeled primary antibody and a fluorescent dye-labeled secondary antibody against the primary antibody. The mononuclear cells stained with the antibody are detected by flow cytometry. Here, the PD-1-expressing cells in each cell are a cell population that expresses PD-1 at a certain threshold or higher, and are, for example, a cell population having a fluorescence intensity that is not detected when a negative control fluorescent dye-labeled antibody that does not recognize PD-1 is used or when a fluorescent dye-labeled antibody of PD-1 is not used in flow cytometry measurement, but is detected only when an anti-PD-1 fluorescent dye-labeled antibody is used. The same applies to CCR7-expressing cells.

[0165] Similarly, CD8 + T cells, CD3 + cells, Foxp3 + The MFI of PD-1 expression in each of T cells and Treg cells (Fr. II) can also be measured, for example, by flow cytometry. Here, these MFIs may be used to calculate the ratio of the number of expression (expression amount) of each molecule per cell instead of the number of expression (expression amount) of each molecule per cell. In addition, a known measurement method using fluorescently labeled beads used to create a calibration curve for quantifying antigen molecules (e.g., a method using BD QuantiBRITE (registered trademark) PE Kit and Quantum (registered trademark) FITC MESF Kit, etc.) can be appropriately used to determine the number of expression of antigen molecules per cell. In addition, for example, Molecules of Equivalent Soluble Fluorochrome (MESF) may be used as a unit of the number of expression (expression amount) of cell surface antigen molecules used in these measurement methods.

[0166] As used herein, "CD8 + The percentage of PD-1 expressing cells in CD8 T cells was + PD-1 expression ratio (%) of CD8 + The relationship between these definitions is the same as "PD-1 expression rate (%) on CD4 + T cells, Foxp3 + The same is true for the percentage (%) of PD-1 expressing cells in T cells, Treg cells (Fr. II), and Treg cells (Fr. III).

[0167] In this specification, "before administration of a drug containing an immune checkpoint inhibitor as an active ingredient" or "before administration of an immune checkpoint inhibitor" includes not only cases where there is no history of treatment with a drug containing the immune checkpoint inhibitor as an active ingredient and it is being administered for the very first time, but also cases where there is a history of treatment with the immune checkpoint inhibitor or other antineoplastic drugs (including immune checkpoint inhibitors other than the immune checkpoint inhibitor in question) in the past.

[0168] As used herein, "about" means that the numerical value may vary by up to 10% below or above the numerical value indicated, or includes the value rounded to the nearest whole number.

[0169] Preferred combinations of two sets of evaluation items constituting the biomarker of the present invention include the following combinations (A) to (C), namely: (A)(1)(i) CD8 in tumor tissue or blood of patients with malignant tumors + Percentage of T cells expressing CCR7, or (ii) The CD8 + The number of PD-1 expressing T cells, the common logarithm of the number of expressing cells or the common logarithm of the number of expressing cells plus 1, and (2) Foxp3 from the same source + MFI of PD-1 expression on T cells versus CD8 + A combination of the ratio of MFI of PD-1 expression on T cells or the square root of the ratio; (B)(1)(i) The percentage (%) of PD-1 expressing Treg cells (Fr.III) in tumor tissue or blood of malignant tumor patients; (ii) Foxp3 from the same source + MFI of PD-1 expression on T cells versus CD8 + The ratio of MFI of PD-1 expression in T cells or the square root of the ratio; (iii) the Foxp3 + Percentage of PD-1 expressing T cells (%) (iv) Percentage (%) of PD-1 expressing cells in Treg cells (Fr. II) derived from the same mouse model; (v) CD4 from the same source + any one selected from the percentage (%) of PD-1 expressing cells in T cells, and (2) The CD8 + The combination of the percentage of PD-1 expressing cells in T cells; and (C) (1) MFI of PD-1 expression on Treg cells (Fr. II) in tumor tissue or blood of patients with malignant tumors, relative to CD3 + the ratio of MFI of PD-1 expression in cells or the square root of the ratio, and (2) CD4 derived from the same source + The combination of the percentage (%) of PD-1 expressing T cells is included. Furthermore, specific conditions for identifying malignant tumor patients for whom immune checkpoint inhibitors are or are not expected to be effective in the combination of the two specified sets of evaluation items can be predetermined according to the following procedure. That is, (1) two sets of predetermined evaluation items are measured for malignant tumor patients before administration of an immune checkpoint inhibitor, (2) the immune checkpoint inhibitor is administered, (3) the effectiveness of the immune checkpoint inhibitor is determined for each patient using a predetermined determination method, (4) for each patient determined to be either effective or ineffective, the measured values ​​of the two sets of evaluation items are plotted, (5) when one or more piecewise lines (discrimination boundaries) that divide (distinguish) the effective group and the ineffective group are varied using an arbitrary numerical value represented by the parameter α value (a numerical value of 0≦α≦1) in the weighted F-measure (fα), which is one of the evaluation indexes in machine learning, a piecewise line that maximizes the value of fα is derived by machine learning, and (6) a combination of one piecewise line or multiple piecewise lines derived for the two sets of evaluation items is defined as a specific condition for identifying the malignant tumor patient using each of the two sets of evaluation items for each biomarker.

[0170] Here, fα is expressed by the following formula:

[0171]

number

[0172] The α value in the formula can be set to, for example, 0.5 when dividing the two groups so as to include as many effective patients as possible while including as few ineffective patients as possible, and when there is a large number of effective patients, for example, when dividing the two groups so as to include as many effective patients as possible, the α value can be set to 0.05, while when dividing the two groups so as to include as few ineffective patients as possible, the α value can be set to, for example, 0.95. Here, "Recall" in the formula means the reproducibility rate, and refers to the proportion of patients who are predicted to be effective in the efficacy assessment among patients who are actually effective, and is expressed by the following formula:

[0173]

number

[0174] [In the formula, "True-Positive" represents the number of patients who were correctly predicted to be effective among those predicted to be effective in a binary classification according to whether or not an immune checkpoint inhibitor is effective, and "False-Negative" represents the number of patients who were incorrectly predicted to be ineffective among those predicted to be ineffective.] Meanwhile, "Precision" in the formula for fα above means the precision rate, which means the proportion of patients who are actually effective among those predicted to be effective in the efficacy assessment, and is calculated using the following formula:

[0175]

number

[0176] [In the formula, "False-Positive" represents the number of patients who were erroneously predicted to be effective among those who were predicted to be effective in the binary classification, and the other symbols have the same meanings as above.]

[0177] In setting the specific conditions constituting the biomarker of the present invention, in addition to the weighted F value f(α) described above, accuracy, specificity, or a composite index including these can also be used, and can be determined, for example, by ROC analysis (Receiver Operating Characteristic analysis) (see Clinical Pathology 42(6): 585-590, 1994).

[0178] The efficacy of the immune checkpoint inhibitor can be determined based on, for example, complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) as determined according to the RECIST guidelines (Response Evaluation Criteria in Solid Tumor, 2000) when the cancer is a solid cancer. For example, CR, PR, and SD patients may be determined as effective (hereinafter, may be referred to as the "responder group"), and PD patients may be determined as ineffective (hereinafter, may be referred to as the "non-responder group"). Alternatively, CR and PR patients may be determined as effective, and SD and PD patients may be determined as ineffective. In addition, CR and PR patients and patients who have maintained SD for at least 6 months may be determined as effective, and patients who have maintained SD for less than 6 months and PD patients may be determined as ineffective. Judgment based on the same criteria may be made, for example, up to 12 months, preferably up to 10 months, more preferably 8 months, and more preferably 6 months after the start of treatment with immune checkpoint inhibitors. Effectiveness or ineffectiveness can also be judged based on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), survival rate, median survival time, etc. Patients whose PFS is maintained for 70 days may be judged as effective, while patients whose PFS is less than 70 days may be judged as ineffective.

[0179] Biomarker 1 The two sets of evaluation items were CD8 in tumor tissue or blood. + Percentage of CCR7 expressing T cells and Foxp3 + MFI of PD-1 expression on T cells versus CD8 + The MFI ratio of PD-1 expression in T cells was selected, (1) using the following formula:

[0180]

number

[0181] [In the formula, Y 1 The CD8 + The percentage of CCR7-expressing T cells (%) is shown. 1-1 represents a number around -637, and X 1 Foxp3 + MFI of PD-1 expression on T cells versus CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells, and Y 1-1 represents any numerical value from about 784 to about 914.], or (2) (i) the following formula:

[0182]

number

[0183] [In the formula, a 1-2 represents a value of approximately -24.0, and Y 1-2 represents any numerical value from about 39.0 to about 50.9, and the other symbols have the same meanings as above.] and (ii) a compound represented by the following formula:

[0184]

number

[0185] [In the formula, a 1-3 represents the value of approximately 666, and Y 1-3represents any numerical value from about -652 to about -522, and the other symbols have the same meanings as above.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy these conditions can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0186] Here, Y in the above formula 1-1 is preferably any number between about 784 and about 853 or any number between about 853 and about 914, more preferably about 853; 1-2 is preferably any number between about 44.6 and about 50.9, or any number between about 39.0 and about 44.6, more preferably about 44.6; 1-3 is preferably an arbitrary numerical value from about -591 to about -522 or an arbitrary numerical value from about -652 to about -591, and is preferably about -591. Note that, when the α value in the weighted F value (fα) is 0.95, Y 1-1 , Y 1-2 and Y 1-3 are approximately 914, approximately 39.0, and approximately -652, respectively. When the α value is set to 0.05, Y 1-1 , Y 1-2 and Y 1-3 are approximately 784, approximately 50.9, and approximately -522, respectively. When the α value is set to 0.5, Y 1-1 , Y 1-2 and Y 1-3 are approximately 853, approximately 44.6, and approximately -591, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 1-1 , Y 1-2 and Y 1-3 The most preferable combination of the above conditions is defined by the numerical values ​​of (the combination of segmented straight lines represented by the three solid lines in FIG. 1).

[0187] Biomarker 2 The two sets of evaluation items were Treg cells (Fr.III) and CD8 +When the percentage (%) of PD-1 expressing cells in each T cell was selected, (1) the following formula:

[0188]

number

[0189] [In the formula, Y 2 represents the percentage (%) of PD-1 expressing cells in the Treg cells (Fr.III), and a 2-1 represents a value of approximately 0.765, and X 2 The CD8 + The percentage of PD-1 expressing T cells is shown. 2-1 represents any numerical value between about 50.6 and about 59.2.], or (2) the condition represented by the following formula:

[0190]

number

[0191] [In the formula, a 2-2 represents a value of approximately 1.56, and Y 2-2 represents an arbitrary numerical value of approximately -44.1 to -14.5, and the other symbols have the same meanings as above.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0192] Here, Y in the above formula 2-1 is preferably any number between about 50.6 and about 54.1 or any number between about 54.1 and about 59.2, more preferably about 54.1; 2-2 is preferably an arbitrary numerical value between about -26.6 and -14.5, or an arbitrary numerical value between about -44.1 and about -26.6, and more preferably about -26.6. When the α value in the weighted F value (fα) is 0.95, Y 2-1 and Y 2-2are approximately 59.2 and approximately -44.1, respectively. When the α value is set to 0.05, Y 2-1 and Y 2-2 are approximately 50.6 and approximately -14.5, respectively. When the α value is set to 0.5, Y 2-1 and Y 2-2 are approximately 54.1 and approximately -26.6, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 2-1 and Y 2-2 The combination of the above conditions defined by the numerical values ​​(the combination of segmented straight lines represented by the two solid lines in FIG. 2) is most preferable.

[0193] Biomarker 3 The two sets of evaluation items were CD8 in tumor tissue or blood. + PD-1 expressing cells and Foxp3 expression in T cells + MFI of PD-1 expression on T cells versus CD8 + When the ratio of MFI of PD-1 expression in T cells was selected, (1)(i) the following formula:

[0194]

number

[0195] [In the formula, Y 3 The CD8 + The number of PD-1 expressing T cells is shown. 3-1 represents a value of approximately -1.59, and X 3 Foxp3 + MFI of PD-1 expression on T cells versus CD8 + represents the square root of the ratio of the MFIs in T cells, and Y 3-1 represents any number between about 4.09 and about 4.89; or (ii) the following formula:

[0196]

number

[0197] "wherein all symbols have the same meanings as above," or (2)(i) the following formula:

[0198]

number

[0199] [In the formula, a 3-2 represents a value of approximately -9.05, and Y 3-2 represents any numerical value between about 10.7 and 13.3, and the other symbols have the same meanings as above.] or (ii) a formula:

[0200]

number

[0201] [wherein all other symbols have the same meanings as above] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0202] Here, Y in the above formula 3-1 is preferably any number between about 4.09 and about 4.42, or any number between about 4.42 and about 4.89, more preferably about 4.42; 3-2 is preferably any value between about 11.7 and about 13.3, or any value between about 10.7 and about 11.7, and more preferably about 11.7. When the α value in the weighted F value (fα) is 0.95, Y 3-1 and Y 3-2 are approximately 4.89 and 13.3, respectively. When the α value is set to 0.05, Y 3-1 and Y 3-2 are approximately 4.09 and 10.7, respectively. When the α value is set to 0.5, Y 3-1 and Y 3-2are approximately 4.42 and 11.7, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 3-1 and Y 3-2 The combination of the above conditions defined by the numerical values ​​(the combination of segmented straight lines represented by the two solid lines in FIG. 3) is most preferable.

[0203] Biomarker 4 The two sets of evaluation items were Foxp3 in tumor tissue or blood. + MFI of PD-1 expression on T cells versus CD8 + The ratio of MFI of PD-1 expression on T cells and the corresponding CD8 + When the percentage (%) of PD-1 expressing cells in T cells was selected, (1) the following formula:

[0204]

number

[0205] [In the formula, Y 4 Foxp3 + MFI of PD-1 expression on T cells versus CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells; a 4-1 represents a number of approximately -0.00273, and X 4 The CD8 + The percentage of PD-1 expressing T cells is shown. 4-1 represents any numerical value from about 0.905 to about 1.46.], or (2) the condition represented by the following formula:

[0206]

number

[0207] [In the formula, a 4-2 represents a value of approximately -0.0294, and Y 4-2represents any numerical value of approximately 2.18 to 3.31, and the other symbols have the same meanings as above.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0208] Here, Y in the above formula 4-1 is preferably any number between about 0.905 and about 1.18 or any number between about 1.18 and about 1.46, more preferably about 1.18; 4-2 is preferably any value between about 2.74 and about 3.31, or any value between about 2.18 and about 2.74, and more preferably about 2.74. When the α value in the weighted F value (fα) is 0.95, Y 4-1 and Y 4-2 are approximately 1.46 and 3.31, respectively. When the α value is set to 0.05, Y 4-1 and Y 4-2 are approximately 0.905 and 2.18, respectively. When the α value is set to 0.5, Y 4-1 and Y 4-2 are approximately 1.18 and 2.74, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 4-1 and Y 4-2 The combination of the above conditions defined by the numerical values ​​(the combination of segmented straight lines represented by the two solid lines in FIG. 4) is most preferable.

[0209] Biomarker 5 The two sets of evaluation items were Foxp3 in tumor tissue or blood. + T cells and CD8 + When the percentage (%) of PD-1 expressing cells in each T cell was selected, the following formula was used:

[0210]

number

[0211] [In the formula, Y 5 Foxp3 + The percentage of PD-1 expressing T cells (%) is shown. 5 represents a value of approximately 2.34, and X 5 The CD8 + The percentage of PD-1 expressing T cells is shown. 5-1 represents any numerical value from about -117 to about 131.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0212] Here, Y in the above formula 5-1 is preferably any numerical value between about -117 and about -54.4 or any numerical value between about -54.4 and about 131, and more preferably about -54.4. When the α value in the weighted F value (fα) is 0.95, Y 5-1 is about -117, and when the alpha value is set to 0.05, Y 5-1 is about 131. When the α value is set to 0.5, Y 5-1 is approximately -54.4, but in selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 5-1 The above condition defined by the numerical values ​​(represented by the solid line in FIG. 5) is most preferable.

[0213] Biomarker 6 The two sets of evaluation items were Treg cells (Fr.II) and CD8 + When the percentage (%) of PD-1 expressing cells in each T cell was selected, (1) the following formula:

[0214]

number

[0215] [In the formula, Y6 represents the percentage (%) of PD-1 expressing cells in the Treg cells (Fr. II), and a 6-1 represents a value of approximately 1.69, and X 6 The CD8 + The percentage of PD-1 expressing T cells is shown. 6-1 represents any numerical value from about 21.4 to about 44.1.], or (2) the condition represented by the following formula:

[0216]

number

[0217] [In the formula, a 6-2 represents a value of approximately 1.78, and Y 6-2 represents any numerical value from about -80.6 to about -21.0, and the other symbols have the same meanings as above.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0218] Here, Y in the above formula 6-1 is preferably any number between about 21.4 and about 31.8 or any number between about 31.8 and about 44.1, more preferably about 31.8; 6-2 is preferably an arbitrary numerical value of about -48.2 to about -21.0 or an arbitrary numerical value of about -80.6 to about -48.2, and more preferably about -48.2. When the α value in the weighted F value (fα) is 0.95, Y 6-1 and Y 6-2 are approximately 44.1 and approximately -80.6, respectively. When the α value is set to 0.05, Y 6-1 and Y 6-2 are approximately 21.4 and -21.0, respectively. When the α value is set to 0.5, Y 6-1 and Y 6-2are approximately 31.8 and approximately -48.2, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 6-1 and Y 6-2 The combination of the above conditions defined by the numerical values ​​(the combination of segmented straight lines represented by the two solid lines in FIG. 6) is most preferable.

[0219] Biomarker 7 The two sets of endpoints were CD4 in tumor tissue or blood. + T cells and CD8 + When the percentage (%) of PD-1 expressing cells in each T cell was selected, (1) the following formula:

[0220]

number

[0221] [In the formula, Y 7 The CD4 + represents the percentage of PD-1 expressing T cells, and X 7 The CD8 + The percentage of PD-1 expressing T cells (%) is shown. 7-1 represents a value of approximately 0.227, and Y 7-1 represents any numerical value from about -13.9 to about 4.03.], or (2) the condition represented by the following formula:

[0222]

number

[0223] [In the formula, a 7-2 represents a value of approximately 3.32, and Y 7-2represents any numerical value from about -199 to about 58.2, and the other symbols have the same meanings as above.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0224] Here, Y in the above formula 7-1 is preferably any number between about -13.9 and about -6.56 or any number between about -6.56 and about 4.03, more preferably about -6.56; 7-2 is preferably any numerical value between about -93.5 and about 58.2, or any numerical value between about -199 and about -93.5, and more preferably about -93.5. When the α value in the weighted F value (fα) is 0.95, Y 7-1 and Y 7-2 are approximately -13.9 and -199, respectively. When the α value is set to 0.05, Y 7-1 and Y 7-2 are approximately 4.03 and 58.2, respectively. When the α value is set to 0.5, Y 7-1 and Y 7-2 are approximately -6.56 and -93.5, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 7-1 and Y 7-2 The combination of the above conditions defined by the numerical values ​​(the combination of segmented straight lines represented by the two solid lines in FIG. 7) is most preferable.

[0225] Biomarker 8 The two sets of evaluation items were the MFI of PD-1 expression on Treg cells (Fr. II) in tumor tissue or blood, and the CD3 + The ratio of MFI of PD-1 expression in cells and CD4 + When the percentage (%) of PD-1 expressing cells in T cells was selected, the following formula was used:

[0226]

number

[0227] [In the formula, Y 8 is the ratio of the MFI of PD-1 expression in the Treg cells (Fr. II) to the CD3 + represents the square root of the ratio of MFI of PD-1 expression in cells, a 8-1 represents a value of approximately -0.00338, and a 8-2 represents a value of approximately 0.270, and X 8 The CD4 + The percentage of PD-1 expressing T cells is shown. 8-1 represents any value between about 0.939 and about 1.37, and Y 8-2 represents any numerical value between about -6.98 and about -0.654.] can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is more likely to be effective, and patients who do not satisfy the condition can be selected as malignant tumor patients for whom the immune checkpoint inhibitor is less likely to be effective.

[0228] Here, Y in the above formula 8-1 is preferably any number between about 0.939 and about 1.17, or any number between about 1.17 and about 1.37, more preferably about 1.17; 8-2 is preferably an arbitrary numerical value of about -4.10 to about -0.654 or an arbitrary numerical value of about -6.98 to about -4.10, and more preferably about -4.10. Note that, when the α value in the weighted F value (fα) is 0.95, Y 8-1 and Y 8-2 are approximately 1.37 and approximately -6.98, respectively. When the α value is set to 0.05, Y 8-1 and Y 8-2 are approximately 0.939 and approximately -0.654, respectively. When the α value is set to 0.5, Y 8-1 and Y 8-2 are approximately 1.17 and approximately -4.10, respectively. In selecting patients with malignant tumors who are more likely to benefit from the immune checkpoint inhibitor, the Y 8-1 and Y8-2 The combination of the above conditions defined by the numerical values ​​(the combination of segmented straight lines represented by the two solid lines in FIG. 8) is most preferable.

[0229] Biomarker 9 The endpoint was Foxp3 in tumor tissue or blood. + MFI of PD-1 expression on T cells from the same source CD8 + The MFI of PD-1 expression in T cells was subtracted from the value, and the following formula was used:

[0230]

number

[0231] [In the formula, Y 9-1 Foxp3 + represents the MFI of PD-1 expression in T cells, 9-2 The CD8 + represents the MFI of PD-1 expression in T cells; 9 represents an arbitrary numerical value (cutoff value) of about -716 to about 166.] can be selected as a malignant tumor patient for whom the immune checkpoint inhibitor is more likely to be effective, and a patient who does not satisfy the condition can be selected as a malignant tumor patient for whom the immune checkpoint inhibitor is less likely to be effective.

[0232] Here, a in the above formula 9 is preferably any numerical value from about -462 to about 166 or from about -716 to about -3.96, more preferably any numerical value from about -462 to about -3.96, and even more preferably about -208.

[0233] Biomarker 10 The evaluation items were the MFI of PD-1 expression on Treg cells (Fr. II) in tumor tissue or blood, and the CD8 + The MFI of PD-1 expression in T cells was subtracted from the value, and the following formula was used:

[0234]

number

[0235] [In the formula, Y 10-1 represents the MFI of PD-1 expression in the Treg cells (Fr. II), and Y 10-2 The CD8 + represents the MFI of PD-1 expression in T cells; 10 represents an arbitrary numerical value (cutoff value) of about -842 to about 133.] can be selected as a malignant tumor patient for whom the immune checkpoint inhibitor is more likely to be effective, and a patient who does not satisfy the condition can be selected as a malignant tumor patient for whom the immune checkpoint inhibitor is less likely to be effective.

[0236] Here, a in the above formula 10 is preferably any numerical value from about -505 to about 133 or from about -842 to about -2.40, more preferably any numerical value from about -505 to about -2.40, and further preferably about -131.

[0237] [Applicable diseases and patients] Examples of malignant tumors to which the therapeutic agent or the patient identification method of the present invention can be applied include, in the case of solid cancers, for example, malignant melanoma (e.g., malignant melanoma in the skin, oral mucosal epithelium, or orbit, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g., serous ovarian cancer and ovarian clear cell adenocarcinoma), nasopharyngeal carcinoma, uterine cancer (e.g., cervical cancer, endometrial and uterine cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (e.g., MSI-H and / or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial carcinoma (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvis cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer , within Examples of the cancer include one or more cancers selected from endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, brain tumor (e.g., glioma (e.g., glioblastoma and gliosarcoma) and meningioma), squamous cell carcinoma, bone and soft tissue sarcoma (e.g., Ewing's sarcoma, childhood rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma), and Kaposi's sarcoma.

[0238] On the other hand, in the case of blood cancer, for example, multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, MALT lymphoma) , bacteriaand / or lymphoblastic leukemia (e.g., classical Hodgkin lymphoma and nodal lymphocyte-predominant Hodgkin lymphoma)), leukemia (e.g., acute myeloid leukemia and chronic myeloid leukemia), primary central nervous system malignant lymphoma, myelodysplastic syndrome, and myeloproliferative syndrome.

[0239] As used herein, "treatment of malignant tumors" includes, for example, treatments performed to (i) reduce the proliferation of tumor cells, (ii) reduce symptoms caused by malignant tumors, (iii) improve the quality of life of malignant tumor patients, (iv) reduce the dose of other anti-malignant tumor drugs or cancer treatment adjuvant drugs already administered, and / or (v) prolong the survival of malignant tumor patients, and "suppression of progression of malignant tumors" means delaying the progression of malignant tumors, stabilizing symptoms associated with malignant tumors, and reversing the progression of symptoms. In addition, "suppression of recurrence of malignant tumors" means preventively suppressing the recurrence of malignant tumors in patients whose cancer lesions have completely or substantially disappeared or been removed by malignant tumor treatment or malignant tumor resection surgery.

[0240] In the present invention, the immune checkpoint inhibitor may be prescribed to patients with malignant tumors who meet the conditions of at least one of biomarkers 1 to 10 according to the present invention and who have the following malignant tumors: (a) patients with malignant tumors for which the therapeutic effect of other anticancer drugs is insufficient or insufficient, or patients with malignant tumors that have worsened after treatment with other anticancer drugs; (b) patients with malignant tumors that are curable or inoperable, metastatic, recurrent, refractory, and / or distantly metastatic; (c) patients with malignant tumors with TPS or CPS of 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more; (d) patients with malignant tumors having MSI-H or dMMR; (e) patients with malignant melanoma or non-small cell lung cancer that is BRAF V600E mutation-positive; (f) patients with malignant tumors that are EGFR gene mutation-positive or ALK fusion gene-positive; or (g) patients with malignant tumors with a high frequency of TMB.

[0241] On the other hand, in the present invention, the immune checkpoint inhibitor may be more likely to be prescribed to patients with malignant tumors who meet the conditions of at least one of biomarkers 1 to 10 of the present invention and who are as follows: (a) patients with malignant tumors who have no history of treatment with other anticancer drugs; (b) patients with malignant tumors whose TPS or CPS is less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%; (c) patients with malignant tumors that do not have MSI-H and / or dMMR or have MSI-L; (d) patients with BRAF V600 wild-type melanoma or non-small cell lung cancer; (e) patients with non-small cell lung cancer that is EGFR gene mutation-negative and / or ALK fusion gene-negative; or (f) patients with malignant tumors with a low frequency of TMB.

[0242] Furthermore, it can also be prescribed as a postoperative adjuvant therapy for prophylactically inhibiting recurrence or metastasis after surgical resection of a malignant tumor, or as a neoadjuvant therapy performed before surgical resection.

[0243] Here, examples of "other antineoplastic agents" include the antineoplastic agents listed in the section on [Concomitant use and combination drugs] below, i.e., alkylating agents, platinum preparations, metabolic antagonists (e.g., folate metabolic antagonists, pyridine metabolic inhibitors, purine metabolic inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormones, molecular targeted drugs, and cancer immunotherapy drugs. In addition, "therapeutic effect of antineoplastic agents is insufficient or not sufficient" includes, for example, cases where the patient is judged to be stable (SD) or progressive (PD) by RECIST even after treatment with antineoplastic agents.

[0244] [Prescription] The dosage of the immune checkpoint inhibitor of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 ng to 1000 mg per dose per adult, or parenterally administered once to several times a day in the range of 0.1 ng to 100 mg per dose per adult, or continuously administered intravenously for 30 minutes to 24 hours a day. Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases where a smaller dosage than the above-mentioned dosage is sufficient, and cases where it is necessary to administer beyond the range.

[0245] For example, Nivolumab, an anti-PD-1 antibody, is administered in the following dosage regimen: Nivolumab may be administered to adults by intravenous infusion at (1) 1 mg / kg (body weight) every 3 weeks, (2) 3 mg / kg (body weight) every 2 weeks, (3) 2 mg / kg (body weight) every 3 weeks, (4) 80 mg every 3 weeks, (5) 240 mg every 2 weeks, (6) 360 mg every 3 weeks, or (7) 480 mg every 4 weeks.

[0246] In particular, Nivolumab is administered intravenously at 3 mg / kg (body weight) every 2 weeks or 2 mg / kg (body weight) every 3 weeks to patients with malignant melanoma, and at 3 mg / kg (body weight) every 2 weeks to patients with non-small cell lung cancer, renal cell carcinoma, classical Hodgkin's lymphoma, head and neck cancer, gastric cancer, and malignant pleural mesothelioma. In addition, as another dosage regimen, for example, Nivolumab is administered intravenously at 240 mg every 2 weeks or 480 mg every 4 weeks to patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, MSI-H or dMMR positive colorectal cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, small cell lung cancer, and malignant pleural mesothelioma. As another dosage regimen, for example, in combination with ipilimumab (3 mg / kg (body weight) once daily, four times at three-week intervals), patients with malignant melanoma may be intravenously administered 1 mg / kg (body weight) of nivolumab at three-week intervals for four doses, followed by intravenous infusion of 3 mg / kg (body weight) of nivolumab at two-week intervals, or intravenously administered 80 mg of nivolumab at three-week intervals for four doses, followed by intravenous infusion of 240 mg of nivolumab at two-week intervals or intravenously administered 480 mg of nivolumab at four-week intervals. For example, for patients with renal cell carcinoma or MSI-H or dMMR-positive colorectal cancer, in combination with ipilimumab (1 mg / kg (body weight) once daily, intravenously injected four times at three-week intervals), 240 mg of nivolumab may be administered intravenously four times at three-week intervals, followed by 240 mg of nivolumab administered intravenously every two weeks or 480 mg of nivolumab administered intravenously every four weeks.

[0247] In the case of pembrolizumab, which is also an anti-PD-1 antibody, it can be administered to adults at (1) 200 mg of pembrolizumab every 3 weeks, (2) 400 mg of pembrolizumab every 6 weeks, or (3) 2 mg / kg (body weight) (up to 200 mg per administration) administered intravenously every 3 weeks. In particular, for patients with malignant melanoma, non-small cell lung cancer, small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H solid tumors or colorectal cancer, urothelial carcinoma, cervical cancer, uterine cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, gastric cancer, esophageal cancer, and Merkel cell carcinoma, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. As an alternative dosage regimen, for example, pediatric patients aged 2 years or older with classical Hodgkin lymphoma, MSI-H solid tumors or colorectal cancer, primary mediastinal B-cell lymphoma, and Merkel cell carcinoma are given 2 mg / kg (body weight) of pembrolizumab (up to 200 mg at a time) by intravenous infusion every 3 weeks.

[0248] In addition, in the case of Cemiplimab-rwlc, which is also an anti-PD-1 antibody, it can be administered to adults at a dose of 350 mg as Cemiplimab-rwlc by intravenous infusion every three weeks. In particular, it is administered to patients with squamous cell carcinoma in the same manner and dosage.

[0249] On the other hand, in the case of Avelumab, an anti-PD-L1 antibody, 10 mg / kg (body weight) of Avelumab can be administered intravenously to adults every two weeks. In particular, 10 mg / kg (body weight) of Avelumab is administered intravenously to patients with Merkel cell carcinoma every two weeks. In addition, in patients with renal cell carcinoma, it is administered in the same dosage and in combination with Axitinib. In the case of Atezolizumab, which is also a PD-L1 antibody, adults are administered (1) 840 mg of Atezolizumab every two weeks, (2) 1200 mg of Atezolizumab every three weeks, or (3) 1680 mg of Atezolizumab every four weeks by intravenous infusion. In particular, Atezolizumab is administered to patients with non-small cell lung cancer or small cell lung cancer and urothelial cancer who have been previously treated with chemotherapy, in the same dosage regime as above, whereby for non-small cell lung cancer patients who have not been treated with chemotherapy, Atezolizumab is administered at 1200 mg once every 3 weeks in combination with other anti-cancer drugs (Bevacizumab, Paclitaxel, and Carboplatin), and for small cell lung cancer patients who have not been treated with chemotherapy, Atezolizumab is administered at 840 mg once every 2 weeks by intravenous infusion in combination with Paclitaxel.

[0250] In addition, in the case of durvalumab, which is also a PD-L1 antibody, patients with non-small cell lung cancer and bladder cancer are administered durvalumab at 10 mg / kg (body weight) by intravenous infusion every two weeks.

[0251] In the case of ipilimumab, an anti-CTLA-4 antibody, it is administered to adults at (1) 3 mg / kg (body weight) once a day or (2) 1 mg / kg (body weight) once a day, four times at three-week intervals, by intravenous infusion. In particular, for patients with malignant melanoma, ipilimumab is administered intravenously at 3 mg / kg (body weight) once a day, four times at three-week intervals, either alone or in combination with Nivolumab, and for patients with renal cell carcinoma and MSI-H colorectal cancer, ipilimumab is administered intravenously at 1 mg / kg (body weight) once a day, four times at three-week intervals, in combination with Nivolumab.

[0252] [Concomitant use and combination drugs] The therapeutic agent etc. of the present invention may be used in combination with one or more other drugs (mainly anti-malignant tumor drugs) used for the treatment of malignant tumors in order to (1) suppress progression, suppress recurrence and / or enhance the therapeutic effect of malignant tumors, (2) reduce the dosage of other drugs used in combination and / or (3) reduce the side effects of other drugs used in combination. In the present invention, the dosage form when formulated in combination with other drugs may be a combination drug form in which both components are blended in one preparation, or may be a separate preparation. When the therapeutic agent etc. of the present invention and other drugs are administered separately, the therapeutic agent etc. of the present invention may be administered first and the other drug may be administered thereafter, or the other drug may be administered first and the therapeutic agent etc. of the present invention may be administered later, or the administration may include a period during which both drugs are administered simultaneously. The administration method for each drug may be the same or different. Depending on the nature of the drug, the therapeutic agent etc. of the present invention may be provided as a kit containing the therapeutic agent etc. of the present invention and other drugs. Here, the dosage of the other drug may be appropriately selected based on the dose used in clinical practice. Any two or more of the other drugs may be administered in combination at an appropriate ratio. The other drugs include not only those that have been discovered so far, but also those that will be discovered in the future.

[0253] Examples of the anticancer drugs that can be cited as major examples of other drugs include alkylating agents (e.g., Dacarbazine, Nimustine, Temozolomide, Fotemustine, Bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil, and Procarbazine, etc.), platinum drugs (e.g., Cisplatin, Carboplatin, Nedaplatin, and Oxaliplatin, etc.), metabolic antagonists (e.g., folic acid metabolic antagonists (e.g., Pemetrexed, Leucovorin, and Methotrexate, etc.), pyridine metabolic inhibitors (e.g., TS-1 (registered trademark), 5-fluorouracil, UFT, Carmofur, etc.), , Doxifluridine, FdUrd, Cytarabine, and Capecitabine), purine metabolism inhibitors (e.g., Fludarabine, Cladribine, and Nelarabine), ribonucleotide reductase inhibitors, nucleotide analogues (e.g., Gemcitabine), topoisomerase inhibitors (e.g., Irinotecan, Nogitecan, and Etoposide), microtubule polymerization inhibitors (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine, and Eribulin), microtubule depolymerization inhibitors (e.g., Docetaxel and Paclitaxel), antitumor antibiotics (e.g., Bleomycin, Mitomycin,C, Doxorubicin, Daunorubicin, Idarubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Peplomycin, Amrubicin, Aclarubicin, and Epirubicin, etc.), cytokine preparations (e.g., IFN-α2a, IFN-α2b, PEG-IFN-α2b, natural IFN-β, and Interleukin-2, etc.), antihormonal drugs (e.g., Tamoxifen, Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole, and Exemestane, etc.), molecular targeted drugs, cancer immunotherapy drugs, and other antibody drugs.

[0254] Here, examples of molecular targeted drugs include ALK inhibitors (e.g., Crizotinib, Ceritinib, Ensartinib, Alectinib, Lorlatinib, etc.), BCR-ABL inhibitors (e.g., Imatinib, Dasatinib, etc.), EGFR inhibitors (e.g., Erlotinib, EGF816, Afatinib, Osimertinib, etc.), mesilate, Gefitinib and Rociletinib, etc.), B-RAF inhibitors (e.g., Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and Zanubrutinib (BGB-3111) etc.), VEGFR inhibitors (e.g., Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib, etc.), FGFR inhibitors (e.g., AZD4547, Vofatmab (B-701), Roblitinib (FGF401) and Pemigatinib (INCB054828) etc.), c-Met inhibitors (e.g., Savolitinib, merestinib, Capmatinib, INC280 and and Glesatinib), Axl inhibitors (e.g., ONO-7475 and Bemcentinib (BGB324)), MEK inhibitors (e.g., Cobimetinib, Binimetinib, Selumetinib, and Trametinib), CDK inhibitors (e.g., Dinaciclib, Abemaciclib, Palbociclib, and trilaciclib), BTK inhibitors (e.g., Ibrutinib and Acalabrutinib), PI3K-δ / γ inhibitors (e.g., Umbralisib (TGR-1202), Parsaclisib (INCB050465), and IPI-549), JAK-1 / 2 inhibitors (e.g., Itacitinib and Ruxolitinib), ERK inhibitors (e.g., SCH 900353), TGFbR1 inhibitors (e.g., Galunisertib), Cancer cell stemness inhibitors (e.g., EGFR inhibitors),Kinase inhibitors (e.g., Amcasertib, etc.), FAK inhibitors (e.g., Defactinib, etc.), Syk / FLT3 dual inhibitors (e.g., Mivavotinib (TAK-659)), ATR inhibitors (e.g., Ceralasertib (AZD6738)), Wee1 kinase inhibitors (e.g., Adavosertib (AZD1775)), multi-tyrosine kinase inhibitors (e.g., Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib, and Midostaurin), mTOR inhibitors (e.g., Temsirolimus, Everolimus, Vistusertib, and Irinotecan), HDAC inhibitors (e.g., Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobiliary nostat and Valproate), PARP inhibitors (e.g., Niraparib, Olaparib, Veliparib, Rucaparib and Beigene-290), aromatase inhibitors (e.g., Exemestane and Letrozole), EZH2 inhibitors (e.g., tazemetostat), Galectin-3 inhibitors (e.g., Belapectin (GR-MD-02)), STAT3 inhibitors (e.g., Napabucasin), DNMT inhibitors (e.g., Azacitidine), BCL-2 inhibitors (e.g., Navitoclax and Venetoclax), SMO inhibitors (e.g., Vismodegib), Hsp90 inhibitors (e.g., XL888), γ-tubulin specific inhibitors (e.g., Glaziovianin A and Plinabulin, HIF2α inhibitors (e.g., PT2385, etc.), glutaminase inhibitors (e.g., CB-839, etc.), E3 ligase inhibitors (e.g., Avadomide, etc.), Nrf2 activators (e.g., Omaveloxolone, etc.), arginase inhibitors (e.g., CB-1158, etc.), cell cycle inhibitors (e.g., Trabectedin, etc.), EphrinB4 inhibitors (e.g., sEphB4-HAS, etc.), IAP antagonists (e.g., Birinapant, etc.), anti-HER2 antibodies (e.g., Trastuzumab, Trastuzumab emtansine, Trastuzumab beta, Trastuzumab deruxtecan, Trastuzumab duocarmazine, Pertuzumab, Margetuximab, Disitamab, Disitamab vedotin, Gancotamab, Timigutuzumab, Zanidatamab, Zenocutuzumab, R48, and ZW33, etc.), anti-HER1 antibodies (e.g., Cetuximab, Panitumumab, Cetuximab sarotalocan, Depatuxizumab, Depatuxizumab mafodotin, Futuximab, Laprituximab, Laprituximab emtansine, Matuzumab, Modotuximab, Petosemtamab, Tomuzotuximab, Losatuxizumab, Losatuxizumab vedotin, Serclutamab, Serclutamab talirine, Imgatuzumab, Futuximab, Zalutumumab, Necitumumab and Nimotuzumab), anti-HER3 antibodies (e.g. Duligotuzumab, Elgemtumab, Istiratumab, Lumretuzumab, Zenocutuzumab, Patritumab, Patritumab) deruxtecan and seribantumab), anti-CD40 antibodies (e.g., bleselumab, dacetuzumab, iscalimab, lucatumumab, mitazalimab, ravagalimab, selicrelumab, teneliximab, abbvl-428 and apx005m), anti-CD70 antibodies (e.g., cusatuzumab, vorsetuzumab, vorsetuzumab mafodotin and arpex-110), anti-VEGF antibodies (e.g., bevacizumab, bevacizumab beta, ranibizumab, abiciparpegol, Aflibercept, Brolucizumab, Conbercept, Dilpacimab, Faricimab, Navicixizumab, Varisacumab and IMC-1C11, etc.), anti-VEGFR1 antibodies (e.g., Icrucumab, etc.), anti-VEGFR2 antibodies (e.g., Ramucirumab, Alacizumab, Alacizumab pegol, Olinvacimab, Pegdinetanib and AMG596, etc.), anti-CD20 antibodies (e.g., Rituximab, Blontuvetmab, Epitumomab, Ibritumomab tiuxetan, Ocaratuzumab, Ocrelizumab, Technetium ( 99 mTc) nofetumomab merpentan, Tositumomab, Veltuzumab, Ofatumumab, Nofetumomab, Ofatumumab, Ublituximab and Obinutuzumab, etc.), anti-CD30 antibodies (e.g., Brentuximab Vedotin and Iratumumab, etc.), anti-CD38 antibodies (e.g., Daratumumab, Isatuximab, Mezagitamab, AT13 / 5 and MOR202, etc.), anti-TNFRSF10B antibodies (e.g., Benufutamab, Conatumumab, Drozitumab, Lexatumumab, Tigatuzumab, Eftozanermin alfa and DS-8273a, etc.), anti-TNFRSF10A antibodies (e.g., Mapatumumab, etc.), anti-MUC1 antibodies (e.g., Cantuzumab, Cantuzumab ravtansine, Clivatuzumab, Clivatuzumab Tetraxetan, Yttrium ( 90Y) clivatuzumab tetraxetan, Epitumomab, Epitumomab cituxetan, Sontuzumab, Gatipotuzumab, Nacolomab, Nacolomab tafenatox, 7F11C7, BrE-3, CMB-401, CTM01 and HMFG1, etc.), anti-MUC5AC antibodies (e.g., Ensituximab, etc.), anti-MUC16 antibodies (e.g., Oregovomab, Abagovomab, Igovomab and Sofituzumab vedotin, etc.), anti-DR5 antibodies (e.g., DS-8273a, etc.), anti-CA125 antibodies (e.g., Oregovomab, etc.), anti-DLL4 antibodies (e.g., Demcizumab, Dilpacimab, Navicizumab, and Enoticumab, etc.), anti-Fucosyl GM1 antibodies (e.g., BMS-986012, etc.), anti-gpNMB antibodies (e.g., Glembatumumab vedotin, etc.), anti-Mesothelin antibodies (e.g., Amatuximab, Anetumab ravtansine, Anetumab corixetan, RG7784, and BMS-986148, etc.), anti-MMP9 antibodies (e.g., Andecaliximab, etc.), anti-GD2 antibodies (e.g., Dinutuximab, Dinutuximab beta, Lorukafusp alfa, Naxitamab, 14G2a, MORAb-028, Surek, TRBs07, and ME361, etc.), anti-c-Met antibodies (e.g., Emibetuzumab, Onartuzumab, Telisotuzumab, and Telisotuzumab vedotin, etc.), anti-FOLR1 antibodies (e.g., Farletuzumab, Mirvetuximab, and Mirvetuximab soravtansine, etc.), anti-CD79b antibodies (e.g., Iladatuzumab, Iladatuzumab vedotin, and Polatuzumab vedotin, etc.), anti-DLL3 antibodies (e.g., Rovalpituzumab and RovalpituzumabTesirine, etc.), anti-CD51 antibodies (e.g., Abituzumab, Etaracizumab, and Intetumumab, etc.), anti-EPCAM antibodies (e.g., Adecatumumab, Catumaxomab, Edrecolomab, Oportuzumab monatox, Citatuzumab bogatox, and Tucotuzumab celmoleukin, etc.), anti-CEACAM5 antibodies (e.g., Altumomab, Arcitumomab, Cergutuzumab amunaleukin, Labetuzumab, Labetuzumab govitecan, 90 Y-cT84.66, AMG211, BW431 / 26, CE25 / B7, COL-1 and T84.66 M5A, etc.), anti-CEACAM6 antibodies (e.g., Tinurilimab, etc.), anti-FGFR2 antibodies (e.g., Aprutumab, Aprutumab ixadotin and Bemarituzumab, etc.), anti-CD44 antibodies (e.g., Bivatuzumab mertansine, etc.), anti-PSMA antibodies (e.g., Indium ( 111 In) capromab pendetide, 177 Lu-J591 and ES414, etc.), anti-Endoglin antibodies (e.g., Carotuximab, etc.), anti-IGF1R antibodies (e.g., Cixutumumab, Figitumumab, Ganitumab, Dalotuzumab, Teprotumumab, Robatumumab, etc.), anti-TNFSF11 antibodies (e.g., Denosumab, etc.), anti-GUCY2C (e.g., Indusatumab vedotin, etc.), anti-SLC39A6 antibodies (e.g., Ladiratuzumab vedotin, etc.), anti-SLC34A2 antibodies (e.g., Lifastuzumab vedotin, etc.), anti-NCAM1 antibodies (e.g., Lorvotuzumab mertansine and N901, etc.), anti-ganglioside GD3 antibodies (e.g., Ecromeximab and Mitumomab), anti-AMHR2 antibodies (e.g., Murlentamab), anti-CD37 antibodies (e.g., Lilotomab, Lutetium ( 177lu) lilotomab satetraxetan, Naratuximab, Naratuximab emtansine, and Otlertuzumab, etc.), anti-IL1RAP antibodies (e.g., Nidanilimab, etc.), anti-PDGFR2 antibodies (e.g., Olaratumab and Tovetumab, etc.), anti-CD200 antibodies (e.g., Samalizumab, etc.), anti-TAG-72 antibodies (e.g., Anatumomab mafenatox, Minretumomab, Indium ( 111 In) satumomab pendetide, CC49, HCC49, and M4, etc.), anti-SLITRK6 antibodies (e.g., Sirtratumab vedotin, etc.), anti-DPEP3 antibodies (e.g., Tamrintamab pamozirine, etc.), anti-CD19 antibodies (e.g., Axicabtagene ciloleucel, Coltuximab ravtansine, Denintuzumab mafodotin, Inebilizumab, Loncastuximab, Loncastuximab tesirine, Obexelimab, Tafasitamab, Taplitumomab paptox, and huAnti-B4, etc.), anti-NOTCH2 / 3 antibodies (e.g., Tarextumab, etc.), anti-tenascin C antibodies (e.g., Tenatumomab, etc.), anti-AXL antibodies (e.g., Enapotamab, Enapotamab vedotin, Tilvestamab, etc.), anti-STEAP1 antibodies (e.g., Vandortuzumab vedotin, etc.), anti-CTAA16 antibody (e.g., Technetium ( 99mTc) votumumab, etc.), CLDN18 antibody (e.g., Zolbetuximab, etc.), anti-GM3 antibody (e.g., Racotumomab, FCGR1, and H22, etc.), anti-PSCA antibody (e.g., MK-4721, etc.), anti-FN extra domain B antibody (e.g., AS1409, etc.), anti-HAVCR1 antibody (e.g., CDX-014, etc.), anti-TNFRSF4 antibody (e.g., MEDI6383, etc.), anti-FAP antibody / IL-2 fusion protein (e.g., RO6874281), anti-CEA antibody / IL-2 fusion protein (e.g., Cergutuzumab, amunaleukin), anti-HER1-MET bispecific antibodies (e.g., Amivantamab, etc.), anti-EPCAM-CD3 bispecific antibodies (e.g., Solitomab and Catumaxomab), anti-Ang2-VEGF bispecific antibodies (e.g., Vanucizumab), anti-HER2-CD3 bispecific antibodies (e.g., Ertumaxomab), anti-HER3-IGF1R bispecific antibodies (e.g., Istiratumab), anti-PMSA-CD3 bispecific antibodies (e.g., Pasotuxizumab), anti-HER1-LGR5 bispecific antibodies (e.g., Petosemtamab), anti-SSTR2-CD3 bispecific antibodies (e.g., Tidutamab), anti-CD30-CD16A bispecific antibodies (e.g., AFM13, etc.), IL3RA-CD3 bispecific antibodies (e.g., Flotetuzumab, b and Vibecotamab), anti-GPRC5D-CD3 bispecific antibodies (e.g., Talquetamab), anti-TNFRSF17-CD3 bispecific antibodies (e.g., Teclistamab), anti-CLEC12A-CD3 bispecific antibodies (e.g., Tepoditamab), anti-HER2-HER3 bispecific antibodies (e.g., Zenocutuzumab), anti-CEA-CD3 bispecific antibodies (e.g., Cibisatamab and RO6958688), anti-CD3-CD19 bispecific antibodies (e.g., Duvortuxizumab and Blinatumomab, etc.), and anti-CD20-CD3 bispecific antibodies (e.g., Plamotamab, Odronextamab, Mosunetuzumab, Glofitamab, Epcoritamab, and REGN1979, etc.).

[0255] In addition, examples of cancer immunotherapeutic drugs include anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP-514 (MEDI0680), Dostarlimab (ANB011 / TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Penpulimab 、STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK103, BI 754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188, etc.), anti-PD-L1 antibodies (e.g. Atezolizumab (RG7446 / MPDL3280A), Avelumab (PF-06834635 / MSB0010718C), Durvalumab (MEDI4736), Manelimab, Pacilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1 014, HLX20, SHR-1316, CS1001 (WBP3155), MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 (TQB2450) and JS003, etc.), PD-1 antagonists (e.g., AUNP-12, the compounds BMS-M1 to BMS-M10, BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001, BM S-1166, Incyte-1 to Incyte-6 compounds, CAMC-1 to CAMC-4 compounds, RG_1 and DPPA-1, etc.), PD-L1 / VISTA antagonists (e.g., CA-170, etc.), PD-L1 / TIM3 antagonists (e.g., CA-327, etc.), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224, etc.), anti-CTLA-4 antibodies (e.g., Ipilimumab (MDX-010), Nurulimab, Zalifrelimab, (AGEN1884) and Tremelimumab, etc.), anti-LAG-3 antibodies (e.g., Relatlimab (BMS-986016 / ONO-4482), Encelimab, Ieramilimab (LAG525), Fianlimab (REGN3767) and Mavezelimab (MK-4280), etc.), LAG-3 fusion proteins (e.g., IMP321, etc.), anti-Tim3 antibodies (e.g., MBG453 and Cobolimab (TSR-022), etc.), anti-KIR antibodies (e.g.,Lirilumab (BMS-986015 / ONO-4483), IPH2101, LY3321367, and MK-4280, etc.), anti-BTLA antibodies, anti-TIGIT antibodies (e.g., Tiragolumab, Etigilimab, Vibostolimab (MTIG-7192A / RG-6058 / RO-7092284), and BMS-986207 (ONO-4686)), anti-VISTA antibodies (e.g., Onvatilimab (JNJ-61610588), etc.), anti-CD137 antibodies (e.g., Urelumab (ONO-4481 / BMS-663513), and Utomilumab (PF-05082566), etc.), anti-CSF-1R antibodies or CSF-1R inhibitors (e.g., Cabiralizumab, b(FPA008 / BMS-986227 / ONO-4687), Emactuzumab (RG7155 / RO5509554), LY3022855, Axatilimab, MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945, and ARRY-382, etc.), anti-OX40 antibodies (e.g., MEDI6469, Ivuxolimab (PF-04518600), MEDI0562, MEDI6383, Efizonerimod, GSK3174998, BMS-986178, and MOXR0916, etc.), anti-HVEM antibodies, anti-CD27 antibodies (e.g., Varlilumab (CDX-1127), etc.), anti-GITR antibodies / GITR fusion proteins (e.g., Efaprinermin alfa, Efgivanermin alfa, MK-4166, INCAGN01876, 、GWN323 and TRX-518, etc.), anti-CD28 antibodies, anti-CCR4 antibodies (e.g., Mogamulizumab, etc.), anti-B7-H3 antibodies (e.g., Enoblituzumab, Mirzotamab, Mirzotamab clezutoclax, and Omburtamab, etc.), anti-ICOS agonist antibodies (e.g., Vopratelimab, (JTX-2011) and GSK3359609, etc.), anti-CD4 antibodies (e.g., MTRX-1011A, TRX-1, Ibalizumab, huB-F5, Zanolimumab, 4162W94, Clenoliximab, Keliximab, AD-519, PRO-542, Cedelizumab, TNX-355, Dacetuzumab, Tregalizumab, Priliximab, MDX-CD4, CAMPATH-9 and IT1208, etc.), anti-DEC-205 antibody / NY-ESO-1 fusion protein (e.g., CDX-1401, etc.), anti-SLAMF7 antibodies (e.g., Azintuxizumab, Azintuxizumab, etc.), vedotin and Elotuzumab, anti-CD73 antibodies (e.g., Oleclumab and BMS-986179, etc.), PEGylated IL-2 (e.g., Bempegaldesleukin (NKTR-214)), anti-CD40 agonist antibodies (e.g., ABBV-428, APX005M, and RO7009789, etc.), IDO inhibitors (e.g., Epacadostat, Indoximod, and BMS-986205, etc.), TLR agonists (e.g., Motolimod, CMP-001, G100, Tilsotolimod (IMO-2125), SD-101, and MEDI9197, etc.), adenosine A2A receptor antagonists (e.g., Preladenant, AZD4635, PBF 509 and CPI-444), anti-NKG2A antibodies (e.g., Monalizumab), anti-CSF-1 antibodies (e.g., PD0360324), immune enhancers (e.g., PV-10), IL-15 superagonists (e.g., ALT-803), soluble LAG3 (e.g., Eftilagimodalpha (IMP321), anti-CD47 antibodies / CD47 antagonists (e.g., ALX148), and IL-12 antagonists (e.g., M9241).

[0256] Furthermore, other antibody drugs include, for example, anti-IL-1β antibodies (eg, Canakinumab, etc.) and anti-CCR2 antibodies (eg, Plozalizumab, etc.).

[0257] [formulation] The immune checkpoint inhibitor or immune checkpoint inhibitor of the present invention, when administered alone or in combination with other drugs, is used in the form of an oral solid or liquid preparation, an oral sustained release preparation or a controlled release preparation, or an injection, topical preparation, inhalant, or suppository for parenteral administration.

[0258] Examples of solid preparations for oral administration include tablets, pills, capsules, powders, granules, etc. Examples of capsules include hard capsules and soft capsules.

[0259] The solid preparation for internal use may be prepared by mixing the immune checkpoint inhibitor of the present invention as it is, or as necessary, with one or more of excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), disintegrants (e.g., calcium cellulose glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, and solubilizers (e.g., glutamic acid, aspartic acid, etc.), and formulating according to a conventional method. If necessary, it may be coated with a coating agent (e.g., sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Furthermore, it may be encapsulated in a capsule made of a material that is easily absorbed by the body, such as gelatin.

[0260] If necessary, the liquid preparation for oral administration may contain one or more of pharma- ceutically acceptable solutions, suspending agents, emulsifying agents, syrups, elixirs, etc. In addition, the liquid preparation may further contain one or more of wetting agents, sweeteners, flavoring agents, aromatic agents, preservatives, buffers, etc.

[0261] In addition, sustained-release preparations for oral administration may contain, in addition to the sustained-release base, a binder and a thickener, and for example, gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, or hydroxyethylmethylcellulose.

[0262] When used as an infusion for injection or drip infusion, the injection or infusion may be in the form of any of an aqueous solution, a suspension, or an emulsion, and may be formulated as a solid agent together with a pharma- ceutically acceptable carrier so that it can be dissolved, suspended, or emulsified when used by adding a solvent. Examples of solvents used in the injection or infusion for drip infusion include distilled water for injection, physiological saline, glucose solution, and isotonic solutions (e.g., solutions of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, and propylene glycol).

[0263] Here, examples of pharma- ceutically acceptable carriers include stabilizers, dissolving agents, suspending agents, emulsifiers, soothing agents, buffers, preservatives, antiseptics, pH adjusters, and antioxidants. Examples of stabilizers that can be used include various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sodium hydrogen sulfite, sodium thiosulfate, sodium edetate, sodium citrate, and dibutylhydroxytoluene. Examples of dissolving agents that can be used include alcohols (e.g., ethanol, etc.), polyalcohols (e.g., propylene glycol and polyethylene glycol, etc.), and nonionic surfactants (e.g., Polysorbate 20 (registered trademark), Polysorbate 80 (registered trademark), and HCO-50, etc.). Examples of suspending agents that can be used include glycerin monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, and sodium lauryl sulfate. Examples of the emulsifier include gum arabic, sodium alginate, and tragacanth. Examples of the soothing agent include benzyl alcohol, chlorobutanol, and sorbitol. Examples of the buffer include phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, and epsilon aminocaproic acid buffer. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax. Examples of the preservative include benzalkonium chloride, paraoxybenzoic acid, and chlorobutanol. Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid.Examples of antioxidants that can be used include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, and phosphoric acid.

[0264] Injections or infusions for drip infusion can be produced by sterilizing in the final step or by an aseptic operation method, for example, sterilizing by filtration with a filter, and then filling into a sterile container. Injections or infusions for drip infusion can also be used by dissolving in a suitable solvent a sterile powder (which may contain a powder of a pharma- ceutically acceptable carrier) obtained by vacuum drying or freeze drying.

[0265] External preparations for parenteral administration can be used in the form of, for example, aerosols, ointments, gels, creams, poultices, patches, liniments, and nasal drops, and are prepared by known methods or commonly used formulations.

[0266] Aerosols, inhalants and sprays may contain stabilizers such as sodium hydrogen sulfite and isotonic buffers such as sodium chloride, sodium citrate or citric acid in addition to commonly used diluents. The manufacturing method of sprays is described in detail in, for example, U.S. Patent Nos. 2,868,691 and 3,095,355.

[0267] Inhalants for parenteral administration include aerosols, powders for inhalation, and liquids for inhalation, and the liquids for inhalation may be in a form that is dissolved or suspended in water or other suitable medium when used.

[0268] These inhalants are produced in accordance with known methods. For example, in the case of inhalation solutions, preservatives (e.g., benzalkonium chloride, paraben, etc.), colorants, buffers (e.g., sodium phosphate, sodium acetate, etc.), isotonicity agents (e.g., sodium chloride, concentrated glycerin, etc.), thickeners (e.g., carboxyvinyl polymers, etc.), absorption enhancers, etc. are appropriately selected as necessary and prepared.

[0269] In the case of powders for inhalation, lubricants (e.g., stearic acid and its salts), binders (e.g., starch and dextrin), excipients (e.g., lactose and cellulose), colorants, preservatives (e.g., benzalkonium chloride, parabens), and absorption enhancers are appropriately selected as needed and prepared.

[0270] When administering liquid preparations for inhalation, sprayers (eg, atomizers and nebulizers) are usually used, and when administering powder preparations for inhalation, inhalation devices for powder preparations are usually used.

[0271] The ointment can be manufactured by a known or commonly used formulation, for example, by mixing or melting the immune checkpoint inhibitor of the present invention in a base. The ointment base can be selected from known or commonly used ones, for example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid esters, myristic acid esters, palmitic acid esters, stearic acid esters, oleic acid esters, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, and cetostearyl alcohol), and the like. The additives may be selected from the group consisting of ethanol, ethanolamine ...

[0272] The gel can be manufactured by a known or commonly used formulation, for example, by dissolving the immune checkpoint inhibitor of the present invention in a base. The gel base is selected from known or commonly used ones, for example, lower alcohols (e.g., ethanol and isopropyl alcohol, etc.), gelling agents (e.g., carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agents (e.g., triethanolamine and diisopropanolamine, etc.), surfactants (e.g., polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and rash prevention agents, which are used alone or in combination of two or more. In addition, it may contain a preservative, an antioxidant, a flavoring agent, etc.

[0273] The cream can be manufactured by a known or commonly used formulation, for example, by dissolving or emulsifying the immune checkpoint inhibitor of the present invention in a base. The cream base can be selected from known or commonly used ones, for example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (e.g., propylene glycol and 1,3-butylene glycol, etc.), higher alcohols (e.g., 2-hexyldecanol and cetanol, etc.), emulsifiers (e.g., polyoxyethylene alkyl ethers and fatty acid esters, etc.), water, absorption enhancers, and rash prevention agents, which are used alone or in combination of two or more. In addition, it may contain a preservative, an antioxidant, a flavoring agent, etc.

[0274] The poultice can be manufactured by a known or commonly used recipe, for example, by dissolving the immune checkpoint inhibitor of the present invention in a base, kneading the mixture, and spreading it on a support. The poultice base can be selected from known or commonly used ones, for example, thickeners (e.g., polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), humectants (e.g., urea, glycerin, propylene glycol, etc.), fillers (e.g., kaolin, zinc oxide, talc, calcium, magnesium, etc.), water, solubilizers, tackifiers, and rash prevention agents, which are used alone or in combination of two or more. In addition, it may contain a preservative, an antioxidant, a flavoring agent, etc.

[0275] The patch can be manufactured by a known or commonly used formulation, for example, by dissolving the immune checkpoint inhibitor of the present invention in a base and spreading it on a support. The base for the patch can be selected from known or commonly used ones, for example, polymer bases, oils and fats, higher fatty acids, tackifiers and rash prevention agents, used alone or in combination of two or more. In addition, it may contain a preservative, an antioxidant, or a flavoring agent.

[0276] The liniment can be manufactured by a known or commonly used formulation, for example, by dissolving, suspending or emulsifying the immune checkpoint inhibitor of the present invention in one or more of water, alcohol (e.g., ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. It may further contain a preservative, an antioxidant, a flavoring agent, etc.

[0277] Other compositions for parenteral administration include suppositories for rectal administration and pessaries for vaginal administration that contain the immune checkpoint inhibitor of the present invention and are formulated in a conventional manner.

[0278] [Testing and measurement kit] The present invention also includes an invention relating to a test or measurement kit for measuring the evaluation items constituting each of the biomarkers 1 to 10 according to the present invention. + T cells, CD3 + T cells, Foxp3 + When measuring the MFI of PD-1 expression in T cells and Treg cells (Fr. II), it may be based on, for example, flow cytometry, while when measuring the MFI of CD8 + T cell count, CD4 + T cell number, Foxp3 + The number of T cells, Treg cells (Fr. II) and Treg cells (Fr. III), as well as the number of PD-1 expressing cells and CCR7 expressing CD8 + When measuring the number of T cells, the method may be based on flow cytometry or immunostaining. In either case, a test or measurement kit based on flow cytometry is preferred.

[0279] The contents of all patent and non-patent literature or references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0280] The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto. Based on the description of the present invention, various changes and modifications can be made by those skilled in the art, and these changes and modifications are also included in the present invention. EXAMPLES

[0281] Example 1: CD8 + Percentage of CCR7-expressing T cells and Foxp3 + T cells and CD8 + Confirmation of a biomarker for determining the efficacy of Nivolumab based on the ratio of MFI of PD-1 expression on each T cell (biomarker 1) CD8 derived from tumor tissues of 29 gastric cancer patients and 16 non-small cell lung cancer patients before Nivolumab administration + Number of CCR7 expressing T cells and CD8 + T cells and Foxp3 +PD-1 expression on each T cell was measured by flow cytometry, and CD8 + Percentage of CCR7-expressing T cells and the corresponding Foxp3 + CD8 versus MFI of PD-1 expression on T cells + The ratio of MFI of PD-1 expression in T cells was calculated. Among the above patients who were administered Nivolumab according to the prescribed regimen, the percentage (%) of CCR7-expressing cells in each patient was plotted on the vertical axis and the square root of the percentage on the horizontal axis for the responder group (patients whose PFS was maintained for 70 days: 23 patients) and non-responder group (patients whose PFS was less than 70 days: 22 patients) (see Figure 1). The three solid lines in the figure are piecewise lines derived by machine learning using the weighted F value (fα) as an index so that when the α value is 0.5, the value of fα is maximized. It was confirmed that if Nivolumab were administered to 22 cancer patients plotted in the closed shaded area on the right side of the figure, separated by the piecewise lines, it would be expected that the drug would be effective in 20 of them (efficacy rate: 90.9%).

[0282] Example 2: Treg cells (Fr.III) and CD8 + Confirmation of biomarkers for determining the efficacy of Nivolumab based on the percentage (%) of PD-1 expressing cells in each T cell (biomarker 2) Treg cells (Fr.III) and CD8 derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) before Nivolumab administration + PD-1 expression in each T cell was measured by flow cytometry, and the percentage (%) of PD-1 expression in each cell was calculated. Among the above patients who were administered Nivolumab according to a prescribed regimen, the responder group (23 patients) and the non-responder group (23 patients) (both groups were defined as in Example 1) were divided into two groups, and the percentage (%) of PD-1 expressing cells in Treg cells (Fr.III) of each patient was plotted on the vertical axis, and the percentage (%) of CD8 + The percentage (%) of PD-1 expressing cells in T cells is plotted on the horizontal axis (see Figure 2). The two solid lines in the figure are piecewise straight lines derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to 27 cancer patients plotted in the closed shaded areas on the upper left and lower right of the figure, separated by the piecewise straight lines, it would be expected that the drug would be effective in 22 of them (efficacy rate: 81.5%).

[0283] Example 3: CD8 + PD-1 expressing cells and Foxp3 in T cells + T cells and CD8 + Confirmation of a biomarker for determining the efficacy of Nivolumab based on the ratio of MFI of PD-1 expression in each T cell (biomarker 3) CD8 derived from tumor tissues of 29 gastric cancer patients and 17 non-small cell lung cancer patients before Nivolumab administration + PD-1 expressing T cells and CD8 + T cells and Foxp3 + PD-1 expression in each T cell was measured by flow cytometry, and the Foxp3 + CD8 versus MFI of PD-1 expression on T cells + The ratio of MFI of PD-1 expression in T cells was calculated. Of the above patients who were administered Nivolumab according to the prescribed regimen, for each of the responder group (23 patients) and the non-responder group (23 patients) (both groups are defined the same as in Example 1), the common logarithm of the value obtained by adding 1 to the number of PD-1 expressing cells for each patient was plotted on the vertical axis, and the square root of the ratio was plotted on the horizontal axis (see Figure 3). The two solid lines in the figure are piecewise straight lines derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to the 22 cancer patients plotted in the closed shaded area separated by the piecewise straight lines (excluding the lower left side of the figure), it would be expected that the drug would be effective in 19 of them (efficacy rate: 86.4%).

[0284] Example 4: Foxp3 + T cells and CD8 + The ratio of MFI of PD-1 expression on each T cell and CD8 + Confirmation of a biomarker for determining the efficacy of Nivolumab based on the percentage (%) of PD-1 expressing T cells (biomarker 4) CD8 derived from tumor tissues of 29 gastric cancer patients and 17 non-small cell lung cancer patients before Nivolumab administration + T cells and Foxp3 + PD-1 expression in each T cell was measured by flow cytometry, and the Foxp3 + CD8 versus MFI of PD-1 expression on T cells + Ratio of MFI of PD-1 expression on T cells and CD8 + The percentage of PD-1 expressing T cells was calculated. Of the above patients who were administered Nivolumab according to the prescribed regimen, the square root of the proportion for each patient was plotted on the vertical axis and the proportion (%) on the horizontal axis for each of the responder group (23 patients) and non-responder group (23 patients) (both groups were defined the same as in Example 1) (see Figure 4). The two solid lines in the figure are piecewise straight lines derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to the 22 cancer patients plotted in the closed shaded area separated by the piecewise straight lines (excluding the lower left side of the figure), it would be expected that the drug would be effective in 18 of them (efficacy rate: 81.8%).

[0285] Example 5: Foxp3 + T cells and CD8 + Confirmation of biomarkers for determining the efficacy of Nivolumab based on the percentage of PD-1 expressing cells in each cell type (biomarker 5) Foxp3 derived from tumor tissues of 29 gastric cancer patients and 17 non-small cell lung cancer patients before Nivolumab administration + T cells and CD8 + PD-1 expression in each T cell was measured by flow cytometry, and the percentage (%) of PD-1 expressing cells in each was calculated. Among the above patients who were administered Nivolumab according to a prescribed regimen, there were a responder group (23 patients) and a non-responder group (23 patients) (both groups were defined as in Example 1). The Foxp3 + The percentage of PD-1 expressing T cells is shown on the vertical axis.+ The percentage of PD-1 expressing cells among the cells was plotted on the horizontal axis (see FIG. 5). The solid line in the figure is a piecewise straight line derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to the 28 cancer patients plotted in the shaded area on the right side of the figure, separated by the piecewise straight line, it would be expected that the drug would be effective in 21 of them (efficacy rate: 75%).

[0286] Example 6: Treg cells (Fr. II) and CD8 + Confirmation of biomarkers for determining the efficacy of Nivolumab based on the percentage of PD-1 expressing cells in each cell type (biomarker 6) Treg cells (Fr. II) and CD8 derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) before Nivolumab administration + PD-1 expression in each T cell was measured by flow cytometry, and the percentage (%) of PD-1 expressing cells in each was calculated. Among the above patients who were administered Nivolumab according to a prescribed regimen, the responder group (23 patients) and the non-responder group (23 patients) (both groups were defined as in Example 1) were divided into two groups, and the percentage (%) of PD-1 expressing cells in Treg cells (Fr. II) of each patient was plotted on the vertical axis, and the percentage (%) of CD8 + The percentage of PD-1 expressing cells among the cells was plotted on the horizontal axis (see FIG. 6). The two solid lines in the figure are piecewise straight lines derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to the 22 cancer patients plotted in the shaded areas on the upper left and lower right of the figure, separated by the piecewise straight lines, it would be expected that the drug would be effective in 19 of them (efficacy rate: 86.4%).

[0287] Example 7: CD4 + Cells and CD8 + Confirmation of biomarkers for determining the efficacy of Nivolumab based on the percentage of PD-1 expressing cells in each cell type (biomarker 7) CD4 derived from tumor tissues of 29 gastric cancer patients and 18 non-small cell lung cancer patients before Nivolumab administration + Cells and CD8+ PD-1 expression in each T cell was measured by flow cytometry, and the percentage (%) of PD-1 expressing cells in each was calculated. Among the patients who were administered Nivolumab according to the prescribed regimen, the responder group (24 patients) and the non-responder group (23 patients) (both groups were defined as in Example 1) were divided into two groups, and the CD4 + The percentage of PD-1 expressing cells in CD8 + The percentage of PD-1 expressing cells among the cells was plotted on the horizontal axis (see FIG. 7). The two solid lines in the figure are piecewise straight lines derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to 29 cancer patients plotted in the shaded area excluding the upper left area of ​​the figure, separated by the piecewise straight lines, it would be expected that the drug would be effective in 22 of them (efficacy rate: 75.9%).

[0288] Example 8: Treg cells (Fr. II) and CD3 + The ratio of MFI of PD-1 expression and CD4 + Confirmation of biomarkers for determining the efficacy of Nivolumab based on the percentage (%) of PD-1 expressing T cells (biomarker 8) CD3 derived from tumor tissues of 29 gastric cancer patients and 18 non-small cell lung cancer patients before Nivolumab administration + cells, Treg cells (Fr. II) and CD4 + PD-1 expression in each T cell was measured by flow cytometry, and the ratio of CD3 to MFI of PD-1 expression in the Treg cells (Fr. II) was + Ratio of MFI of PD-1 expression in cells and CD4 + The percentage of PD-1 expressing T cells was calculated. Among the above patients who were administered Nivolumab according to the prescribed regimen, the square root of the ratio for each patient was plotted on the vertical axis and the proportion (%) on the horizontal axis for each of the responder group (22 patients who achieved CR, PR, or SD) and non-responder group (25 patients who achieved PD) (see Figure 8). The two solid lines in the figure are piecewise straight lines derived by machine learning similar to that described above, and it was confirmed that if Nivolumab were administered to the 21 cancer patients plotted in the shaded area in the upper left corner of the figure, separated by the piecewise straight lines, it would be expected that the drug would be effective in 17 of them (efficacy rate: 81.0%).

[0289] Example 9: Foxp3 + T cells and CD8 + Confirmation of a biomarker for determining the efficacy of Nivolumab based on MFI of PD-1 expression on each T cell (biomarker 9) Foxp3 derived from tumor tissues of 29 gastric cancer patients and 18 non-small cell lung cancer patients before Nivolumab administration + T cells and CD8 + The MFI of PD-1 expression in each T cell was measured by flow cytometry, and the Foxp3 + The MFI of PD-1 expression on T cells was used to determine the CD8 + The MFI of PD-1 expression in T cells was subtracted to calculate the value. Among the above patients who were administered Nivolumab according to the prescribed regimen, the values ​​for each patient were plotted for the responder group (12 patients who achieved CR or PR) and the non-responder group (35 patients who achieved SD or PD) (see Figure 9). The dotted line in the figure is a dividing line derived by ROC analysis, and it was confirmed that if Nivolumab were administered to 13 cancer patients with values ​​below the value indicated by the dividing line (-208) (sensitivity in ROC analysis = 0.833; specificity = 0.914), it would be expected that the drug would be effective in 10 of them (efficacy rate: 76.9%).

[0290] Example 10: Treg cells (Fr. II) and CD8 + Identification of a biomarker for determining the efficacy of Nivolumab based on MFI of PD-1 expression in each T cell (biomarker 10) Treg cells (Fr. II) and CD8 derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) before Nivolumab administration +The MFI of PD-1 expression in each T cell was measured by flow cytometry, and the MFI of PD-1 expression in the Treg cells (Fr. II) was used to determine the CD8 + The MFI of PD-1 expression in T cells was subtracted to calculate the value. Among the above patients who were administered Nivolumab according to the prescribed regimen, the values ​​for each patient were plotted for the responder group (12 patients who achieved CR or PR) and the non-responder group (35 patients who achieved SD or PD) (see Figure 10). The dotted line in the figure is a dividing line derived by ROC analysis, and it was confirmed that if Nivolumab were administered to 12 cancer patients with values ​​below the value indicated by the dividing line (-131) (sensitivity in ROC analysis = 0.833; specificity = 0.943), it would be expected that the drug would be effective in 10 of them (efficacy rate: 83.3%). [Industrial Applicability]

[0291] By analyzing the combinations of specific pairs of evaluation items of the present invention and the specific conditions defined by each combination of those pairs, it is possible to identify malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors.

Claims

1. CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells (1) express the following formula: [0010] [In the formula, Y 1 The CD8 + The percentage of CCR7-expressing T cells is shown. 1-1 represents a number around -637, and X 1 Foxp3 + The mean fluorescence intensity (MFI) of PD-1 expression on T cells versus the corresponding CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells, and Y 1-1 represents any numerical value from about 784 to about 914; or (2) (i) the following formula: [0025] [In the formula, a 1-2 represents a value of approximately -24.0, and Y 1-2 represents any numerical value from about 39.0 to about 50.9, and the other symbols have the same meanings as above.] and (ii) a compound represented by the following formula: [0030] [In the formula, a 1-3 represents the value of approximately 666, and Y 1-3 represents any numerical value from about -652 to about -522, and the other symbols have the same meanings as above.], wherein the malignant tumor is gastric cancer or non-small cell lung cancer.

2. Y 1-1 is about 853, and Y 1-2 is about 44.6, and Y 1-3 The method of claim 1, wherein the α-amino acid sequence is about -591.

3. CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells (1) use the following formula: [0045] [In the formula, Y 3 The CD8 + The number of PD-1 expressing T cells is shown. 3-1 represents a value of approximately -1.59, and X 3 Foxp3 + MFI of PD-1 expression on T cells versus CD8 + represents the square root of the ratio of MFI of PD-1 expression in T cells, and Y 3-1 represents any numerical value from about 4.09 to about 4.89; or (2) the condition represented by the following formula: [0050] [In the formula, a 3-2 represents a value of approximately -9.05, and Y 3-2 represents any numerical value from about 10.7 to about 13.3, and the other symbols have the same meanings as above.], wherein the malignant tumor is gastric cancer or non-small cell lung cancer.

4. Y 3-1 is about 4.42, and Y 3-2 The method of claim 3, wherein the β-amino acid salt is about 11.

7.

5. The agent according to any one of claims 1 to 4, wherein the malignant tumor patient is a patient before administration of a drug containing Nivolumab as an active ingredient.

6. The agent according to any one of claims 1 to 5, wherein the malignant tumor patient has no history of treatment with other anti-malignant tumor drugs.

7. The agent according to any one of claims 1 to 6, wherein TPS or CPS is less than 50%, less than 25%, less than 10%, less than 5% or less than 1%.

8. The agent according to any one of claims 1 to 7, wherein the malignant tumor does not have MSI-H and / or dMMR.

9. The agent according to any one of claims 1 to 8, wherein the malignant tumor has a low TMB frequency.

10. (1) CD8 in samples derived from tumor tissue or blood of patients with malignant tumors, using flow cytometry or immunohistochemistry + (2) the number of T cells and the number of CCR7 expressing cells among them, and the CD8 + Foxp3 in T cells and their samples + (1a) measuring PD-1 expression in each of the CD8 T cells; + (2a) Percentage of CCR7-expressing T cells and (2b) Foxp3 + MFI of PD-1 expression on T cells versus CD8 + A method for identifying malignant tumor patients who are more likely to benefit from Nivolumab, comprising determining the ratio of MFI of PD-1 expression in T cells and, based on a combination of said percentages and said ratios or the square root value of said ratios, said malignant tumor being gastric cancer or non-small cell lung cancer.

11. (1) CD8 in samples derived from tumor tissue or blood of patients with malignant tumors, using flow cytometry or immunohistochemistry + (2) the number of PD-1 expressing T cells and the CD8 + Foxp3 in T cells and their samples + PD-1 expression was measured on each T cell, and the Foxp3 + MFI of PD-1 expression on T cells versus CD8 + A method for identifying malignant tumor patients who are more likely to benefit from Nivolumab, comprising determining a ratio of MFIs of PD-1 expression in T cells, and based on a combination of (i) the number of PD-1 expressing cells, the common logarithm of the number of cells, or the common logarithm of the number of cells plus 1, and (ii) the ratio or the square root of the ratio, wherein the malignant tumor is gastric cancer or non-small cell lung cancer.

12. The method according to claim 10 or 11, wherein the malignant tumor patient is a patient prior to administration of Nivolumab.

13. (1) (i) CD8 in tumor tissue or blood of patients with malignant tumors + Percentage of T cells expressing CCR7, or (ii) the CD8 + The number of PD-1 expressing T cells, the common logarithm of the number of said cells or the common logarithm of the value obtained by adding 1 to the number of said cells, and (2) Foxp3 from the same source + MFI of PD-1 expression on T cells versus CD8 + Use of the ratio of MFI of PD-1 expression in T cells or a combination of the square root values ​​of said ratios as a biomarker for predicting the effectiveness of Nivolumab in inhibiting progression, inhibiting recurrence and / or treating a malignant tumor, wherein the malignant tumor is gastric cancer or non-small cell lung cancer.

14. (1) The CD8 + (1) the percentage of CCR7-expressing T cells and (2) the Foxp3 + MFI of PD-1 expression on T cells versus CD8 + The use of a ratio of MFIs of PD-1 expression in T cells or a combination of the square root values ​​of said ratios as a biomarker as described in claim 13.

15. (1) The CD8 + (1) the number of PD-1-expressing T cells, the common logarithm of the number of said cells or the common logarithm of the value obtained by adding 1 to the number of said cells, and (2) the number of said Foxp3 + MFI of PD-1 expression on T cells versus CD8 + The use of a ratio of MFIs of PD-1 expression in T cells or a combination of the square root values ​​of said ratios as a biomarker as described in claim 13.

16. The use according to any one of claims 13 to 15, wherein the malignant tumor patient is a patient before administration of Nivolumab.

Images