Biomarker for assessing efficacy of immune checkpoint inhibitor

Abstract

To provide a method for identifying a patient with malignant tumor which can be expected to benefit more from an immune checkpoint inhibitor, and an agent for suppressing the progression of, suppressing the recurrence of, and / or treating the malignant tumor, being prescribed based thereon.SOLUTION: The present invention provides agents for suppressing the progression of, suppressing the recurrence of, and / or treating malignant tumor, being prescribed based on identifying a patient with malignant tumor which can be expected to benefit more from an immune checkpoint inhibitor, based on a combination of two sets of evaluation items and specific conditions defined by each of the combinations thereof.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for identifying a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected (hereinafter, may be abbreviated as "the patient identification method of the present invention"), and a treatment for suppressing the progression, recurrence, and / or treatment of malignant tumors characterized by a prescription based thereon.

Background Art

[0002] Cancer immunotherapy is different from conventional treatments such as surgical operations, radiation therapy, and drug therapy with anti-malignant tumor drugs and molecular target drugs. It acts on the immune surveillance mechanism originally possessed by malignant tumor patients themselves to enhance the immunity against malignant tumors, thereby suppressing or treating the progression of malignant tumors. According to recent tumor immunity research, the progression of malignant tumors is involved in an immunosuppressive environment centered on the tumor local area, and it has become known that the tumor itself utilizes a system to avoid the immune surveillance mechanism. As molecules utilized in such an avoidance system, so-called immune checkpoint molecule groups such as PD-1 or its ligand PD-L1 are known, and these inhibitors have already achieved certain results clinically.

[0003] However, it is still a fact that there are malignant tumor patients in whom sufficient therapeutic effects are not recognized even by these immune checkpoint inhibitors, and it is urgent to identify an effective marker that can identify patients in whom the effects can be expected.

[0004] So far, there is a report (Non-Patent Document 1) suggesting that the ratio of the number of CD8 + T cells to the number of Treg cells in peripheral blood may be correlated with the prognosis of malignant tumor patients. However, by evaluating at least a combination of two items according to the present invention, the effectiveness of an immune checkpoint inhibitor can be predicted before administration, and there is no reported treatment method of prescribing the immune checkpoint inhibitor to patients identified based on the biomarker.

Prior Art Documents

Non-Patent Literature

[0005]

Non-Patent Literature 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a method for identifying a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, and a method for suppressing the progression, recurrence, and / or treatment of a malignant tumor characterized by a prescription based on the same.

Means for Solving the Problems

[0007] As a result of intensive studies by the inventors of the present invention, it has been found that specific conditions defined by the evaluation items described in this specification and combinations of each two sets thereof can be biomarkers for predicting the efficacy of immune checkpoint inhibitors, and the present invention has been completed. That is, the present invention is as follows. [1] CD8 + T cells and Foxp3 + T cells are (1) the following formula:

[0008]

Equation

[0009] [wherein, Y1 represents the percentage (%) of CCR7-expressing cells in the CD8 + T cells, a 1-1 represents a numerical value of about -637, X1 represents the mean fluorescence intensity (Mean Fluorescence Intensity (hereinafter abbreviated as MFI)) of PD-1 expression in the Foxp3 + T cells relative to the CD8 +Represents the square root value of the ratio of the MFI of PD-1 expression in T cells, Y 1-1 represents any numerical value from about 784 to about 914.], or the condition represented by (2)(i) the following formula:

[0010]

Equation

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

[0012]

Equation

[0013] [In the formula, a 1-3 represents a numerical value of about 666, Y 1-3 represents any numerical value from about -652 to about -522, and the other symbols have the same meaning as described above.], characterized in that it is administered to a cancer patient satisfying two conditions represented by, a cancer progression inhibitor, recurrence inhibitor and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient (the combination of the conditions represented in the formulas of (1) and (2)(i) and (2)(ii) herein may be abbreviated as "biomarker 1" hereinafter. Also, in this specification, the "cancer progression inhibitor, recurrence inhibitor and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient" of the present invention may be abbreviated as "the therapeutic agent etc. of the present invention" in general.). [2] The agent according to the above item [1], wherein Y 1-1 represents any numerical value from about 853 to about 914. [3] The agent according to the above item [1] or [2], wherein Y 1-2 represents any numerical value from about 39.0 to about 44.6. [4] The agent according to any one of the above items [1] to [3], wherein Y 1-3 represents any numerical value from about -652 to about -591. [5] Y 1-1 The agent according to item [1], [3] or [4] above, wherein Y represents any numerical value from about 784 to about 853. [6] Y 1-2 The agent according to item [1], [2], [4] or [5] above, wherein Y represents any numerical value from about 44.6 to about 50.9. [7] Y 1-3 The agent according to any one of items [1] to [3], [5] and [6] above, wherein Y represents any numerical value from about -591 to about -522. [8] Y 1-1 The agent according to item [1], [3], [4], [6] or [7] above, wherein Y is about 853. [9] Y 1-2 The agent according to item [1], [2], [4], [5], [7] or [8] above, wherein Y is about 44.6.

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

[11] CD8 in the tumor tissue or blood of a malignant tumor patient + T cells and Foxp3 + T cells satisfy (1) the condition represented by the following formula:

[0014]

Number

[0015] [wherein all symbols have the same meaning as in item [1] above], or (2) (i) the following formula:

[0016]

Number

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

[0018]

Number

[0019] [In the formula, all symbols have the same meaning as in the previous section [1].] A therapeutic agent for suppressing the progression, recurrence and / or treating malignant tumors, comprising an immune checkpoint inhibitor as an active ingredient, which is administered to a patient with malignant tumors satisfying two conditions represented by the following.

[12] Treg cells (Fr.III) and CD8 in the tumor tissue or blood of a patient with malignant tumors + T cells satisfy (1) the following mathematical formula:

[0020]

Number

[0021] [In the formula, Y2 represents the percentage (%) of PD-1-expressing cells in the Treg cells (Fr.III), a 2-1 represents a numerical value of about 0.765, X2 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cells, and Y 2-1 represents any numerical value from about 50.6 to about 59.2.], or (2) the following mathematical formula:

[0022]

Number

[0023] [In the formula, a 2-2 represents a numerical value of about 1.56, Y 2-2 represents any numerical value from about -44.1 to about -14.5, and other symbols have the same meaning as described above.]. A therapeutic agent for suppressing the progression, recurrence and / or treating malignant tumors, comprising an immune checkpoint inhibitor as an active ingredient, which is administered to the patient with malignant tumors satisfying the conditions (where the combination of the conditions represented by the formulas (1) and (2) here may be abbreviated as "biomarker 2" hereinafter).

[13] The agent according to the previous section

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

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

[12] or

[13] , which 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] , which represents any numerical value from about 50.6 to about 54.1.

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

[12] ,

[13] or

[15] , which 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] , which is about 54.1.

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

[12] ,

[13] ,

[15] or

[17] , which is about -26.6.

[19] Treg cells (Fr.III) and CD8 in the tumor tissue or blood of a malignant tumor patient + T cells satisfy the condition represented by the following formula:

[0024]

Number

[0025] [wherein all symbols have the same meaning as in the preceding item

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

[0026]

Number

[0027] [wherein all symbols have the same meaning as in the preceding item

[12] ]. A therapeutic agent for suppressing the progression, recurrence and / or treatment of malignant tumors, which contains an immune checkpoint inhibitor as an active ingredient, and is characterized in that it is administered to the malignant tumor patient who satisfies the condition.

[20] CD8 in the tumor tissue or blood of a malignant tumor patient + T cells and Foxp3 + T cells satisfy the condition represented by the following formula: (1)(i) the following formula:

[0028]

Number

[0029] [wherein, Y3 represents the number of PD-1-expressing cells in the CD8 + T cells, a 3-1 represents a numerical value of about -1.59, and X3 represents 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, and represents the square root value of the ratio of the MFI of PD-1 expression in the CD8 3-1 T cells, and Y

[0030] [Number]

[0031] [wherein, all symbols represent the same meaning as described above.], or (2)(i) the following mathematical formula:

[0032] [Number]

[0033] [wherein, a 3-2 represents a numerical value of about -9.05, Y 3-2 represents any numerical value from about 10.7 to about 13.3, and the other symbols represent the same meaning as described above.], or (ii) the following mathematical formula:

[0034] [Number]

[0035] [wherein, all symbols represent the same meaning as described above.]. A therapeutic agent for suppressing the progression and recurrence of a malignant tumor and / or treating a malignant tumor, which contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with a malignant tumor satisfying the conditions represented by the above (1) and (2) (the combination of the conditions represented by the formulas in (1) and (2) above may be abbreviated as "biomarker 3" hereinafter).

[21] Y 3-1 The agent described in the preceding item

[20] , wherein Y represents any numerical value from about 4.42 to about 4.89.

[22] Y 3-2 The agent described in the preceding item

[20] or

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

[23] Y 3-1 The agent described in the preceding item

[20] or

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

[24] Y 3-2 The agent described in the preceding item

[20] ,

[21] or

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

[25] Y 3-1 The agent described in the preceding item

[20] ,

[22] or

[24] , wherein Y is about 4.42.

[26] Y 3-2 The agent described in the preceding item

[20] ,

[21] ,

[23] or

[25] , wherein Y is about 11.7.

[27] CD8 + T cells and Foxp3 + T cells in the tumor tissue or blood of a malignant tumor patient satisfy the condition represented by (1)(i) the following formula:

[0036]

Number

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

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

[0038]

Number

[0039] [wherein all symbols have the same meaning as in the preceding item

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

[0040]

Number

[0041] [In the formula, all symbols represent the same meaning as in the previous item

[20] .] Or (ii) the following mathematical formula:

[0042]

Number

[0043] [In the formula, all symbols represent the same meaning as in the previous item

[20] .], which is characterized by being administered to the malignant tumor patient satisfying the conditions represented by the formula, and is a therapeutic agent for suppressing the progression, recurrence and / or treatment of malignant tumors, with an immune checkpoint inhibitor as an active ingredient.

[28] CD8 in the tumor tissue or blood of a malignant tumor patient + T cells and Foxp3 + T cells are (1) the following mathematical formula:

[0044]

Number

[0045] [In the formula, Y4 represents 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, a 4-1 represents a numerical value of about -0.00273, X4 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cells, and Y 4-1 represents any numerical value from about 0.905 to 1.46.], or (2) the following mathematical formula:

[0046]

Number

[0047] [In the formula, a 4-2 represents a numerical value of about -0.0294, and Y 4-2represents any numerical value from about 2.18 to about 3.31, and other symbols represent the same meaning as described above.], and is administered to a patient with the malignant tumor satisfying the conditions represented by the formula. A therapeutic agent for suppressing the progression, recurrence, and / or treatment of a malignant tumor containing an immune checkpoint inhibitor as an active ingredient (the combination of conditions represented by the formulas (1) and (2) in this case may be abbreviated as "biomarker 4" hereinafter).

[29] Y 4-1 represents any numerical value from about 1.18 to about 1.46, and the agent according to the preceding item

[28] .

[30] Y 4-2 represents any numerical value from about 2.74 to about 3.31, and the agent according to the preceding item

[28] or

[29] .

[31] Y 4-1 represents any numerical value from about 0.905 to about 1.18, and the agent according to the preceding item

[28] or

[30] .

[32] Y 4-2 represents any numerical value from about 2.18 to about 2.74, and the agent according to the preceding item

[28] ,

[29] or

[31] .

[33] Y 4-1 is about 1.18, and the agent according to the preceding item

[28] ,

[30] or

[32] .

[34] Y 4-2 is about 2.74, and the agent according to the preceding item

[28] ,

[29] ,

[31] or

[33] .

[35] CD8 in the tumor tissue or blood of a patient with a malignant tumor + T cells and Foxp3 + T cells are (1) the following mathematical formula:

[0048]

Number

[0049] [wherein all symbols represent the same meaning as in the preceding item

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

[0050]

Number

[0051] [In the formula, all symbols have the same meaning as in the previous section

[28] .] A therapeutic agent for suppressing the progression, recurrence, and / or treatment of malignant tumors, comprising an immune checkpoint inhibitor as an active ingredient, which is administered to a patient with the malignant tumor satisfying the condition represented by the formula.

[36] Foxp3 in the tumor tissue or blood of a patient with a malignant tumor + T cells and CD8 + T cells satisfy the following mathematical formula:

[0052]

Number

[0053] [In the formula, Y5 represents the percentage of PD-1-expressing cells in the Foxp3 + T cells, a5 represents a numerical value of about 2.34, X5 represents the percentage of PD-1-expressing cells in the CD8 + T cells, and Y 5-1 represents any numerical value from about -117 to about 131.] A therapeutic agent for suppressing the progression, recurrence, and / or treatment of malignant tumors, comprising an immune checkpoint inhibitor as an active ingredient, which is administered to a patient with the malignant tumor satisfying the condition represented by the formula (the condition represented by the above formula may be abbreviated as "biomarker 5" hereinafter).

[37] Y 5-1 represents any numerical value from about -117 to about -54.4, the agent according to the previous item

[36] .

[38] Y 5-1 represents any numerical value from about -54.4 to about 131, the agent according to the previous item

[36] .

[39] Y 5-1 is about -54.4, the agent according to the previous item

[36] .

[40] Foxp3 in the tumor tissue or blood of a patient with a malignant tumor + T cells and CD8 + T cells satisfy the following mathematical formula:

[0054]

Number

[0055] [In the formula, all symbols represent the same meaning as in the previous section

[36] .] A therapeutic agent for suppressing the progression, recurrence and / or treating malignant tumors, comprising an immune checkpoint inhibitor as an active ingredient, which is administered to the patient with malignant tumors satisfying the conditions represented by the formula.

[41] Treg cells (Fr.II) and CD8 in the tumor tissue or blood of a patient with malignant tumors + T cells satisfy (1) the following mathematical formula:

[0056]

Number

[0057] [In the formula, Y6 represents the percentage (%) of PD-1-expressing cells in the Treg cells (Fr.II), a 6-1 represents a numerical value of about 1.69, X6 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cells, and Y 6-1 represents any numerical value from about 21.4 to about 44.1.], or (2) the following mathematical formula:

[0058]

Number

[0059] [In the formula, a 6-2 represents a numerical value of about 1.78, Y 6-2 represents any numerical value from about -80.6 to about -21.0, and other symbols represent the same meaning as described above.]. A therapeutic agent for suppressing the progression, recurrence and / or treating malignant tumors, comprising an immune checkpoint inhibitor as an active ingredient, which is administered to the patient with malignant tumors satisfying the conditions represented by the formula (the combination of the conditions represented by the formulas (1) and (2) here may be abbreviated as "biomarker 6" hereinafter).

[42] Y 6-1 represents any numerical value from about 31.8 to about 44.1, and the agent according to the previous section

[41] .

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

[41] or

[42] , which 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] , which 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] , which 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] , which is about 31.8.

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

[41] ,

[42] ,

[44] or

[46] , which is about -48.2.

[48] Treg cells (Fr.II) and CD8 in the tumor tissue or blood of a malignant tumor patient + T cells satisfy (1) the following formula:

[0060]

Number

[0061] [wherein all symbols have the same meaning as in the preceding item

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

[0062]

Number

[0063] [wherein all symbols have the same meaning as in the preceding item

[41] ]. The agent for suppressing the progression, recurrence and / or treatment of malignant tumors, which contains an immune checkpoint inhibitor as an active ingredient, is characterized in that it is administered to the malignant tumor patient satisfying the conditions represented by the formula.

[49] CD4 in the tumor tissue or blood of a malignant tumor patient + T cells and CD8 + T cells satisfy (1) the following formula:

[0064]

Number

[0065] [In the formula, Y7 represents the percentage (%) of PD-1-expressing cells in the CD4 + T cells, a 7-1 represents a numerical value of about 0.227, and X7 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cells, and Y 7-1 represents any numerical value from about -13.9 to 4.03.], or (2) the following mathematical formula:

[0066] [Number]

[0067] [In the formula, a 7-2 represents a numerical value of about 3.32, Y 7-2 represents any numerical value from about -199 to 58.2, and the other symbols have the same meaning as described above.], which is characterized by being administered to a patient with the malignant tumor that satisfies the condition represented by the above formula, and is a therapeutic agent for suppressing the progression, recurrence, and / or treatment of malignant tumors containing an immune checkpoint inhibitor as an active ingredient (the combination of the conditions represented by the formulas (1) and (2) in this case may be abbreviated as "biomarker 7" hereinafter).

[50] Y 7-1 represents any numerical value from about -13.9 to about -6.56, and the agent according to the previous item

[49] .

[51] Y 7-2 represents any numerical value from about -199 to about -93.5, and the agent according to the previous item

[49] or

[50] .

[52] Y 7-1 represents any numerical value from about -6.56 to about 4.03, and the agent according to the previous item

[49] or

[51] .

[53] Y 7-2 represents any numerical value from about -93.5 to about 58.2, and the agent according to the previous item

[49] ,

[50] or

[52] .

[54] Y 7-1 is about -6.56, and the agent according to the previous item

[49] ,

[51] or

[53] .

[55] Y 7-2The agent described in the preceding items

[49] ,

[50] ,

[52] or

[54] , which is about -93.5.

[56] CD4 in tumor tissue or blood of a malignant tumor patient + T cells and CD8 + T cells satisfy the condition represented by (1) the following formula:

[0068]

Number

[0069] [wherein all symbols have the same meaning as in the preceding item

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

[0070]

Number

[0071] [wherein all symbols have the same meaning as in the preceding item

[49] ]. A therapeutic agent for inhibiting the progression, recurrence and / or treatment of malignant tumors, which contains an immune checkpoint inhibitor as an active ingredient, and is administered to the malignant tumor patient satisfying the condition.

[57] CD3 in tumor tissue or blood of a malignant tumor patient + cells, Treg cells (Fr.II) and CD4 + T cells satisfy the following formula:

[0072]

Number

[0073] [wherein Y8 represents the square root value of the ratio of the MFI of PD-1 expression in the CD3 + cells to the MFI of PD-1 expression in the Treg cells (Fr.II), a 8-1 represents a numerical value of about -0.00338, X8 represents the percentage of PD-1-expressing cells in the CD4 + T cells, Y 8-1 represents an arbitrary numerical value from about 0.939 to about 1.37, a 8-2represents a numerical value of approximately 0.270, and Y 8-2 represents any numerical value from approximately -6.98 to approximately -0.654. A therapeutic agent for inhibiting the progression and recurrence of malignant tumors and / or treating malignant tumors, which contains an immune checkpoint inhibitor as an active ingredient, and is administered to the malignant tumor patient satisfying the condition represented by [Here, the combination of conditions represented by the above formula may be abbreviated as "biomarker 8" hereinafter.].

[58] Y 8-1 represents any numerical value from approximately 1.17 to approximately 1.37, and the agent according to the previous item

[57] .

[59] Y 8-2 represents any numerical value from approximately -6.98 to approximately -4.10, and the agent according to the previous item

[57] or

[58] .

[60] Y 8-1 represents any numerical value from approximately 0.939 to approximately 1.17, and the agent according to the previous item

[57] or

[59] .

[61] Y 8-2 represents any numerical value from approximately -4.10 to approximately -0.654, and the agent according to the previous item

[57] ,

[58] or

[60] .

[62] Y 8-1 is approximately 1.17, and the agent according to the previous item

[57] ,

[59] or

[61] .

[63] Y 8-2 is approximately -4.10, and the agent according to the previous item

[57] ,

[58] ,

[60] or

[62] .

[64] CD3 in the tumor tissue or blood of a malignant tumor patient + cells, Treg cells (Fr.II) and CD4 + T cells satisfy the following mathematical formula:

[0074]

Number

[0075] [In the formula, all symbols represent the same meaning as in the previous item

[57] .] A therapeutic agent for inhibiting the progression and recurrence of malignant tumors and / or treating malignant tumors, which contains an immune checkpoint inhibitor as an active ingredient, and is administered to the malignant tumor patient satisfying the condition represented by

[65] Foxp3 in the tumor tissue or blood of a malignant tumor patient+ T cells and CD8 + The T cells satisfy the following formula:

[0076] [Number]

[0077] [wherein, Y 9-1 represents the MFI of PD-1 expression in the Foxp3 + T cells, Y 9-2 represents the MFI of PD-1 expression in the CD8 + T cells, and a9 represents any numerical value from about -716 to about 166.] The malignant tumor progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, which is administered to a patient with a malignant tumor satisfying the condition represented by the formula (hereinafter, the condition represented by the above formula may be abbreviated as "biomarker 9").

[66] The agent according to the preceding item

[65] , wherein a9 represents any numerical value from about -462 to about 166.

[67] The agent according to the preceding item

[65] , wherein a9 represents any numerical value from about -716 to about -3.96.

[68] The agent according to the preceding item

[65] , wherein a9 represents any numerical value from about -462 to about -3.96.

[69] The agent according to the preceding item

[65] , wherein a9 is about -208.

[70] Treg cells (Fr.II) and CD8 in the tumor tissue or blood of a patient with a malignant tumor + The T cells satisfy the following formula:

[0078] [Number]

[0079] [wherein, Y 10-1 represents the MFI of PD-1 expression in the Treg cells (Fr.II), Y 10-2 represents the MFI of PD-1 expression in the CD8 + T cells, and a 10represents any numerical value from approximately -842 to approximately 133. A therapeutic agent for suppressing the progression, recurrence, and / or treating malignant tumors, which contains an immune checkpoint inhibitor as an active ingredient, and is administered to a patient with malignant tumors satisfying the condition represented by (where the condition represented by the above formula may be abbreviated as "biomarker 10" hereinafter).

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

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

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

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

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

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

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

[70] , wherein is approximately -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 agent according to the preceding item

[75] , wherein the anti-PD-1 antibody is 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.

[77] The agent according to the preceding item

[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 according to the preceding item

[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 hematological cancer.

[80] The solid cancer is one or more cancers selected from malignant melanoma (e.g., malignant melanoma in the skin, oral mucosa epithelium, or intraorbital region, 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 cancer (e.g., clear cell renal cell cancer), 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 corpus cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (colon-rectal cancer) (e.g., high-frequency microsatellite instability (hereinafter abbreviated as "MSI-H") and / or mismatch repair deficiency (hereinafter abbreviated as "dMMR") positive colon-rectal cancer), rectal cancer, colon cancer, hepatocellular cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvic cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, skin cancer (e.g., choroidal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, 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 sarcoma, pediatric rhabdomyosarcoma, uterine corpus leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma), and Kaposi sarcoma, and is the agent described in the preceding item

[79] .

[81] The agent according to the preceding item

[79] , wherein the blood cancer is one or more cancers selected from multiple myeloma, malignant lymphoma (e.g., non-Hodgkin lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, lymphoplasmacytic lymphoma, 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 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 according to 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 pediatric 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 with insufficient or inadequate therapeutic effect by other anti-cancer drugs.

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

[84] , wherein the malignant tumor is a malignant tumor that has progressed after treatment with other anti-cancer drugs.

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

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

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

[86] , which is prescribed in adjuvant postoperative therapy or adjuvant preoperative therapy.

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

[87] , wherein the malignant tumor is inoperable for radical cure or resection, metastatic, recurrent, refractory, and / or distant metastatic.

[89] The ratio of tumor cells expressing PD-L1 among tumor cells in the 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, multiplied by 100 (hereinafter abbreviated as "CPS") is 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more, and the agent according to any one of the preceding items [1] to

[88] .

[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 according to 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 malignant melanoma or non-small cell lung cancer is positive for the BRAF V600E mutation.

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

[80] to

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

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

[80] to

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

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

[96] , wherein the tumor mutation burden (hereinafter abbreviated as "TMB") of the malignant tumor is high-frequency (10 6 The number of mutations per base is 10 or more).

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

[96] , wherein the TMB of the malignant tumor is low-frequency (10 6 The number of mutations per base is less than 10).

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

[98] , which is used in combination with another anti-cancer drug.

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

[84] to

[86] and

[99] , wherein the other anti-cancer drug is one or more drugs selected from alkylating agents, platinum preparations, antimetabolites (for example, folic acid antimetabolites, pyridine metabolism inhibitors, purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, anti-tumor antibiotics, cytokine preparations, anti-hormone drugs, molecular target drugs, and cancer immunotherapy drugs.

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

[0100] , wherein the cancer patient is a patient before 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 a tissue containing at least the tumor mass itself, the invasive periphery of the tumor, or lymph nodes adjacent to the tumor. [1-1] CD8 + T cells and Foxp3 + T cells satisfy (1) the condition represented by the following formula:

[0080]

Number

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

[0082]

Number

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

[0084]

Number

[0085] [In the formula, all symbols represent the same meaning as in the previous item [1].] A method for suppressing the progression, recurrence, and / or treatment of malignant tumors, which comprises administering an effective amount of an immune checkpoint inhibitor to a malignant tumor patient who satisfies (or has been confirmed to satisfy) two conditions represented by the above. [1-2] Treg cells (Fr.III) and CD8 in the tumor tissue or blood of a malignant tumor patient + T cells satisfy (1) the following mathematical formula:

[0086]

Number

[0087] [In the formula, all symbols represent the same meaning as in the previous item

[12] .] The condition represented by the formula, or (2) the following mathematical formula:

[0088]

Number

[0089] [In the formula, all symbols represent the same meaning as in the previous item

[12] .] A method for suppressing the progression, recurrence, and / or treatment of malignant tumors, which comprises administering an effective amount of an immune checkpoint inhibitor to a malignant tumor patient who satisfies (or has been confirmed to satisfy) the condition represented by the formula. [1-3] CD8 in the tumor tissue or blood of a malignant tumor patient + T cells and Foxp3 + T cells satisfy (1) (i) the following mathematical formula:

[0090]

Number

[0091] [In the formula, all symbols represent the same meaning as in the previous item

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

[0092] [Mathematics]

[0093] [In the formula, all symbols have the same meaning as in the previous item

[20] .] The condition represented by, or the following formula (2)(i):

[0094] [Mathematics]

[0095] [In the formula, all symbols have the same meaning as in the previous item

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

[0096] [Mathematics]

[0097] [In the formula, all symbols have the same meaning as in the previous item

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

[0098] [Mathematics]

[0099] [In the formula, all symbols have the same meaning as in the previous item

[28] .] The condition represented by, or (2) the following formula:

[0100] [Mathematics]

[0101] A method for suppressing the progression, recurrence and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient who satisfies (or is confirmed to satisfy) the condition represented by [[wherein all symbols have the same meaning as in the previous section

[28] ]]. [1-5] Foxp3 in the tumor tissue or blood of a malignant tumor patient + T cells and CD8 + The T cells satisfy the following formula:

[0102]

Number

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

[36] ]. A method for suppressing the progression, recurrence and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient who satisfies (or is confirmed to satisfy) the condition represented by the above. [1-6] Treg cells (Fr.II) and CD8 in the tumor tissue or blood of a malignant tumor patient + The T cells satisfy (1) the following formula:

[0104]

Number

[0105] [wherein all symbols have the same meaning as in the previous section

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

[0106]

Number

[0107] [wherein all symbols have the same meaning as in the previous section

[41] ]. A method for suppressing the progression, recurrence and / or treating a malignant tumor, comprising administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient who satisfies (or is confirmed to satisfy) the condition represented by [1-7] CD4 in the tumor tissue or blood of a malignant tumor patient + T cells and CD8 + T cells satisfy the condition represented by (1) the following mathematical formula:

[0108] [Number]

[0109] [In the formula, all symbols represent the same meaning as in the previous item

[49] .] Or (2) the following mathematical formula:

[0110] [Number]

[0111] [In the formula, all symbols represent the same meaning as in the previous item

[49] .] A method for suppressing the progression, recurrence, and / or treatment of malignant tumors, including administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient who satisfies (or has been confirmed to satisfy) the condition represented by the formula. [1-8] CD3 in the tumor tissue or blood of a malignant tumor patient + cells, Treg cells (Fr.II) and CD4 + T cells satisfy the following mathematical formula:

[0112] [Number]

[0113] [In the formula, all symbols represent the same meaning as in the previous item

[57] .] A method for suppressing the progression, recurrence, and / or treatment of malignant tumors, including administering an effective amount of an immune checkpoint inhibitor to the malignant tumor patient who satisfies (or has been confirmed to satisfy) the condition represented by the formula. [1-9] Foxp3 in the tumor tissue or blood of a malignant tumor patient + T cells and CD8 + T cells satisfy the following mathematical formula:

[0114] [Number]

[0115] [In the formula, all symbols have the same meaning as in the previous item

[65] .] A method for suppressing the progression, recurrence, and / or treating malignant tumors, which comprises administering an effective amount of an immune checkpoint inhibitor to a malignant tumor patient who satisfies (or has been confirmed to satisfy) the conditions represented by the formula. [1-10] Treg cells (Fr.II) and CD8 in the tumor tissue or blood of a malignant tumor patient + T cells satisfy the following mathematical formula:

[0116] [Number]

[0117] [In the formula, all symbols have the same meaning as in the previous item

[70] .] A method for suppressing the progression, recurrence, and / or treating malignant tumors, which comprises administering an effective amount of an immune checkpoint inhibitor to a malignant tumor patient who satisfies (or has been confirmed to satisfy) the conditions represented by the formula. In addition, 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] By flow cytometry or immunostaining method, (1) the number of CD8 + T cells and the number of CCR7-expressing cells among them in a sample derived from the tumor tissue or blood of a malignant tumor patient, and (2) the PD-1 expression in each of the CD8 + T cells and Foxp3 + T cells in the same sample are measured respectively, and (1a) the percentage (%) of CCR7-expressing cells in the CD8 + T cells and (2a) the MFI of PD-1 expression in the Foxp3 + T cells relative to the CD8 +A method for determining the ratio of the mean fluorescence intensity (MFI) of PD-1 expression in T cells, and identifying malignant tumor patients in whom the effect of an immune checkpoint inhibitor can be more expected or malignant tumor patients in whom the effect of an immune checkpoint inhibitor cannot be expected, based on the ratio (%) and the combination of the ratio or the square root value of the ratio. [2-2] As malignant tumor patients in whom the effect of an immune checkpoint inhibitor can be more expected, those in whom the CD8 + T cells and Foxp3 + T cells satisfy (1) the condition represented by the following formula:

[0118]

Equation

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

[0120]

Equation

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

[0122]

Equation

[0123] [wherein all symbols have the same meaning as in the preceding item [1]]. The method according to the preceding item [2-1], which identifies patients who satisfy the two conditions represented by the formula. [2-3] Y 1-1 represents any numerical value from about 853 to about 914. The method according to the preceding item [2-2]. [2-4] Y 1-2 represents any numerical value from about 39.0 to about 44.6. The method according to the preceding item [2-2] or [2-3]. [2-5] Y 1-3The method according to any one of the preceding items [2-2] to [2-4], which represents 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], which 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], which represents any numerical value from about 44.6 to about 50.9. [2-8] Y 1-3 The method according to any one of the preceding items [2-2] to [2-4], [2-6] and [2-7], which represents any numerical value from about -591 to about -522. [2-9] Y 1-1 The method according to the preceding item [2-2], [2-4], [2-5], [2-7] or [2-8], which is about 853. [2-10] Y 1-2 The method according to the preceding item [2-2], [2-3], [2-5], [2-6], [2-8] or [2-9], which is about 44.6. [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], which is about -591. [2-12] By flow cytometry or immunostaining method, measure the number of each cell of Treg cells (Fr.III) and CD8 + T cells in a sample derived from a tumor tissue or blood of a malignant tumor patient, and measure the number of PD-1 expressing cells of each of them, and for each of the Treg cells (Fr.III) and the CD8 + Determine the percentage (%) of PD-1 expressing cells in each of the T cells, and based on the combination of the two percentages (%), identify a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-13] As a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, the Treg cells (Fr.III) and CD8 + T cells are (1) the following formula:

[0124] [Mathematics]

[0125] [wherein all symbols have the same meanings as in the previous item

[12] ]. The conditions represented by, or the following mathematical formula (2):

[0126] [Mathematics]

[0127] The method according to the previous item [2-12], which identifies a patient who satisfies the condition represented by [wherein all symbols have the same meanings as in the previous item

[12] ]. [2-14] Y 2-1 represents any numerical value from about 54.1 to about 59.2, the method according to the previous item [2-13]. [2-15] Y 2-2 represents any numerical value from about -44.1 to about -26.6, the method according to the previous item [2-13] or [2-14]. [2-16] Y 2-1 represents any numerical value from about 50.6 to about 54.1, the method according to the previous item [2-13] or [2-15]. [2-17] Y 2-2 represents any numerical value from about -26.6 to about -14.5, the method according to the previous item [2-13], [2-14] or [2-16]. [2-18] Y 2-1 is about 54.1, the method according to the previous item [2-13], [2-15] or [2-17]. [2-19] Y 2-2 is about -26.6, the method according to the previous item [2-13], [2-14], [2-16] or [2-18]. [2-20] By flow cytometry or immunostaining method, (1) the number of PD-1-expressing cells among CD8 + T cells in a sample derived from a tumor tissue or blood of a malignant tumor patient, and (2) the CD8 + T cells and Foxp3 +Measure the expression of PD-1 in each T cell, and the Foxp3 + Determine the ratio of the MFI of PD-1 expression in the CD8 + T cell to the MFI of PD-1 expression in the T cell, and (i) the number of PD-1-expressing cells, the common logarithm of the number of cells, or the common logarithm of the number obtained by adding 1 to the number of cells, and (ii) a method for identifying a cancer patient in whom the effect of an immune checkpoint inhibitor can be more expected or a cancer patient in whom the effect of an immune checkpoint inhibitor cannot be expected, based on a combination of the ratio or the square root value of the ratio. [2-21] As a cancer patient in whom the effect of an immune checkpoint inhibitor can be more expected, the CD8 + T cell and Foxp3 + T cells are such that (1) (i) the following formula:

[0128]

Number

[0129] [wherein all symbols have the same meaning as in the previous item

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

[0130]

Number

[0131] [wherein all symbols have the same meaning as in the previous item

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

[0132]

Number

[0133] [wherein all symbols have the same meaning as in the previous item

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

[0134]

Number

[0135] [Wherein, all symbols have the same meaning as in the preceding paragraph

[20] .] A method according to the preceding paragraph [2-20] for identifying a patient who satisfies the conditions represented by the formula. [2-22] Y 3-1 A method according to the preceding paragraph [2-21], wherein Y represents any numerical value from about 4.42 to about 4.89. [2-23] Y 3-2 A method according to the preceding paragraph [2-21] or [2-22], wherein Y represents any numerical value from about 111.7 to about 13.3. [2-24] Y 3-1 A method according to the preceding paragraph [2-21] or [2-23], wherein Y represents any numerical value from about 4.09 to about 4.42. [2-25] Y 3-2 A method according to the preceding paragraph [2-21], [2-22] or [2-24], wherein Y represents any numerical value from about 10.7 to about 11.7. [2-26] Y 3-1 A method according to the preceding paragraph [2-21], [2-23] or [2-25], wherein Y is about 4.42. [2-27] Y 3-2 A method according to the preceding paragraph [2-21], [2-22], [2-24] or [2-26], wherein Y is about 11.7. [2-28] By flow cytometry or immunostaining method, (1) PD-1 expression in CD8 + T cells and Foxp3 + T cells in each of the tumor tissue or blood-derived samples of malignant tumor patients, and (2) the cell number of the CD8 + T cells and the number of PD-1-expressing cells among them are measured respectively, and (1a) 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 and (2a) the percentage of PD-1-expressing cells in the CD8 + T cells are determined respectively, and based on the combination of the ratio or the square root value of the ratio and the percentage (%), a method for identifying a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-29] As a patient with a malignant tumor in whom the effect of an immune checkpoint inhibitor can be more expected, the CD8 + T cell and Foxp3 + T cell satisfies the condition represented by (1) the following mathematical formula:

[0136] [Number]

[0137] [wherein all symbols represent the same meaning as in the previous item

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

[0138] [Number]

[0139] [wherein all symbols represent the same meaning as in the previous item

[28] ]. The method described in the previous item [2-28] for identifying a patient who satisfies the condition. [2-30] Y 4-1 represents any numerical value from about 1.18 to about 1.46, the method described in the previous item [2-29]. [2-31] Y 4-2 represents any numerical value from about 2.74 to about 3.31, the method described in the previous item [2-29] or [2-30]. [2-32] Y 4-1 represents any numerical value from about 0.905 to about 1.18, the method described in the previous item [2-29] or [2-31]. [2-33] Y 4-2 represents any numerical value from about 2.18 to about 2.74, the method described in the previous item [2-29], [2-30] or [2-32]. [2-34] Y 4-1 is about 1.18, the method described in the previous item [2-29], [2-31] or [2-33]. [2-35] Y 4-2 is about 2.74, the method described in the previous item [2-29], [2-30], [2-32] or [2-34]. [2-36] By flow cytometry or immunostaining, Foxp3 in a sample derived from a tumor tissue or blood of a malignant tumor patient + T cells and CD8 + The number of each of these T cells and the number of their PD-1-expressing cells are measured respectively, and for the Foxp3 + T cells and the CD8 + T cells, the percentage (%) of PD-1-expressing cells in each of them is determined, and based on the combination of these two percentages (%), a method for identifying a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-37] As a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, the Foxp3 + T cells and CD8 + T cells satisfy the following formula:

[0140]

Number

[0141] [Wherein all symbols have the same meaning as in the previous item

[36] .] The method according to the previous item [2-36], which identifies a patient who satisfies the conditions represented by. [2-38] Y 5-1 represents any numerical value from about -117 to about -54.4, the method according to the previous item [2-37]. [2-39] Y 5-1 represents any numerical value from about -54.4 to about 131, the method according to the previous item [2-37]. [2-40] Y 5-1 is about -54.4, the method according to the previous item [2-37]. [2-41] By flow cytometry or immunostaining, Treg cells (Fr.II) and CD8 in a sample derived from a tumor tissue or blood of a malignant tumor patient + The number of each of these T cells and the number of their PD-1-expressing cells are measured respectively, and for 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, based on the combination of the two percentages, malignant tumor patients in whom the effect of an immune checkpoint inhibitor can be more expected or malignant tumor patients in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-42] The Treg cells (Fr.II) and CD8 as malignant tumor patients in whom the effect of an immune checkpoint inhibitor can be more expected + The T cells satisfy (1) the condition represented by the following formula:

[0142]

Equation

[0143] [wherein all symbols have the same meaning as in the previous item

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

[0144]

Equation

[0145] [wherein all symbols have the same meaning as in the previous item

[41] ]. The method according to the previous item [2-41], which identifies patients who satisfy the condition. [2-43] Y 6-1 represents any numerical value from about 31.8 to about 44.1. The method according to the previous item [2-42]. [2-44] Y 6-2 represents any numerical value from about -80.6 to about -48.2. The method according to the previous item [2-42] or [2-43]. [2-45] Y 6-1 represents any numerical value from about 21.4 to about 31.8. The method according to the previous item [2-42] or [2-44]. [2-46] Y 6-2 represents any numerical value from about -48.2 to about -21.0. The method according to the previous item [2-42], [2-43] or [2-45]. [2-47] Y 6-1 is about 31.8. The method according to the previous item [2-42], [2-44] or [2-46]. [2-48] Y 6-2 is about -48.2, and is the method according to the preceding items [2-42], [2-43], [2-45] or [2-47]. [2-49] By flow cytometry or immunostaining, CD4 in a sample derived from tumor tissue or blood of a malignant tumor patient + T cells and CD8 + The number of each of these T cells and the number of PD-1-expressing cells thereof are measured respectively, and for the CD4 + T cells and the CD8 + The percentage (%) of PD-1-expressing cells in each of the T cells is determined, and based on the combination of the two percentages (%), a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected is identified. [2-50] As a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, the CD4 + T cells and CD8 + T cells satisfy (1) the condition represented by the following formula:

[0146]

Number

[0147] [wherein all symbols have the same meaning as in the preceding item

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

[0148]

Number

[0149] [wherein all symbols have the same meaning as in the preceding item

[49] ], and the method according to the preceding item [2-49] for identifying a patient who satisfies the condition. [2-51] Y 7-1 represents any numerical value from about -13.9 to about -6.56, and is the method according to the preceding item [2-50]. [2-52] Y 7-2The method according to the preceding item [2-50] or [2-51], which 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], which 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], which represents any numerical value from about -93.5 to about 58.2. [2-55] Y 7-1 The method according to the preceding item [2-50], [2-52] or [2-54], which is about -6.56. [2-56] Y 7-2 The method according to the preceding item [2-50], [2-51], [2-53] or [2-55], which is about -93.5. [2-57] By flow cytometry or immunostaining, (1) the expression of PD-1 in CD3 + cells and the Treg cells (Fr.II) and (2) the number of CD4 + T cells and the number of PD-1-expressing cells among them in each sample of a tumor tissue or blood derived from a malignant tumor patient are measured respectively, and (1a) the ratio of the MFI of PD-1 expression in the CD3 + cells to the MFI of PD-1 expression in the Treg cells (Fr.II) and (2a) the percentage (%) of PD-1-expressing cells in the CD4 + T cells are determined respectively, and based on the combination of the ratio or the square root value of the ratio and the percentage (%), a method for identifying a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-58] As a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, CD3 + cells, Foxp3 + T cells and CD4 + T cells are as follows:

[0150]

Equation

[0151] The method according to [2-57] for identifying a patient who satisfies the condition represented by [wherein all symbols have the same meaning as in the preceding item

[57] ]. [2-59] Y 8-1 The method according to the preceding item [2-58], wherein Y 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 Y 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 Y 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 Y represents any numerical value from about -4.10 to about -0.654. [2-63] Y 8-1 The method according to the preceding item [2-59], [2-61] or [2-62], wherein Y is about 1.17. [2-64] Y 8-2 The method according to the preceding item [2-58], [2-59], [2-61] or [2-63], wherein Y is about -4.10. [2-65] By flow cytometry or immunostaining, measure the PD-1 expression in Foxp3 + T cells and CD8 + T cells in each sample derived from the tumor tissue or blood of a malignant tumor patient, and determine the value obtained by subtracting the MFI of PD-1 expression in the CD8 + T cells from the MFI of PD-1 expression in the Foxp3 + T cells, and based on this value, identify a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-66] As a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, the Foxp3 + T cells and CD8 +A method according to [2-65] for identifying a patient who satisfies the condition represented by the following mathematical formula:

[0152] [Number]

[0153] [wherein all symbols have the same meaning as in the previous item

[65] ]. [2-67] An agent according to the previous item [2-66], wherein a9 represents any numerical value from about -462 to about 166. [2-68] An agent according to the previous item [2-66], wherein a9 represents any numerical value from about -716 to about -3.96. [2-69] An agent according to the previous item [2-66], wherein a9 represents any numerical value from about -462 to about -3.96. [2-70] An agent according to the previous item [2-66], wherein a9 is about -208. [2-71] By flow cytometry or immunostaining, measure the PD-1 expression in each of the Treg cells (Fr.II) and CD8 + T cells in a sample derived from a tumor tissue or blood of a malignant tumor patient, and subtract the MFI of the PD-1 expression in the CD8 + T cells from the MFI of the PD-1 expression in the Treg cells (Fr.II) to determine a value, and based on this value, identify a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, or a malignant tumor patient in whom the effect of an immune checkpoint inhibitor cannot be expected. [2-72] As a malignant tumor patient in whom the effect of an immune checkpoint inhibitor can be more expected, the Treg cells (Fr.II) and CD8 + T cells satisfy the following mathematical formula:

[0154] [Number]

[0155] [wherein all symbols have the same meaning as in the previous item

[70] ]. A method according to [2-71] for identifying a patient who satisfies the condition represented by this formula. [2-73] a 10 The agent according to the preceding item [2-72], wherein a represents any numerical value from about -505 to about 133. [2-74] a 10 The agent according to the preceding item [2-72], wherein a represents any numerical value from about -842 to about -2.40. [2-75] a 10 The agent according to the preceding item [2-72], wherein a represents any numerical value from about -505 to about -2.40. [2-76] a 10 The agent according to the preceding item [2-72], wherein a is about -131. [2-77] The method according to 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 method according to the preceding item [2-77], wherein the anti-PD-1 antibody is 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. [2-79] The method according to the preceding item [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 according to the preceding item [2-77], wherein the anti-CTLA-4 antibody is Ipilimumab, Zalifrelimab, Nurulimab or Tremelimumab. [2-81] The method according to 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 method according to the preceding item [2-81], wherein the solid cancer is one or more cancers selected from malignant melanoma (for example, malignant melanoma in the skin, oral mucosa epithelium, or orbit), non-small cell lung cancer (for example, squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (for example, oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer, and tongue cancer), renal cell cancer (for example, clear cell renal cell cancer), breast cancer, ovarian cancer (for example, serous ovarian cancer and ovarian clear cell adenocarcinoma), nasopharyngeal cancer, uterine cancer (for example, cervical cancer, endometrial cancer, and corpus cancer), anal cancer (for example, anal canal cancer), colorectal cancer (colon-rectal cancer) (for example, MSI-H and / or dMMR-positive colon-rectal cancer), rectal cancer, colon cancer, hepatocellular cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (for example, bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvic cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, skin cancer (for example, uveal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, brain tumor (for example, glioma (for example, glioblastoma and gliosarcoma) and meningioma), squamous cell carcinoma, bone and soft tissue sarcoma (for example, Ewing sarcoma, pediatric rhabdomyosarcoma, uterine corpus leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma), and Kaposi sarcoma. [2-83] The method according to the preceding item [2-81], wherein the blood cancer is one or more cancers selected from multiple myeloma, malignant lymphoma (for example, non-Hodgkin lymphoma (for example, follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, lymphoplasmacytic lymphoma, 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 lymphoma (for example, classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma)), leukemia (for example, acute myeloid leukemia and chronic myeloid leukemia), primary central nervous system malignant lymphoma, myelodysplastic syndrome, and myeloproliferative syndrome. [2-84] The method according to the preceding item [2-81], where the malignant tumor is non-small cell lung cancer or gastric cancer. [2-85] The method according to any one of the preceding items [2-1] to [2-81], where the malignant tumor is pediatric cancer or cancer of unknown primary origin. [2-86] The method according to any one of the preceding items [2-1] to [2-85], where the malignant tumor is a cancer with insufficient or inadequate therapeutic effect by other anti-cancer drugs. [2-87] The method according to any one of the preceding items [2-1] to [2-86], where the malignant tumor is a cancer that has progressed after treatment with other anti-cancer drugs. [2-88] The method according to any one of the preceding items [2-1] to [2-85], where the malignant tumor patient has no treatment history with other anti-cancer drugs. [2-89] The method according to any one of the preceding items [2-1] to [2-88], which is prescribed for adjuvant therapy after surgery or adjuvant therapy before surgery. [2-90] The method according to any one of the preceding items [2-1] to [2-89], where 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 items [2-1] to [2-90], where 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 items [2-1] to [2-90], where TPS or CPS is less than 50%, less than 25%, less than 5%, or less than 1%. [2-93] The method according to any one of the preceding items [2-1] to [2-92], where the malignant tumor has MSI-H and / or dMMR. [2-94] The method according to any one of the preceding items [2-1] to [2-92], where 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 items [2-82] to [2-94], where malignant melanoma or non-small cell lung cancer is positive for BRAF V600E mutation. [2-96] The method according to any one of the preceding items [2-82] to [2-94], wherein the malignant melanoma or non-small cell lung cancer is BRAF V600 wild type. [2-97] The method according to any one of the preceding items [2-82] to [2-96], wherein the non-small cell lung cancer is positive for EGFR gene mutation and / or positive for ALK fusion gene. [2-98] The method according to any one of the preceding items [2-82] to [2-96], wherein the non-small cell lung cancer is negative for EGFR gene mutation and / or negative for ALK fusion gene. [2-99] The method according to any one of the preceding items [2-1] to [2-98], wherein the TMB of the malignant tumor is at a high frequency. [2-100] The method according to any one of the preceding items [2-1] to [2-98], wherein the TMB of the malignant tumor is at a low frequency. [2-101] The method according to any one of the preceding items [2-1] to [2-100], wherein the patient with the malignant tumor is a patient before 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 includes at least the tumor mass itself, the invasive peripheral part of the tumor, or a tissue including lymph nodes adjacent to the tumor. [3-0] (1) The percentage (%) of CCR7-expressing cells in CD8 + T cells in the tumor tissue or blood of a patient with a malignant tumor, (2) The number of PD-1-expressing cells among the CD8 + T cells, the common logarithm of the number of expressing cells, or the common logarithm of the value obtained by adding 1 to the number of cells, (3) The ratio of the MFI of PD-1 expression in CD8 + T cells to the MFI of PD-1 expression in the same-derived Foxp3 + T cells, or the square root value of the ratio, (4) The percentage (%) of PD-1-expressing cells in the same-derived Treg cells (Fr.III), (5) The percentage (%) of PD-1-expressing cells in the Foxp3 + T cells, (6) The percentage (%) of PD-1-expressing cells in the same-derived Treg cells (Fr.II), (7) Isogenic CD4 + Percentage of PD-1-expressing cells in T cells (%), (8) Said CD8 + Percentage of PD-1-expressing cells in T cells (%), (9) Ratio of MFI of PD-1 expression in said Treg cells (Fr.II) to MFI of PD-1 expression in isogenic CD3 + Cells, or square root value of said ratio, (10) Said CD4 + Percentage of PD-1-expressing cells in T cells (%), (11) Said Foxp3 + Value obtained by subtracting MFI of PD-1 expression in said CD8 + T cells from MFI of PD-1 expression in Foxp3 (12) Value obtained by subtracting MFI of PD-1 expression in said CD8 + T cells from MFI of PD-1 expression in Treg cells (Fr.II), and any one selected from the above, preferably a combination of any two evaluation items, for use as a biomarker for predicting the inhibitory effect on the progression of malignant tumors, recurrence suppression and / or treatment efficacy by immune checkpoint inhibitors. [3-1] (1)(i) Percentage of CCR7-expressing cells in CD8 + T cells in the tumor tissue or blood of said malignant tumor patient, or (ii) Number of PD-1-expressing cells among said CD8 + T cells, common logarithm value of said number of expressing cells or common logarithm value of the value obtained by adding 1 to said number of cells, and (2) Ratio of MFI of PD-1 expression in isogenic Foxp3 + T cells to MFI of PD-1 expression in said CD8 + T cells, or square root value of said ratio, for use as the biomarker described in the preceding item [3-0]. [3-2] (1)(i) Percentage of PD-1-expressing cells in Treg cells (Fr.III) in the tumor tissue or blood of said malignant tumor patient, (ii) Isogenic Foxp3 +The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells + The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio, (iii) the Foxp3 + The percentage of PD-1-expressing cells in CD8 T cells of the same origin, (iv) the percentage of PD-1-expressing cells in Treg cells of the same origin (Fr.II) and (v) any one selected from the percentage of PD-1-expressing cells in CD4 T cells of the same origin, and + and (2) the use of the combination of the percentage of PD-1-expressing cells in CD8 T cells of the same origin as the biomarker described in the preceding item [3-0]. (2) The use of the combination of the percentage of PD-1-expressing cells in CD8 T cells of the same origin as the biomarker described in the preceding item [3-0]. + The use of the combination of the percentage of PD-1-expressing cells in CD8 T cells of the same origin as the biomarker described in the preceding item [3-0]. [3-3] (1) The percentage of CCR7-expressing cells in CD8 T cells of the same origin and (2) the ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio + The percentage of CCR7-expressing cells in CD8 T cells of the same origin and (2) the Foxp3 + The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio + The use of the combination of the ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio, as the biomarker described in the preceding item [3-1]. [3-4] The use of the combination of the percentage of PD-1-expressing cells in each of the Treg cells (Fr.III) and CD8 T cells of the same origin as the biomarker described in the preceding item [3-2]. + The use of the combination of the percentage of PD-1-expressing cells in each of the Treg cells (Fr.III) and CD8 T cells of the same origin as the biomarker described in the preceding item [3-2]. [3-5] (1) The number of PD-1-expressing cells in CD8 T cells of the same origin, the common logarithm value of the number of cells, or the common logarithm value of the value obtained by adding 1 to the number of cells, and (2) the ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio + The number of PD-1-expressing cells in CD8 T cells of the same origin, the common logarithm value of the number of cells, or the common logarithm value of the value obtained by adding 1 to the number of cells, and (2) the Foxp3 + The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio + The use of the combination of the ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio, as the biomarker described in the preceding item [3-1]. [3-6] (1) The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio, and (2) the CD8 + The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio, and (2) the CD8 + The ratio of the MFI of PD-1 expression in CD8 T cells of the same origin to the MFI of PD-1 expression in CD8 T cells of the same origin, or the square root value of the ratio, and (2) the CD8 +Use as a biomarker as described in the preceding item [3-2] for the combination of the percentages (%) of PD-1-expressing cells in T cells. [3-7] The said Foxp3 + T cells and CD8 + Use as a biomarker as described in the preceding item [3-2] for the combination of the respective percentages (%) of PD-1-expressing cells in each of the T cells. [3-8] The said Treg cells (Fr.II) and CD8 + Use as a biomarker as described in the preceding item [3-2] for the combination of the respective percentages (%) of PD-1-expressing cells in each of the T cells. [3-9] The said CD4 + T cells and CD8 + Use as a biomarker as described in the preceding item [3-2] for the combination of the respective percentages (%) of PD-1-expressing cells in each of the T cells. [3-10] (1) The ratio of the MFI of PD-1 expression in the said Treg cells (Fr.II) to the MFI of PD-1 expression in the said CD3 + cells or the square root value of the said ratio and (2) Use as a biomarker as described in the preceding item [3-0] for the combination of the percentages (%) of PD-1-expressing cells in the said CD4 + T cells. [3-11] Use as a biomarker for predicting the inhibitory effect on the progression of malignant tumors, recurrence suppression, and / or treatment efficacy of immune checkpoint inhibitors of the value obtained by subtracting the MFI of PD-1 expression in CD8 + T cells derived from the same origin from the MFI of PD-1 expression in Foxp3 + T cells in the tumor tissue or blood of a malignant tumor patient. [3-12] Use as a biomarker for predicting the inhibitory effect on the progression of malignant tumors, recurrence suppression, and / or treatment efficacy of immune checkpoint inhibitors of the value obtained by subtracting the MFI of PD-1 expression in CD8 + T cells derived from the same origin from the MFI of PD-1 expression in Treg cells (Fr.II) in the tumor tissue or blood of a malignant tumor patient. [3-13] The use according to any one of the preceding items [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 use according to the preceding item [3-13], wherein the anti-PD-1 antibody is 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. [3-15] The use according to the preceding item [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 according to the preceding item [3-13], wherein the anti-CTLA-4 antibody is Ipilimumab, Zalifrelimab, Nurulimab or Tremelimumab. [3-17] Use according to any one of the preceding items [3-0] to [3-16], where the malignant tumor is a solid cancer or a blood cancer. [3-18] The solid cancer is melanoma (e.g., melanoma in 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 cancer (e.g., clear cell renal cell cancer), 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 (colon-rectal cancer) (e.g., MSI-H and / or dMMR-positive colon-rectal cancer), rectal cancer, colon cancer, hepatocellular cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvic cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, skin cancer (e.g., uveal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, 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 sarcoma, pediatric rhabdomyosarcoma, uterine body leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma), and Kaposi sarcoma, and is the use according to the preceding item [3-17]. [3-19] The use according to the preceding item [3-17], wherein the blood cancer is one or more cancers selected from multiple myeloma, malignant lymphoma (e.g., non-Hodgkin lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, lymphoplasmacytic lymphoma, 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 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. [3-20] The use according to any one of the preceding items [3-0] to [3-16], wherein the malignant tumor is a pediatric cancer or a cancer of unknown primary origin. [3-21] The use according to any one of the preceding items [3-0] to [3-20], wherein the malignant tumor patient is a patient before 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 a tissue including at least the tumor mass itself, the invasive periphery of the tumor, or the lymph nodes adjacent to the tumor. [Advantages of the Invention]

[0156] By measuring the biomarker according to the present invention, it becomes possible to identify malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected. [Brief Description of the Drawings]

[0157]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0158] As used herein, the "immune checkpoint inhibitor" refers to, for example, anti-PD-1 antibodies (such as 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 (such as 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 and JS003, etc.), PD-1 antagonists (such as AUNP-12, each compound of BMS-M1 to BMS-M10 (see WO2014 / 151634, WO2016 / 039749, WO2016 / 057624, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 149351, WO2017 / 151830 and WO2017 / 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.each compound of Incyte-1 to Incyte-6 (see WO2017 / 070089, WO2017 / 087777, WO2017 / 106634, WO2017 / 112730, WO2017 / 192961 and WO2017 / 205464), each compound of CAMC-1 to CAMC-4 (see WO2017 / 202273, WO2017 / 202274, WO2017 / 202275 and WO2017 / 202276), RG_1 (see WO2017 / 118762) and DPPA-1 (Angew. Chem. Int. Ed.(see, for example, 2015, 54, 11760-11764), PD-L1 / VISTA antagonists (such as CA-170), PD-L1 / TIM3 antagonists (such as CA-327), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (such as AMP-224), anti-CTLA-4 antibodies (such as Ipilimumab, Zalifrelimab, Nurulimab, and Tremelimumab), anti-LAG-3 antibodies (such as Relatlimab, Ieramilimab, Fianlimab, Encelimab, and Mavezelimab), LAG-3 fusion proteins (such as IMP321), anti-Tim3 antibodies (such as MBG453 and Cobolimab), anti-KIR antibodies (such as Lirilumab, IPH2101, LY3321367, and MK-4280), anti-BTLA antibodies, anti-TIGIT antibodies (such as Tiragolumab, Etigilimab, Vibostolimab, and BMS-986207), anti-VISTA antibodies (such as Onvatilimab), anti-CSF-1R antibodies or CSF-1R inhibitors (such as Cabiralizumab, Emactuzumab, LY3022855, MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945, and ARRY-382), etc. Also, in this specification, a drug containing these substances as an active ingredient is referred to as an "immune checkpoint inhibitor". Note that 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] The "immune checkpoint inhibitor" in the present invention is preferably an anti-PD-1 antibody and an anti-PD-L1 antibody. In particular, 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. Examples of 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 include the following (1) to (12), namely, (1) The percentage (%) of CCR7-expressing cells in CD8 + T cells in the tumor tissue or blood of a malignant tumor patient, (2) The number of PD-1-expressing cells among the CD8 + T cells, the common logarithm of the number of expressing cells, or the common logarithm of the value obtained by adding 1 to the number of cells, (3) The ratio of the MFI of PD-1 expression in the same-derived Foxp3 + T cells to the MFI of PD-1 expression in the CD8 + T cells, or the square root value of the ratio, (4) The percentage (%) of PD-1-expressing cells in the same-derived Treg cells (Fr.III), (5) The percentage (%) of PD-1-expressing cells in the Foxp3 + T cells, (6) The percentage (%) of PD-1-expressing cells in the same-derived Treg cells (Fr.II), (7) The same-derived CD4 +Percentage of PD-1-expressing cells in T cells (%), (8) For the CD8 + Percentage of PD-1-expressing cells in T cells (%), (9) Ratio of the MFI of PD-1 expression in the Treg cells (Fr.II) to the MFI of PD-1 expression in the same-derived CD3 + cells or the square root value of the ratio, (10) For the CD4 + Percentage of PD-1-expressing cells in T cells (%), (11) For the Foxp3 + Value obtained by subtracting the MFI of PD-1 expression in CD8 + T cells from the MFI of PD-1 expression in the Foxp3 (12) Value obtained by subtracting the MFI of PD-1 expression in CD8 + T cells from the MFI of PD-1 expression in the Treg cells (Fr.II) are included.

[0161] In this specification, CD8 + T cells mean cells among T cells that are positive for the surface antigen CD8, and can be identified, for example, as CD3-positive, CD4-negative, and CD8-positive cells. In this specification, CD4 + T cells mean cells among T cells that are positive for CD4. In this specification, CD3 + cells mean cells that are positive for CD3. In this specification, Foxp3 + T cells mean cells among T cells that are positive for Foxp3.

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

[0163] In the present invention, examples of the "tumor tissue" from which immune cells constituting each evaluation item are collected include tissues containing at least the tumor mass itself, the invasive peripheral part of the tumor, or lymph nodes adjacent to the tumor, and can be collected by known methods, for example, forceps biopsy, aspiration biopsy, needle biopsy, surgical biopsy, or surgical operation for tumor resection. Further, in the present invention, examples of the "blood" from which immune cells constituting each evaluation item are collected include peripheral blood. The sample derived from the tumor tissue may be obtained by mechanically crushing the tumor tissue and then extracting it by a known method, and further, if necessary, immune cells constituting each evaluation item may be isolated and further purified. Also, the destruction of the tumor tissue may be by enzyme treatment. On the other hand, the sample derived from the blood may be the blood itself, and further, if necessary, immune cells constituting each evaluation item may be isolated and further purified by, for example, density gradient centrifugation.

[0164] In the present invention, CD8 + T cell count, CD4 + T cell count, Foxp3 + T cell count, the cell counts of Treg cells (Fr.II) and Treg cells (Fr.III), their PD-1 expressing cell counts, and the CCR7 expressing CD8 + T cell count can be measured and calculated by measurement methods such as flow cytometry or immunohistochemical staining. Specifically, monocytes isolated from tumor tissue, peripheral blood, etc. are stained with a fluorescent dye-labeled antibody. Here, the fluorescent dye-labeled antibody also includes staining with an unlabeled primary antibody and a fluorescent dye-labeled secondary antibody against it. The monocytes 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 above a certain threshold. For example, in flow cytometry measurement, when a negative control fluorescent dye-labeled antibody that does not recognize PD-1 is used, or when a fluorescent dye-labeled antibody for PD-1 is not used, it is not detected, and it is a cell population having a fluorescence intensity 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 CD8

[0166] In the present specification, "the proportion (%) of PD-1-expressing cells in CD8 + T cells" is synonymous with "the PD-1 expression ratio (%) of CD8 + cells" or "the PD-1 expression proportion (%) in CD8 + T cells", and the relationship between these definitions is the same for CD4 + T cells, Foxp3 + T cells, the proportion (%) of the number of PD-1-expressing cells in each of Treg cells (Fr.II) and Treg cells (Fr.III).

[0167] In the present 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 the case where there is no history of treatment with a drug containing the immune checkpoint inhibitor as an active ingredient and it is administered for the first time, but also the case before administration of the drug when there is a history of treatment with the immune checkpoint inhibitor or other anti-cancer drugs (including immune checkpoint inhibitors other than the immune checkpoint inhibitor).

[0168] As used herein, "about" means that the stated numerical value may vary by up to 10% below or above the stated value, or that it may also include values that round to the stated value.

[0169] As preferred combinations of two sets of evaluation items constituting the biomarker according to the present invention, there are the following combinations in (A) to (C), that is, (A)(1)(i) The percentage (%) of CCR7-expressing cells in CD8 + T cells in the tumor tissue or blood of a malignant tumor patient, or (ii) The number of PD-1-expressing cells among the CD8 + T cells, the common logarithm of the number of expressing cells, or the common logarithm of the value obtained by adding 1 to the number of cells, and (2) The ratio of the MFI of PD-1 expression in CD8 + T cells to the MFI of PD-1 expression in the same-derived Foxp3 + T cells, or the square root value of the ratio; (B)(1)(i) The percentage (%) of PD-1-expressing cells in Treg cells (Fr.III) in the tumor tissue or blood of a malignant tumor patient, (ii) The ratio of the MFI of PD-1 expression in CD8 + T cells to the MFI of PD-1 expression in the same-derived Foxp3 + T cells, or the square root value of the ratio, (iii) The percentage (%) of PD-1-expressing cells in the Foxp3 + T cells, (iv) The percentage (%) of PD-1-expressing cells in the same-derived Treg cells (Fr.II), and (v) The percentage (%) of PD-1-expressing cells in the same-derived CD4 + T cells, any one selected from these, and (2) The combination with the percentage (%) of PD-1-expressing cells in the CD8 + T cells; and (C)(1) The ratio of the MFI of PD-1 expression in CD3 cells derived from the same source to the MFI of PD-1 expression in Treg cells (Fr.II) in the tumor tissue or blood of a malignant tumor patient, or the square root value of the ratio, and + (2) The combination of the percentage (%) of PD-1-expressing cells in CD4 T cells derived from the same source. (2) The combination of the percentage (%) of PD-1-expressing cells in CD4 + T cells derived from the same source. Furthermore, in the combination of the two sets of predetermined evaluation items, specific conditions for identifying malignant tumor patients in whom the effect of an immune checkpoint inhibitor can be expected or cannot be expected can be determined in advance according to the following procedure. That is, (1) for a malignant tumor patient before administration of an immune checkpoint inhibitor, measure two sets of predetermined evaluation items, (2) administer the immune checkpoint inhibitor, (3) determine the effectiveness of the immune checkpoint inhibitor for each patient by a predetermined determination method, (4) plot each patient determined to be either effective or ineffective based on the measured values of the two sets of evaluation items, (5) when varying one or more discrimination lines (discrimination boundaries) that distinguish (discriminate) the effective group and the ineffective group at an arbitrary numerical value represented by the parameter α value (a numerical value of 0 ≤ α ≤ 1) in the weighted F-value (fα) (Weighted F-measure (fα)), which is one of the evaluation indicators in machine learning, derive a discrimination line that maximizes the numerical value of fα by machine learning, (6) determine the combination of one discrimination line or a plurality of discrimination lines derived for the two sets of evaluation items as specific conditions for identifying the malignant tumor patient by each of the two sets of evaluation items for each biomarker.

[0170] Here, fα is the following mathematical formula:

[0171]

Number

[0172] Although it can be calculated by the following formula, the α value in the formula can be determined as 0.5 when distinguishing between the two so as to include as many of the valid patients as possible and as few of the invalid patients as possible. For example, when the number of valid patients is large, the α value can be determined as 0.05 when distinguishing between the two so as to include as many of the valid patients as possible. On the other hand, when distinguishing between the two so as to include as few of the invalid patients as possible, the α value can be determined as 0.95, for example. Here, "Recall" in the formula means recall rate, which means the proportion of patients who are predicted to be valid in the validity determination among the patients who are actually valid. The following formula:

[0173] [Number]

[0174] [In the formula, "True-Positive" is the number of patients correctly predicted among the patients predicted to be valid in the binary classification classified according to whether the immune checkpoint inhibitor is effective or not, and "False-Negative" represents the number of patients mispredicted among the patients predicted to be invalid. It can be calculated by this formula. On the other hand, "Precision" in the formula for fα means precision rate, which means the proportion of patients who are actually valid among the patients predicted to be valid in the validity determination. The following formula:

[0175] [Number]

[0176] [In the formula, "False-Positive" represents the number of patients mispredicted among the patients predicted to be valid in the binary classification, and the other symbols have the same meaning as described above. It can be calculated by this formula.

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

[0178] The efficacy determination of the immune checkpoint inhibitor is determined based on, for example, Complete Response (CR), Partial Response (PR), Progressive Disease (PD), and Stable Disease (SD) when the cancer is a solid cancer, in accordance with the RECIST guidelines (Response Evaluation Criteria in Solid Tumor, 2000). For example, each patient with CR, PR, and SD may be judged as effective (hereinafter, may be described as the "Responder group"), and each patient with PD may be judged as ineffective (hereinafter, may be described as the "Non-Responder group"), or each patient with CR and PR may be judged as effective, and each patient with SD and PD may be judged as ineffective. Also, each patient with CR and PR and a patient in whom SD is maintained for at least 6 months may be judged as effective, and a patient with SD of less than 6 months and a patient with PD may be judged as ineffective. The determination based on the same criteria may be made, for example, at a time point from the start of treatment by administration of the immune checkpoint inhibitor up to 12 months, preferably up to 10 months, more preferably at the time point of 8 months, and even more preferably at the time point of 6 months. Also, it can be determined whether it is effective or ineffective based on the overall response rate (ORR), progression-free survival (PFS), overall survival (OS), survival rate, or median survival period. In some cases, a patient with PFS maintained for 70 days may be judged as effective, while a patient with PFS of less than 70 days may be judged as ineffective.

[0179] Biomarker 1 As the two sets of evaluation items, the percentage of CCR7-expressing cells (%) in CD8 + T cells in tumor tissue or blood and the ratio of the mean fluorescence intensity (MFI) of PD-1 expression in the same-derived Foxp3 + T cells to the MFI of PD-1 expression in the CD8 + T cells were selected. When the ratio of the MFI of PD-1 expression in the CD8

[0180]

Equation

[0181] [In the formula, Y1 represents the percentage of CCR7-expressing cells (%) in the CD8 + T cells, a 1-1 represents a numerical value of approximately -637, X1 represents 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, and Y 1-1 represents an arbitrary numerical value from approximately 784 to approximately 914.], or (2) (i) the following formula:

[0182]

Equation

[0183] [In the formula, a 1-2 represents a numerical value of approximately -24.0, Y 1-2 represents an arbitrary numerical value from approximately 39.0 to approximately 50.9, and the other symbols have the same meaning as described above.], and (ii) the following formula:

[0184]

Equation

[0185] [In the formula, a 1-3 represents a numerical value of approximately 666, Y 1-3represents any numerical value from approximately -652 to approximately -522, and the other symbols represent the same meanings as described above. Malignant tumor patients who satisfy the two conditions represented by [] can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, and patients who do not satisfy the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor is less expected.

[0186] Here, Y in the above formula 1-1 is preferably any numerical value from approximately 784 to approximately 853 or any numerical value from approximately 853 to approximately 914, more preferably approximately 853, and Y 1-2 is preferably any numerical value from approximately 44.6 to approximately 50.9 or any numerical value from approximately 39.0 to approximately 44.6, more preferably approximately 44.6, and Y 1-3 is preferably any numerical value from approximately -591 to approximately -522 or any numerical value from approximately -652 to approximately -591, preferably approximately -591. 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, and when the α value is 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 0.5, Y 1-1 Y 1-2 and Y 1-3 are approximately 853, approximately 44.6, and approximately -591 respectively. However, in selecting malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, the combination of the above conditions (the combination of the segmented straight lines represented by the three solid lines in Figure 1) defined by the numerical values of Y 1-1 Y 1-2 and Y 1-3 when the α value is 0.5 is most preferred.

[0187] Biomarker 2 As the two sets of evaluation items, Treg cells (Fr.III) and CD8 in tumor tissue or blood +When selecting the percentage (%) of PD-1-expressing cells in each T cell, (1) the following formula:

[0188]

Equation

[0189] [In the formula, Y2 represents the percentage (%) of PD-1-expressing cells in the Treg cell (Fr.III), a 2-1 represents a numerical value of about 0.765, X2 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cell, and Y 2-1 represents any numerical value from about 50.6 to about 59.2.], or (2) the following formula:

[0190]

Equation

[0191] [In the formula, a 2-2 represents a numerical value of about 1.56, Y 2-2 represents any numerical value from about -44.1 to -14.5, and the other symbols have the same meaning as described above.]. Malignant tumor patients who satisfy the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, and patients who do not satisfy the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor cannot be more expected.

[0192] Here, Y 2-1 in the above formula is preferably any numerical value from about 50.6 to about 54.1 or any numerical value from about 54.1 to about 59.2, more preferably about 54.1, and Y 2-2 is preferably any numerical value from about -26.6 to -14.5 or any numerical value from about -44.1 to about -26.6, 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 0.05, Y 2-1 and Y 2-2 are approximately 50.6 and approximately -14.5, respectively. When the α value is 0.5, Y 2-1 and Y 2-2 are approximately 54.1 and approximately -26.6, respectively. However, in selecting patients with malignant tumors for whom the effect of the immune checkpoint inhibitor can be more expected, the combination of the above conditions (the combination of the two solid lines in Figure 2 representing the sectional straight lines) defined by the numerical values of the Y 2-1 and Y 2-2 is most preferable.

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

[0194]

Number

[0195] [In the formula, Y3 represents the number of PD-1-expressing cells in the CD8 + T cells, a 3-1 represents a numerical value of approximately -1.59, X3 represents 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 same-derived Foxp3 + T cells, and Y 3-1 represents any numerical value from approximately 4.09 to approximately 4.89.] Or (ii) the following mathematical formula:

[0196]

Number

[0197] The condition represented by "wherein all symbols have the same meaning as described above", or the following formula (2)(i):

[0198]

Number

[0199] [wherein, a 3-2 represents a numerical value of about -9.05, Y 3-2 represents an arbitrary numerical value of about 10.7 to 13.3, and the other symbols have the same meaning as described above.] or (ii) the following formula:

[0200]

Number

[0201] [wherein all other symbols have the same meaning as described above.] A patient with a malignant tumor satisfying the condition can be selected as a patient with a malignant tumor in whom the effect of the immune checkpoint inhibitor can be more expected, and a patient not satisfying the condition can be selected as a patient with a malignant tumor in whom the effect of the immune checkpoint inhibitor can be less expected.

[0202] Here, Y in the above formula 3-1 is preferably an arbitrary numerical value of about 4.09 to about 4.42 or an arbitrary numerical value of about 4.42 to about 4.89, more preferably about 4.42, and Y 3-2 is preferably an arbitrary numerical value of about 11.7 to about 13.3 or an arbitrary numerical value of about 10.7 to about 11.7, 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 about 4.89 and about 13.3 respectively, and when the α value is 0.05, Y 3-1 and Y 3-2 are about 4.09 and about 10.7 respectively. When the α value is 0.5, Y 3-1 and Y 3-2are approximately 4.42 and approximately 11.7, respectively. However, when selecting patients with malignant tumors who can more hopefully expect the effects of the immune checkpoint inhibitor, when the α value is 0.5, the above-mentioned Y 3-1 and Y 3-2 The combination of the above conditions defined by the numerical values (the combination of the two solid lines in Figure 3 representing the piecewise straight lines) is most preferable.

[0203] Biomarker 4 As the two sets of evaluation items, the ratio of the mean fluorescence intensity (MFI) of PD-1 expression in CD8 + T cells to that in Foxp3 + T cells in tumor tissue or blood, and the percentage (%) of PD-1-expressing cells in the CD8 + T cells were selected. When (1) the following formula:

[0204]

Equation

[0205] [In the formula, Y4 represents the square root value of the ratio of the MFI of PD-1 expression in CD8 + T cells to that in Foxp3 + T cells, a 4-1 represents a numerical value of approximately -0.00273, X4 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cells, and Y 4-1 represents any numerical value from approximately 0.905 to approximately 1.46.], or (2) the following formula:

[0206]

Equation

[0207] [In the formula, a 4-2 represents a numerical value of approximately -0.0294, and Y 4-2represents any numerical value from approximately 2.18 to 3.31, and other symbols represent the same meaning as described above. Malignant tumor patients who satisfy the conditions represented by [ ] can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, and patients who do not satisfy the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be less expected.

[0208] Here, Y in the above formula 4-1 is preferably any numerical value from approximately 0.905 to approximately 1.18 or any numerical value from approximately 1.18 to approximately 1.46, more preferably approximately 1.18, and Y 4-2 is preferably any numerical value from approximately 2.74 to approximately 3.31 or any numerical value from approximately 2.18 to approximately 2.74, more preferably approximately 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 approximately 3.31 respectively, and when the α value is 0.05, Y 4-1 and Y 4-2 are approximately 0.905 and approximately 2.18 respectively. When the α value is 0.5, Y 4-1 and Y 4-2 are approximately 1.18 and approximately 2.74 respectively. However, in selecting malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, the combination of the above conditions (the combination of the two solid lines in FIG. 4 representing the dividing straight lines) defined by the numerical values of Y 4-1 and Y 4-2 when the α value is 0.5 is most preferred.

[0209] Biomarker 5 As the two sets of evaluation items, when the percentage of PD-1-expressing cells (%) in each of Foxp3 + T cells and CD8 + T cells in tumor tissue or blood is selected, the following mathematical formula:

[0210]

Equation

[0211] [wherein, Y5 represents Foxp3 + represents the percentage of PD-1-expressing cells in T cells, a5 represents a numerical value of about 2.34, and X5 represents CD8 + represents the percentage of PD-1-expressing cells in T cells, and Y 5-1 represents any numerical value from about -117 to about 131. A patient with a malignant tumor satisfying the condition represented by [] can be selected as a patient with a malignant tumor in whom the effect of the immune checkpoint inhibitor can be more expected, and a patient not satisfying the condition can be selected as a patient with a malignant tumor in whom the effect of the immune checkpoint inhibitor cannot be more expected.

[0212] Here, Y in the above formula 5-1 is preferably any numerical value from about -117 to about -54.4 or any numerical value from about -54.4 to 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 α value is 0.05, Y 5-1 is about 131. When the α value is 0.5, Y 5-1 is about -54.4. However, in selecting a patient with a malignant tumor in whom the effect of the immune checkpoint inhibitor can be more expected, the above condition (the segmented straight line represented by the solid line in FIG. 5) defined by the numerical value of Y 5-1 when the α value is 0.5 is most preferable.

[0213] Biomarker 6 When selecting the percentage of PD-1-expressing cells (%) in each of Treg cells (Fr.II) and CD8 + T cells in tumor tissue or blood as the two sets of evaluation items, (1) the following mathematical formula:

[0214]

Number

[0215] [wherein, Y6 represents the percentage (%) of PD-1-expressing cells in the Treg cells (Fr.II), and a 6-1 represents a numerical value of about 1.69, X6 represents the percentage (%) of PD-1-expressing cells in the CD8 + T cells, and Y 6-1 represents any numerical value from about 21.4 to about 44.1.], or (2) the following mathematical formula:

[0216]

Number

[0217] [wherein, a 6-2 represents a numerical value of about 1.78, Y 6-2 represents any numerical value from about -80.6 to about -21.0, and the other symbols have the same meaning as described above.], a malignant tumor patient satisfying the condition can be selected as a malignant tumor patient in whom the effect of the immune checkpoint inhibitor can be more expected, and a patient not satisfying the condition can be selected as a malignant tumor patient in whom the effect of the immune checkpoint inhibitor cannot be more expected.

[0218] Here, Y 6-1 in the above formula is preferably any numerical value from about 21.4 to about 31.8 or any numerical value from about 31.8 to about 44.1, more preferably about 31.8, and Y 6-2 is preferably any numerical value from about -48.2 to about -21.0 or any numerical value from about -80.6 to about -48.2, 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 about 44.1 and about -80.6, respectively, and when the α value is 0.05, Y 6-1 and Y 6-2 are about 21.4 and about -21.0, respectively. When the α value is 0.5, Y 6-1 and Y 6-2 are about 31.8 and about -48.2, respectively. However, in selecting a malignant tumor patient in whom the effect of the immune checkpoint inhibitor can be more expected, the Y when the α value is 0.56-1 and Y 6-2 The combination of the above conditions defined by the numerical values (the combination of the divided straight lines represented by the two solid lines in FIG. 6) is most preferable.

[0219] Biomarker 7 As the two sets of evaluation items, when selecting the percentage of PD-1-expressing cells (%) in each of CD4 + T cells and CD8 + T cells, (1) the following formula:

[0220] [Equation]

[0221] [wherein, Y7 represents the percentage of PD-1-expressing cells (%) in the CD4 + T cells, X7 represents the percentage of PD-1-expressing cells (%) in the CD8 + T cells, a 7-1 represents a numerical value of about 0.227, and Y 7-1 represents any numerical value from about -13.9 to about 4.03.], or (2) the following formula:

[0222] [Equation]

[0223] [wherein, a 7-2 represents a numerical value of about 3.32, and Y 7-2 represents any numerical value from about -199 to about 58.2, and the other symbols have the same meanings as described above.], malignant tumor patients satisfying the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, and patients not satisfying the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor cannot be more expected.

[0224] Here, Y in the above formula 7-1Preferably, it is any numerical value from about -13.9 to about -6.56 or any numerical value from about -6.56 to about 4.03, more preferably about -6.56, Y 7-2 Preferably, it is any numerical value from about -93.5 to about 58.2 or any numerical value from about -199 to about -93.5, 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 about -13.9 and about -199 respectively. When the α value is 0.05, Y 7-1 and Y 7-2 are about 4.03 and about 58.2 respectively. When the α value is 0.5, Y 7-1 and Y 7-2 are about -6.56 and about -93.5 respectively. However, in selecting malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, the Y 7-1 and Y 7-2 The combination of the above conditions defined by the numerical values (the combination of the two solid lines in FIG. 7 representing the segmented straight lines) is most preferred.

[0225] Biomarker 8 As the two sets of evaluation items, the ratio of the MFI of PD-1 expression in CD3 + cells to the MFI of PD-1 expression in the same-derived CD3 + cells and the percentage (%) of PD-1-expressing cells in the same-derived CD4

[0226]

Equation

[0227] [In the formula, Y8 represents the square root value of the ratio of the MFI of PD-1 expression in the CD3 + cells to the MFI of PD-1 expression in the Treg cells (Fr.II), a 8-1 represents a numerical value of about -0.00338, a 8-2represents a numerical value of approximately 0.270, and X8 represents the proportion (%) of PD-1-expressing cells in the CD4 + T cells, and Y 8-1 represents any numerical value from approximately 0.939 to approximately 1.37, and Y 8-2 represents any numerical value from approximately -6.98 to approximately -0.654. A malignant tumor patient who satisfies the conditions represented by [] can be selected as a malignant tumor patient in whom the effect of the immune checkpoint inhibitor can be more expected, and a patient who does not satisfy the conditions can be selected as a malignant tumor patient in whom the effect of the immune checkpoint inhibitor cannot be more expected.

[0228] Here, Y in the above formula 8-1 is preferably any numerical value from approximately 0.939 to approximately 1.17 or any numerical value from approximately 1.17 to approximately 1.37, more preferably approximately 1.17, and Y 8-2 is preferably any numerical value from approximately -4.10 to approximately -0.654 or any numerical value from approximately -6.98 to approximately -4.10, more preferably approximately -4.10. 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 0.05, Y 8-1 and Y 8-2 are approximately 0.939 and approximately -0.654, respectively. When the α value is 0.5, Y 8-1 and Y 8-2 are approximately 1.17 and approximately -4.10, respectively. However, in selecting a malignant tumor patient in whom the effect of the immune checkpoint inhibitor can be more expected, the combination of the above conditions (the combination of the divided straight lines represented by the two solid lines in FIG. 8) defined by the numerical values of the Y 8-1 and Y 8-2 at this time is most preferred.

[0229] Biomarker 9 As an evaluation item, Foxp3 in tumor tissue or blood + The MFI of PD-1 expression in T cells is used to determine the same-derived CD8 +When selecting the value obtained by subtracting the MFI of PD-1 expression in T cells, the following formula:

[0230]

Number

[0231] [In the formula, Y 9-1 represents the MFI of PD-1 expression in the Foxp3 + T cells, Y 9-2 represents the MFI of PD-1 expression in the CD8 + T cells, and a9 represents any numerical value from approximately -716 to approximately 166 (cut-off value).] Malignant tumor patients who satisfy the conditions represented by this can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor can be more expected, and patients who do not satisfy the conditions can be selected as malignant tumor patients in whom the effect of the immune checkpoint inhibitor cannot be more expected.

[0232] Here, as a9 in the above formula, it is preferably any numerical value from approximately -462 to approximately 166 or from approximately -716 to approximately -3.96, more preferably any numerical value from approximately -462 to approximately -3.96, and even more preferably approximately -208.

[0233] Biomarker 10 As an evaluation item, when selecting the value obtained by subtracting the MFI of PD-1 expression in CD8 + T cells from the MFI of PD-1 expression in Treg cells (Fr.II) in tumor tissue or blood, the following formula:

[0234]

Number

[0235] [In the formula, Y 10-1 represents the MFI of PD-1 expression in the Treg cells (Fr.II), Y 10-2 represents the MFI of PD-1 expression in the CD8 + T cells, and a10 represents any numerical value from approximately -842 to approximately 133 (cut-off value). A malignant tumor patient who satisfies the condition represented by [the formula] can be selected as a malignant tumor patient in whom the effect of the immune checkpoint inhibitor can be more expected, and a patient who does not satisfy the condition can be selected as a malignant tumor patient in whom the effect of the immune checkpoint inhibitor is less expected.

[0236] Here, a in the above formula 10 is preferably any numerical value from approximately -505 to approximately 133 or from approximately -842 to approximately -2.40, more preferably any numerical value from approximately -505 to approximately -2.40, and even more preferably approximately -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 mucosa epithelium, or intraorbital region), 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 cancer (e.g., clear cell renal cell cancer), 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 corpus cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (colon and rectal cancer) (e.g., MSI-H and / or dMMR-positive colon and rectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvic cancer, and urethral cancer), prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, skin cancer (e.g., choroidal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, 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 sarcoma, pediatric rhabdomyosarcoma, uterine corpus leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma), and Kaposi sarcoma.

[0238] On the one hand, when it comes to blood cancers, for example, one or more cancers selected from multiple myeloma, malignant lymphoma (e.g., non-Hodgkin lymphoma (e.g., follicular lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, MALT lymphoma, lymphoplasmacytic lymphoma, 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 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 are included.

[0239] As used herein, "treatment of malignant tumors" includes, for example, (i) reducing the proliferation of tumor cells, (ii) reducing the symptoms caused by malignant tumors, (iii) improving the quality of life of patients with malignant tumors, (iv) reducing the dosage of other anti-malignant tumor drugs or cancer treatment adjuvants already administered, and / or (v) performing treatment to extend the survival of patients with malignant tumors. "Inhibiting the progression of malignant tumors" means delaying the progression of malignant tumors, stabilizing the symptoms associated with malignant tumors, and regressing the progression of symptoms. Also, "inhibiting the recurrence of malignant tumors" means prophylactically suppressing the recurrence of malignant tumors in patients in whom cancer lesions have been completely or substantially eliminated or removed by treatment of malignant tumors or surgical resection of malignant tumors.

[0240] In the present invention, the immune checkpoint inhibitor satisfies the conditions of at least one of Biomarkers 1 to 10 according to the present invention, and is prescribed to the following patients with malignant tumors, namely, (a) patients with malignant tumors in whom the therapeutic effect of other anti-cancer drugs is insufficient or not sufficient, or patients with malignant tumors that have worsened after treatment with other anti-cancer drugs; (b) patients with malignant tumors that are inoperable for radical cure or resection, metastatic, recurrent, refractory and / or distant metastatic; (c) patients with malignant tumors in which TPS or CPS is 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 are positive for BRAF V600E mutation; (f) patients with malignant tumors that are positive for EGFR gene mutation or ALK fusion gene; or (g) patients with malignant tumors in which TMB is frequent.

[0241] On the other hand, in the present invention, the immune checkpoint inhibitor satisfies the conditions of at least one of Biomarkers 1 to 10 according to the present invention, and is more likely to be prescribed to the following patients with malignant tumors, namely, (a) patients with malignant tumors who have no history of treatment with other anti-cancer drugs; (b) patients with malignant tumors in which 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 malignant melanoma or non-small cell lung cancer that are BRAF V600 wild type; (e) patients with non-small cell lung cancer that are negative for EGFR gene mutation and / or ALK fusion gene; or (f) patients with malignant tumors in which TMB is infrequent.

[0242] Furthermore, it can also be prescribed as an adjuvant therapy for preventing recurrence or metastasis after surgical resection of malignant tumors or as neoadjuvant therapy performed before surgical resection.

[0243] Here, the "other anti-cancer drugs" include the anti-cancer drugs listed in the section on [Combined and Formulated Agents] below, namely, alkylating agents, platinum preparations, antimetabolites (e.g., folic acid antimetabolites, pyridine metabolism inhibitors, purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormonal drugs, molecular target drugs, and cancer immunotherapy drugs, each exemplified drugs. Also, "the therapeutic effect of the anti-cancer drug is insufficient or not sufficient" means, for example, in RECIST, when it is determined to be stable (SD) or progressive (PD) even by treatment with the anti-cancer drug.

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

[0245] For example, in the case of Nivolumab, an anti-PD-1 antibody, it is administered at the following usage and dosage. That is, for adults, as Nivolumab, (1) 1 mg / kg (body weight) once at 3-week intervals, (2) 3 mg / kg (body weight) once at 2-week intervals, (3) 2 mg / kg (body weight) once at 3-week intervals, (4) 80 mg once at 3-week intervals, (5) 240 mg once at 2-week intervals, (6) 360 mg once at 3-week intervals, or (7) 480 mg once at 4-week intervals can be administered by intravenous drip injection.

[0246] In particular, for patients with malignant melanoma, Nivolumab is administered by intravenous drip injection at a dose of 3 mg / kg (body weight) once every two weeks or 2 mg / kg (body weight) once every three weeks. For patients with non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, head and neck cancer, gastric cancer, and malignant pleural mesothelioma, Nivolumab is administered by intravenous drip injection at a dose of 3 mg / kg (body weight) once every two weeks. As another dosage regimen, for example, for 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, Nivolumab is administered by intravenous drip injection at a dose of 240 mg once every two weeks or 480 mg once every four weeks. Furthermore, as another dosage regimen, for example, in combination with Ipilimumab (intravenous drip injection 4 times at a dose of 3 mg / kg (body weight) once a day every three weeks) for patients with malignant melanoma, Nivolumab is administered by intravenous drip injection 4 times at a dose of 1 mg / kg (body weight) every three weeks, and then Nivolumab is administered by intravenous drip injection at a dose of 3 mg / kg (body weight) once every two weeks, or Nivolumab is administered by intravenous drip injection 4 times at a dose of 80 mg every three weeks, and then Nivolumab is administered by intravenous drip injection at a dose of 240 mg once every two weeks or 480 mg once every four weeks. Also, for example, in combination with Ipilimumab (intravenous drip injection 4 times at a dose of 1 mg / kg (body weight) once a day every three weeks) for patients with renal cell carcinoma or MSI-H or dMMR-positive colorectal cancer, Nivolumab is administered by intravenous drip injection 4 times at a dose of 240 mg every three weeks, and then Nivolumab is administered by intravenous drip injection at a dose of 240 mg once every two weeks or 480 mg once every four weeks.

[0247] In the case of Pembrolizumab, which is the same anti-PD-1 antibody, for adults, as Pembrolizumab, it can be administered by intravenous drip injection at a dose of (1) 200 mg once every 3 weeks, (2) 400 mg once every 6 weeks, or (3) 2 mg / kg (body weight) (with a maximum of 200 mg per single dose) once every 3 weeks. In particular, for each patient with malignant melanoma, non-small cell lung cancer, small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H solid cancer or colorectal cancer, urothelial cancer, cervical cancer, endometrial cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, gastric cancer, esophageal cancer, and Merkel cell carcinoma, as Pembrolizumab, it is administered by intravenous drip injection at a dose of 200 mg once every 3 weeks or 400 mg once every 6 weeks. Also, as another dosage regimen, for example, for each patient with classical Hodgkin lymphoma, MSI-H solid cancer or colorectal cancer, primary mediastinal B-cell lymphoma, and Merkel cell carcinoma in children aged 2 years or older, as Pembrolizumab, it is administered by intravenous drip injection at a dose of 2 mg / kg (body weight) (up to 200 mg per single dose) once every 3 weeks.

[0248] In the case of Cemiplimab-rwlc, which is also the same anti-PD-1 antibody, for adults, as Cemiplimab-rwlc, it can be administered by intravenous drip injection at a dose of 350 mg once every 3 weeks. In particular, for patients with squamous cell carcinoma, it is administered with the same dosage regimen.

[0249] On the one hand, in the case of Avelumab, an anti-PD-L1 antibody, for adults, Avelumab can be administered by intravenous infusion at a dose of 10 mg / kg (body weight) once every two weeks. In particular, for patients with Merkel cell carcinoma, Avelumab is administered by intravenous infusion at a dose of 10 mg / kg (body weight) once every two weeks. Also, for patients with renal cell carcinoma, in combination with Axitinib, it is administered at the same dosage and administration schedule. In the case of Atezolizumab, the same PD-L1 antibody, for adults, Atezolizumab is administered by intravenous infusion (1) at a dose of 840 mg once every two weeks, (2) at a dose of 1200 mg once every three weeks, or (3) at a dose of 1680 mg once every four weeks. In particular, for patients with previously treated non-small cell lung cancer or small cell lung cancer and urothelial cancer, Atezolizumab is administered at the same dosage and administration schedule as above. Here, for untreated non-small cell lung cancer, in combination with other anti-cancer agents (Bevacizumab, Paclitaxel, and Carboplatin), and for untreated small cell lung cancer, in combination with other anti-cancer agents (Carboplatin and Etoposide), it is administered at a dose of 1200 mg once every three weeks, respectively. Also, for patients with triple-negative breast cancer, in combination with Paclitaxel, Atezolizumab is administered by intravenous infusion at a dose of 840 mg once every two weeks.

[0250] Furthermore, in the case of Durvalumab, the same PD-L1 antibody, for patients with non-small cell lung cancer and bladder cancer, Durvalumab is administered by intravenous infusion at a dose of 10 mg / kg (body weight) once every two weeks.

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

[0252] [Combination and formulation agents] The therapeutic agent and the like of the present invention may be used in combination with one or more other agents (mainly anti-cancer drugs) used for the treatment purpose of the above-mentioned malignant tumors for (1) suppressing the progression of malignant tumors, suppressing recurrence and / or enhancing the therapeutic effect, (2) reducing the dosage of other drugs used in combination, and / or (3) reducing the side effects of other drugs used in combination. In the present invention, the administration form in the case of formulating in combination with other drugs may be in the form of a formulation in which both components are formulated in one preparation, or in the form of administration as separate preparations. When the therapeutic agent and the like of the present invention and other drugs are administered separately, the therapeutic agent and the like of the present invention may be administered first, and then the other drug may be administered, or the other drug may be administered first, and then the therapeutic agent and the like of the present invention may be administered. Also, in the above administration, there may be a period during which both drugs are administered simultaneously for a certain period. Also, the administration methods of each drug may be the same or different. Depending on the nature of the drug, it can also be provided as a kit containing the therapeutic agent and the like of the present invention and other drugs. Here, the dosage of other drugs can be appropriately selected based on the clinically used dosage. Also, two or more arbitrary other drugs may be administered in an appropriate ratio in combination. Also, the above-mentioned other drugs include not only those found so far but also those to be found in the future.

[0253] Examples of main anti-cancer drugs, which can be cited as main examples of other drugs, include, for example, alkylating agents (such as Dacarbazine, Nimustine, Temozolomide, Fotemustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil, and Procarbazine, etc.), platinum preparations (such as Cisplatin, Carboplatin, Nedaplatin, and Oxaliplatin, etc.), antimetabolites (such as folic acid antimetabolites (such as Pemetrexed, Leucovorin, and Methotrexate, etc.), pyridine metabolism inhibitors (such as TS-1 (registered trademark), 5-fluorouracil, UFT, Carmofur, Doxifluridine, FdUrd, Cytarabine, and Capecitabine, etc.), purine metabolism inhibitors (such as Fludarabine, Cladribine, and Nelarabine, etc.)), ribonucleotide reductase inhibitors, nucleotide analogs (such as Gemcitabine, etc.), topoisomerase inhibitors (such as Irinotecan, Nogitecan, and Etoposide, etc.), microtubule polymerization inhibitors (such as Vinblastine, Vincristine, Vindesine, Vinorelbine, and Eribulin, etc.), microtubule depolymerization inhibitors (such as Docetaxel and Paclitaxel), anti-tumor antibiotics (such as Bleomycin, MitomycinC, doxorubicin, daunorubicin, idarubicin, etoposide, mitoxantrone, vinblastine, vincristine, peplomycin, amrubicin, aclarubicin, epirubicin, etc.), cytokine preparations (e.g., IFN-α2a, IFN-α2b, pegIFN-α2b, natural IFN-β, interleukin-2, etc.), anti-hormonal drugs (e.g., tamoxifen, fulvestrant, goserelin, leuprorelin, anastrozole, letrozole, exemestane, etc.), molecular target drugs, cancer immunotherapy drugs, and other antibody drugs, etc.

[0254] Here, examples of molecular target drugs include ALK inhibitors (such as Crizotinib, Ceritinib, Ensartinib, Alectinib, and Lorlatinib, etc.), BCR-ABL inhibitors (such as Imatinib and Dasatinib, etc.), EGFR inhibitors (such as Erlotinib, EGF816, Afatinib, Osimertinib mesilate, Gefitinib, and Rociletinib, etc.), B-RAF inhibitors (such as Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib, and Zanubrutinib (BGB-3111), etc.), VEGFR inhibitors (such as Bevacizumab, Apatinib, Lenvatinib, Aflibercept, and Axitinib, etc.), FGFR inhibitors (such as AZD4547, Vofatmab (B-701), Roblitinib (FGF401), and Pemigatinib (INCB054828), etc.), c-Met inhibitors (such as Savolitinib, merestinib, Capmatinib, INC280, and Glesatinib, etc.), Axl inhibitors (such as ONO-7475 and Bemcentinib (BGB324), etc.), MEK inhibitors (such as Cobimetinib, Binimetinib, Selumetinib, and Trametinib, etc.), CDK inhibitors (such as Dinaciclib, Abemaciclib, Palbociclib, and trilaciclib, etc.), BTK inhibitors (such as Ibrutinib and Acalabrutinib, etc.), PI3K-δ / γ inhibitors (such as Umbralisib (TGR-1202), Parsaclisib (INCB050465), and IPI-549, etc.), JAK-1 / 2 inhibitors (such as Itacitinib and Ruxolitinib, etc.), ERK inhibitors (such as SCH 900353, etc.), TGFbR1 inhibitors (such as Galunisertib, etc.), Cancer cell stemnessKinase inhibitors (e.g., Amcasertib, etc.), FAK inhibitors (e.g., Defactinib, etc.), Syk / FLT3 dual inhibitors (e.g., Mivavotinib (TAK-659), etc.), ATR inhibitors (e.g., Ceralasertib (AZD6738), etc.), Wee1 kinase inhibitors (e.g., Adavosertib (AZD1775), etc.), multi-tyrosine kinase inhibitors (e.g., Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib, and Midostaurin, etc.), mTOR inhibitors (e.g., Temsirolimus, Everolimus, Vistusertib, and Irinotecan, etc.), HDAC inhibitors (e.g., Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobinostat, and Valproate, etc.), PARP inhibitors (e.g., Niraparib, Olaparib, Veliparib, Rucaparib, and Beigene-290, etc.), aromatase inhibitors (e.g., Exemestane and Letrozole, etc.), EZH2 inhibitors (e.g., tazemetostat, etc.), galectin-3 inhibitors (e.g., Belapectin (GR-MD-02), etc.), STAT3 inhibitors (e.g., Napabucasin, etc.), DNMT inhibitors (e.g., Azacitidine), BCL-2 inhibitors (e.g., Navitoclax and Venetoclax, etc.), SMO inhibitors (e.g., Vismodegib, etc.), Hsp90 inhibitors (e.g., XL888, etc.), γ-tubulin specific inhibitors (e.g., Glaziovianin A and Plinabulin, etc.), 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, etc.), anti-HER3 antibodies (e.g., Duligotuzumab, Elgemtumab, Istiratumab, Lumretuzumab, Zenocutuzumab, Patritumab, Patritumab deruxtecan and Seribantumab, etc.), anti-CD40 antibodies (e.g., Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Ravagalimab, Selicrelumab, Teneliximab, ABBV-428 and APX005M, etc.), anti-CD70 antibodies (e.g., Cusatuzumab, Vorsetuzumab, Vorsetuzumab mafodotin and ARGX-110, etc.), 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, Navicixizumab 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 (such as Abituzumab, Etaracizumab, and Intetumumab, etc.), anti-EPCAM antibodies (such as Adecatumumab, Catumaxomab, Edrecolomab, Oportuzumab monatox, Citatuzumab bogatox, and Tucotuzumab celmoleukin, etc.), anti-CEACAM5 antibodies (such as 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 (such as Tinurilimab, etc.), anti-FGFR2 antibodies (such as Aprutumab, Aprutumab ixadotin, and Bemarituzumab, etc.), anti-CD44 antibodies (such as Bivatuzumab mertansine, etc.), anti-PSMA antibodies (such as Indium ( 111 In) capromab pendetide, 177 Lu-J591, and ES414, etc.), anti-Endoglin antibodies (such as Carotuximab, etc.), anti-IGF1R antibodies (such as Cixutumumab, Figitumumab, Ganitumab, Dalotuzumab, Teprotumumab, and Robatumumab, etc.), anti-TNFSF11 antibodies (such as Denosumab, etc.), anti-GUCY2C (such as Indusatumab vedotin, etc.), anti-SLC39A6 antibodies (such as Ladiratuzumab vedotin, etc.), anti-SLC34A2 antibodies (such as Lifastuzumab vedotin, etc.), anti-NCAM1 antibodies (such as Lorvotuzumab mertansine and N901, etc.), anti-ganglioside GD3 antibodies (such as Ecromeximab and Mitumomab, etc.), anti-AMHR2 antibodies (such as Murlentamab, etc.), anti-CD37 antibodies (such as 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, and Tilvestamab, etc.), anti-STEAP1 antibodies (e.g., Vandortuzumab vedotin, etc.), anti-CTAA16 antibodies (e.g., Technetium ( 99(e.g., votumumab), CLDN18 antibodies (e.g., Zolbetuximab), anti-GM3 antibodies (e.g., Racotumomab, FCGR1, and H22), anti-PSCA antibodies (e.g., MK-4721), anti-FN extra domain B antibodies (e.g., AS1409), anti-HAVCR1 antibodies (e.g., CDX-014), anti-TNFRSF4 antibodies (e.g., MEDI6383), 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 antibody (e.g., Amivantamab), anti-EPCAM-CD3 bispecific antibody (e.g., Solitomab and Catumaxomab), anti-Ang2-VEGF bispecific antibody (e.g., Vanucizumab), anti-HER2-CD3 bispecific antibody (e.g., Ertumaxomab), anti-HER3-IGF1R bispecific antibody (e.g., Istiratumab), anti-PMSA-CD3 bispecific antibody (e.g., Pasotuxizumab), anti-HER1-LGR5 bispecific antibody (e.g., Petosemtamab), anti-SSTR2-CD3 bispecific antibody (e.g., Tidutamab), anti-CD30-CD16A bispecific antibody (e.g., AFM13), IL3RA-CD3 bispecific antibody (e.g., Flotetuzumab and Vibecotamab), anti-GPRC5D-CD3 bispecific antibody (e.g., Talquetamab), anti-TNFRSF17-CD3 bispecific antibody (e.g., Teclistamab), anti-CLEC12A-CD3 bispecific antibody (e.g., Tepoditamab), anti-HER2-HER3 bispecific antibody (e.g., Zenocutuzumab), anti-CEA-CD3 bispecific antibody (e.g., Cibisatamab and RO6958688), anti-CD3-CD19 bispecific antibody (e.g., Duvortuxizumab and Blinatumomab), and anti-CD20-CD3 bispecific antibody (e.g., Plamotamab, Odronextamab, Mosunetuzumab, Glofitamab, Epcoritamab, and REGN1979).

[0255] In addition, examples of cancer immunotherapeutic agents 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, AMP-514, 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, Pacmilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, 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, each compound of 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, BMS-1166, each compound of Incyte-1 to Incyte-6, each compound of CAMC-1 to CAMC-4, 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 (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 antibody·GITR fusion proteins (such as Efaprinermin alfa, Efgivanermin alfa, MK-4166, INCAGN01876, INCAGN01876, GWN323, and TRX-518, etc.), anti-CD28 antibody, anti-CCR4 antibody (such as Mogamulizumab, etc.), anti-B7-H3 antibody (such as Enoblituzumab, Mirzotamab, Mirzotamab clezutoclax, and Omburtamab, etc.), anti-ICOS agonist antibody (such as Vopratelimab (JTX-2011) and GSK3359609, etc.), anti-CD4 antibody (such as 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 (such as CDX-1401, etc.), anti-SLAMF7 antibody (such as Azintuxizumab, Azintuxizumab vedotin, and Elotuzumab, etc.), anti-CD73 antibody (such as Oleclumab and BMS-986179, etc.), PEGylated IL-2 (such as Bempegaldesleukin (NKTR-214), etc.), anti-CD40 agonist antibody (such as ABBV-428, APX005M, and RO7009789, etc.), IDO inhibitor (such as Epacadostat, Indoximod, and BMS-986205, etc.), TLR agonist (such as Motolimod, CMP-001, G100, Tilsotolimod (IMO-2125), SD-101, and MEDI9197, etc.), adenosine A2A receptor antagonist (such as Preladenant, AZD4635, PBF 509, and CPI-444, etc.), anti-NKG2A antibody (such as Monalizumab, etc.), anti-CSF-1 antibody (such as PD0360324, etc.), immunopotentiator (such as PV-10, etc.), IL-15 superagonist (such as ALT-803, etc.),Examples include soluble LAG3 (such as Eftilagimod alpha (IMP321)), anti-CD47 antibodies / CD47 antagonists (such as ALX148), and IL-12 antagonists (such as M9241).

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

[0257] [Formulations] When the immune checkpoint inhibitor or immune checkpoint inhibitor drug according to the present invention is administered alone or in combination with other drugs, it is used in the form of solid oral preparations or oral liquid preparations for oral administration, sustained-release preparations or release-controlled preparations in oral administration, or injections, external preparations, inhalants or suppositories for parenteral administration.

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

[0259] The solid oral preparation may be used by mixing the immune checkpoint inhibitor according to the present invention as it is or, if necessary, with any one or more of excipients (such as lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), disintegrants (such as calcium carboxymethyl cellulose, etc.), lubricants (such as magnesium stearate, etc.), stabilizers and solubilizing agents (such as glutamic acid and aspartic acid, etc.) and formulating according to conventional methods. If necessary, it may be coated with a coating agent (such as sucrose, gelatin, hydroxypropyl cellulose and hydroxypropyl methylcellulose phthalate, etc.) or coated with two or more layers. Furthermore, it may be included in capsules made of substances that are easily absorbed in the body, such as gelatin.

[0260] For an oral liquid for oral administration, if necessary, it may contain any one or more of pharmaceutically acceptable aqueous solutions, suspending agents, emulsifying agents, syrups, elixirs, etc. Further, this liquid may further contain any one or more of wetting agents, sweeteners, flavoring agents, fragrances, preservatives, buffering agents, etc.

[0261] In addition, a sustained-release preparation for oral administration may contain, in addition to a sustained-release base, a binder, a thickening agent, etc. For example, gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, guar gum, gelatin, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose, or hydroxyethylmethyl cellulose, etc. may be used.

[0262] When used as an injection or an infusion for intravenous drip, the injection or the infusion may be in any form of an aqueous solution, a suspension, or an emulsion, and may also be formulated as a solid agent together with a pharmaceutically acceptable carrier so that it can be dissolved, suspended, or emulsified and used by adding a solvent at the time of use. As the solvent used for an injection or an infusion for intravenous drip, for example, distilled water for injection, physiological saline, glucose solution, and isotonic solutions (for example, solutions of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, and propylene glycol, etc.) can be used.

[0263] Here, examples of pharmaceutically acceptable carriers include stabilizers, solubilizing agents, suspending agents, emulsifying agents, 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 bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, and dibutylhydroxytoluene. Examples of solubilizing agents that can be used include alcohols (such as ethanol), polyalcohols (such as propylene glycol and polyethylene glycol), and nonionic surfactants (such as polysorbate 20 (registered trademark), polysorbate 80 (registered trademark), and HCO-50). Examples of suspending agents that can be used include glycerol monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, and sodium lauryl sulfate. Examples of emulsifying agents that can be used include gum arabic, sodium alginate, and tragacanth. Examples of soothing agents that can be used include benzyl alcohol, chlorobutanol, and sorbitol. Examples of buffers that can be used include phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, glutamate buffer, and epsilon-aminocaproic acid buffer. Examples of preservatives that can be used include methyl paraben, ethyl paraben, propyl paraben, butyl paraben, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax. Examples of antiseptics that can be used include benzalkonium chloride, paraben, and chlorobutanol. Examples of pH adjusters that can be used include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid.As antioxidants, for example, (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, 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 can be used.

[0264] Injections or infusions for drip infusion can be manufactured by sterilizing in the final step or by filtering and sterilizing using aseptic techniques such as a filter, and then filling into a sterile container. In addition, injections or infusions for drip infusion can also be used by dissolving a sterile powder (which may contain a powder of a pharmaceutically acceptable carrier) obtained by vacuum drying and freeze drying in an appropriate solvent at the time of use.

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

[0266] Sprays, inhalants, and sprays may contain, in addition to commonly used diluents, stabilizers such as sodium bisulfite and buffering agents that provide isotonicity, such as isotonic agents like sodium chloride, sodium citrate, or citric acid. The manufacturing method of sprays is described in detail, for example, in U.S. Patent Nos. 2868691 and 3095355.

[0267] Inhalants for parenteral administration include aerosols, inhalation powders, or inhalation solutions, and the inhalation solutions may be in a form that is dissolved or suspended in water or other appropriate media at the time of use.

[0268] These inhalants are manufactured according to known methods. For example, in the case of inhalation solutions, preservatives (such as benzalkonium chloride and parabens, etc.), coloring agents, buffering agents (such as sodium phosphate and sodium acetate, etc.), isotonic agents (such as sodium chloride and concentrated glycerin, etc.), thickening agents (such as carboxyvinyl polymer, etc.) and absorption promoters, etc. are appropriately selected as needed and prepared.

[0269] In the case of inhalation powders, lubricants (such as stearic acid and its salts, etc.), binders (such as starch and dextrin, etc.), excipients (such as lactose and cellulose, etc.), coloring agents, preservatives (such as benzalkonium chloride, parabens, etc.) and absorption promoters, etc. are appropriately selected as needed and prepared.

[0270] When administering an inhalation solution, usually a nebulizer (such as an atomizer and a nebulizer, etc.) is used. When administering an inhalation powder, usually an inhalation dispenser for powder drugs is used.

[0271] The ointment can be produced according to a known or commonly used formulation. For example, it is prepared by mixing or melting the immune checkpoint inhibitor according to the present invention in a base. The ointment base can be selected from those known or commonly used. For example, higher fatty acids or higher fatty acid esters (such as adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, and oleic acid ester, etc.), waxes (such as beeswax, spermaceti wax, and ceresin, etc.), surfactants (such as polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohols (such as cetanol, stearyl alcohol, and cetostearyl alcohol, etc.), silicone oils (such as dimethylpolysiloxane, etc.), hydrocarbons (such as hydrophilic petrolatum, white petrolatum, purified lanolin, and liquid paraffin, etc.), glycols (such as ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, and macrogol, etc.), vegetable oils (such as castor oil, olive oil, sesame oil, and turpentine oil, etc.), animal oils (such as mink oil, egg yolk oil, squalane, and squalene, etc.), water, absorption promoters, or anti-inflammatory agents are used alone or in combination of two or more. Furthermore, it may contain a humectant, a preservative, a stabilizer, an antioxidant, or a flavoring agent, etc.

[0272] The gel preparation can be manufactured according to a known or commonly used formulation. For example, it is prepared by melting the immune checkpoint inhibitor according to the present invention in a base. The gel base is selected from known or commonly used ones. For example, lower alcohols (such as ethanol and isopropyl alcohol, etc.), gelling agents (such as carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and ethyl cellulose, etc.), neutralizing agents (such as triethanolamine and diisopropanolamine, etc.), surfactants (such as polyethylene glycol monostearate, etc.), gums, water, absorption promoters, and anti-inflammatory agents are used alone or in combination of two or more. Furthermore, it may contain preservatives, antioxidants, flavoring agents, etc.

[0273] The cream preparation can be manufactured according to a known or commonly used formulation. For example, it is manufactured by melting or emulsifying the immune checkpoint inhibitor according to 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 (such as propylene glycol and 1,3-butylene glycol, etc.), higher alcohols (such as 2-hexyldecanol and cetyl alcohol, etc.), emulsifiers (such as polyoxyethylene alkyl ethers and fatty acid esters, etc.), water, absorption promoters, and anti-inflammatory agents are used alone or in combination of two or more. Furthermore, it may contain preservatives, antioxidants, flavoring agents, etc.

[0274] The wet compress agent can be produced according to a known or commonly used formulation. For example, the immune checkpoint inhibitor according to the present invention is melted in a base, spread and applied on a support as a kneaded product for production. The wet compress base can be selected from those known or commonly used. For example, thickeners (such as polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, and methylcellulose, etc.), wetting agents (such as urea, glycerin, and propylene glycol, etc.), fillers (such as kaolin, zinc oxide, talc, calcium, and magnesium, etc.), water, solubilizing agents, tackifiers, and anti-inflammatory agents are selected alone or in combination of two or more and used. Furthermore, it may contain preservatives, antioxidants, or flavoring agents, etc.

[0275] The patch can be produced according to a known or commonly used formulation. For example, the immune checkpoint inhibitor according to the present invention is melted in a base and spread and applied on a support for production. The base for the patch can be selected from those known or commonly used. For example, polymer bases, fats and oils, higher fatty acids, tackifiers, and anti-inflammatory agents are selected alone or in combination of two or more and used. Furthermore, it may contain preservatives, antioxidants, or flavoring agents, etc.

[0276] The liniment can be produced according to a known or commonly used formulation. For example, the immune checkpoint inhibitor according to the present invention is dissolved, suspended, or emulsified alone or in two or more selected from water, alcohols (such as ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soaps, emulsifiers, and suspending agents for preparation. Furthermore, it may contain preservatives, antioxidants, or flavoring agents, etc.

[0277] As other compositions for parenteral administration, suppositories for rectal administration and pessaries for vaginal administration, etc., which contain the immune checkpoint inhibitor according to the present invention and are formulated by conventional methods, are included.

[0278] [Inspection and Measurement Kit] The present invention also includes an invention related to a test or measurement kit for measuring evaluation items each constituting Biomarkers 1 to 10 according to the present invention. Each of the test or measurement kits is for CD8 + T cells, CD3 + T cells, Foxp3 + When measuring the MFI of PD-1 expression in each of T cells and Treg cells (Fr.II), for example, it may be based on flow cytometry. On the other hand, for CD8 + T cell count, CD4 + T cell count, Foxp3 + T cell count, the cell counts of Treg cells (Fr.II) and Treg cells (Fr.III), their PD-1-expressing cell counts, and the CCR7-expressing CD8 + T cell count, when measuring, it may be based on flow cytometry or immunohistochemistry. In any case, a test or measurement kit based on flow cytometry is preferred.

[0279] In this specification, the contents of all patent documents, non-patent documents or reference documents explicitly cited can all be cited here as part of this specification.

[0280] The present invention will be further described in detail by the following examples, but the scope of the present invention is not limited thereto. Various changes and modifications are possible for those skilled in the art based on the description of the present invention, and these changes and modifications are also included in the present invention.

Examples

[0281] Example 1: CD8 + Percentage of CCR7-expressing cells in T cells (%) and Foxp3 + T cells and CD8 + Confirmation of a biomarker for nivolumab efficacy determination based on the ratio of the mean fluorescence intensity (MFI) of PD-1 expression in each of the CD8 The number of CCR7-expressing cells in CD8 + T cells and the same CD8 + T cells and Foxp3 +The PD-1 expression in each T cell was measured by flow cytometry, and in CD8 + T cells, the percentage of CCR7-expressing cells (%) and in the Foxp3 + T cells, the ratio of the mean fluorescence intensity (MFI) of PD-1 expression in CD8 + T cells to the MFI of PD-1 expression was calculated. Among the above patients administered Nivolumab according to a predetermined prescription, for each of the Responder group (23 patients with PFS maintained for 70 days) and the Non-Responder group (22 patients with PFS less than 70 days), the percentage of the CCR7-expressing cells (%) of each patient was plotted on the vertical axis, and the square root value of the ratio was plotted on the horizontal axis (see Figure 1). The three solid lines in the figure are classification lines derived by machine learning such that when the α value is 0.5, the numerical value of the weighted F value (fα) is maximized, using the weighted F value (fα) as an index. When Nivolumab is hypothetically administered to 22 cancer patients plotted in the shaded closed region on the right side of the figure separated by the classification line, it was confirmed that the effect can be expected in 20 of them (effective rate: 90.9%).

[0282] T cells and CD8 + Confirmation of a biomarker for nivolumab efficacy determination based on the percentage of PD-1-expressing cells in each of the CD8 Before Nivolumab administration, the PD-1 expression in Treg cells (Fr.III) and CD8 + T cells derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) was measured by flow cytometry, and the percentage of PD-1 expression in those cells was calculated. Among the above patients administered Nivolumab according to a predetermined prescription, for each of the Responder group (23 patients) and the Non-Responder group (23 patients) (both groups are the same as defined in Example 1), 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 PD-1-expressing cells in CD8 + T cells was plotted on the horizontal axis (see Figure 2). The two solid lines in the figure are dividing lines derived by the same machine learning as described above. When Nivolumab is hypothetically administered to 27 cancer patients plotted in the shaded closed regions on the upper left and lower right sides of the figure separated by the dividing lines, it was confirmed that the effect could be expected in 22 of them (effective rate: 81.5%).

[0283] Example 3: CD8 + Number of PD-1-expressing cells in CD8 + T cells and CD8 + T cells and the ratio of the MFI of PD-1 expression in each of the CD8 The number of PD-1-expressing cells in CD8 + T cells derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) before Nivolumab administration, and the same CD8 + The expression of PD-1 in T cells and Foxp3 + The expression of PD-1 in each of the T cells was measured by flow cytometry, and the ratio of the MFI of PD-1 expression in the Foxp3 + T cells to the MFI of PD-1 expression in CD8 + T cells was calculated. Among the above patients administered Nivolumab according to a predetermined prescription, for each of the Responder group (23 patients) and the Non-Responder group (23 patients) (both groups are the same as defined in Example 1), the common logarithm of the value obtained by adding 1 to the number of PD-1-expressing cells of each patient was plotted on the vertical axis, and the square root value of the ratio was plotted on the horizontal axis (see Figure 3). The two solid lines in the figure are dividing lines derived by the same machine learning as described above. When Nivolumab is hypothetically administered to 22 cancer patients plotted in the shaded closed regions excluding the lower left side of the figure separated by the dividing lines, it was confirmed that the effect could be expected in 19 of them (effective rate: 86.4%).

[0284] Example 4: Foxp3 + T cells and CD8 + T cells and the ratio of the MFI of PD-1 expression in each of the CD8 + T cells and the percentage of PD-1-expressing cells in CD8 PD-1 expression in CD8 + T cells and Foxp3 + T cells from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) before nivolumab administration was measured by flow cytometry, and the ratio of the mean fluorescence intensity (MFI) of PD-1 expression in the Foxp3 + T cells to the MFI of PD-1 expression in CD8 + T cells and the percentage of PD-1-expressing cells (%) in CD8 + T cells were calculated. Among the above patients administered nivolumab according to a predetermined prescription, for each of the Responder group (23 patients) and the Non-Responder group (23 patients) (both groups are the same as the definitions in Example 1), the square root value of the ratio of each patient was plotted on the vertical axis, and the percentage (%) was plotted on the horizontal axis (see Figure 4). The two solid lines in the figure are the piecewise straight lines derived by the same machine learning as described above. When nivolumab is hypothetically administered to 22 cancer patients plotted in the shaded closed region excluding the lower left side of the figure, which is separated by the piecewise straight line, it was confirmed that the effect can be expected in 18 of them (effective rate: 81.8%).

[0285] Example 5: Foxp3 + T cells and CD8 + Confirmation of a biomarker for nivolumab efficacy determination based on the percentage of PD-1-expressing cells in each of the cells (Biomarker 5) PD-1 expression in Foxp3 + T cells and CD8 + T cells from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (17 cases) before nivolumab administration was measured by flow cytometry for each, and the percentage of PD-1-expressing cells (%) in each was calculated. Among the above patients administered nivolumab according to a predetermined prescription, for each of the Responder group (23 patients) and the Non-Responder group (23 patients) (both groups are the same as the definitions in Example 1), the percentage of PD-1-expressing cells (%) in Foxp3 + T cells was plotted on the vertical axis, and CD8+ The percentage of PD-1-expressing cells in cells (%) was plotted on the horizontal axis (see Figure 5). The solid line in the figure is a piecewise straight line derived by the same machine learning as described above. When Nivolumab is hypothetically administered to 28 cancer patients plotted in the shaded area on the right side of the figure separated by the piecewise straight line, it was confirmed that the effect can be expected in 21 of them (response rate: 75%).

[0286] Example 6: Treg cells (Fr.II) and CD8 + Confirmation of a biomarker for nivolumab efficacy determination based on the percentage of PD-1-expressing cells in each of the cells (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 + The PD-1 expression in each of Treg cells (Fr.II) and CD8 T cells was measured by flow cytometry, and the percentage of PD-1-expressing cells (%) in each was calculated. Among the above patients administered Nivolumab according to a predetermined prescription, for each of the Responder group (23 cases) and the Non-Responder group (23 cases) (both groups are the same as defined in Example 1), with the percentage of PD-1-expressing cells (%) in the Treg cells (Fr.II) of each patient on the vertical axis and the percentage of PD-1-expressing cells (%) in CD8 cells on the horizontal axis, a plot was made (see Figure 6). + The percentage of PD-1-expressing cells in cells (%) was plotted on the horizontal axis (see Figure 6). The two solid lines in the figure are piecewise straight lines derived by the same machine learning as described above. When Nivolumab is hypothetically administered to 22 cancer patients plotted in the shaded areas on the upper left and lower right sides of the figure separated by the piecewise straight lines, it was confirmed that the effect can be expected in 19 of them (response rate: 86.4%).

[0287] Example 7: CD4 + Cells and CD8 + Confirmation of a biomarker for nivolumab efficacy determination based on the percentage of PD-1-expressing cells in each of the cells (Biomarker 7) CD4 cells and CD8 derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) before Nivolumab administration + cells and CD8+ The 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 administered Nivolumab according to a predetermined prescription, for each of the Responder group (24 patients) and the Non-Responder group (23 patients) (both groups are the same as defined in Example 1), the CD4 + The percentage of PD-1-expressing cells in cells was plotted on the vertical axis, and the percentage of PD-1-expressing cells in CD8 + cells was plotted on the horizontal axis (see Figure 7). The two solid lines in the figure are piecewise straight lines derived by the same machine learning as above. When Nivolumab is hypothetically administered to 29 cancer patients plotted in the shaded area (excluding the upper left area in the figure) separated by the piecewise straight line, it was confirmed that the effect can be expected in 22 of them (effective rate: 75.9%).

[0288] Example 8: Treg cells (Fr.II) and CD3 + The ratio of the MFI of PD-1 expression in each of the cells and CD4 + T cells and the percentage of PD-1-expressing cells in CD4 The PD-1 expression in CD3 + cells, Treg cells (Fr.II), and CD4 + in T cells derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) before Nivolumab administration was measured by flow cytometry, and the ratio of the MFI of PD-1 expression in CD3 + cells to the MFI of PD-1 expression in the Treg cells (Fr.II) and the percentage of PD-1-expressing cells in CD4 + T cells were calculated. Among the above patients administered Nivolumab according to a predetermined prescription, for each of the Responder group (patients who were CR, PR, and SD, 22 patients) and the Non-Responder group (25 patients who were PD), the square root value of the ratio of each patient was plotted on the vertical axis, and the percentage was plotted on the horizontal axis (see Figure 8). The two solid lines in the figure are the classification lines derived by the same machine learning as described above. When Nivolumab is hypothetically administered to 21 cancer patients plotted in the shaded area in the upper left of the figure separated by the classification line, it was confirmed that the effect can be expected in 17 of them (effective rate: 81.0%).

[0289] Example 9: Foxp3 + T cells and CD8 + Confirmation of a biomarker for nivolumab efficacy determination based on the MFI of PD-1 expression in each of the CD8 Foxp3 derived from tumor tissues of gastric cancer patients (29 cases) and non-small cell lung cancer patients (18 cases) before Nivolumab administration + T cells and CD8 + The MFI of PD-1 expression in each of the T cells and CD8 + T cells was measured by flow cytometry, and a value obtained by subtracting the MFI of PD-1 expression in the CD8 + T cells from the MFI of PD-1 expression in the Foxp3 For each of the Responder group (12 patients who were CR or PR) and the Non-Responder group (35 patients who were SD or PD) among the above patients administered Nivolumab according to a predetermined prescription, the values of each patient were plotted (see Figure 9). The dotted line in the figure is the classification line derived by ROC analysis. When Nivolumab is hypothetically administered to 13 cancer patients showing values below the value (-208) indicated by the classification line (sensitivity = 0.833; specificity = 0.914 in ROC analysis), it was confirmed that the effect can be expected in 10 of them (effective rate: 76.9%).

[0290] Example 10: Treg cells (Fr.II) and CD8 + Confirmation of Biomarker for Nivolumab Efficacy Assessment 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 value obtained by subtracting the MFI of PD-1 expression in the Treg cells (Fr.II) from the MFI of PD-1 expression in the CD8 + T cell was calculated. For each of the Responder group (12 patients who were CR or PR) and the Non-Responder group (35 patients who were SD or PD) among the above patients administered Nivolumab according to a predetermined prescription, the numerical values of each patient were plotted (see Figure 10). The dotted line in the figure is the discrimination line derived by ROC analysis. When Nivolumab is hypothetically administered to 12 cancer patients showing numerical values below the value (-131) indicated by the discrimination line (sensitivity = 0.833; specificity = 0.943 in ROC analysis), it was confirmed that the effect could be expected in 10 of them (effective rate: 83.3%).

Industrial Applicability

[0291] By analyzing a specific combination of two sets of evaluation items of the present invention and specific conditions defined by each combination of these two sets, it is possible to identify malignant tumor patients in whom the effect of immune checkpoint inhibitors can be more expected.

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 + 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: [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.],

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. Treg cells (Fr.III) and CD8 in tumor tissues and blood of patients with malignant tumors + T cells (1) express the following formula: [0045] [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 from about 50.6 to about 59.2; or (2) the condition represented by the following formula: [0050] [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.],

4. Y 2-1 is about 54.1, and Y 2-2 The method of claim 3, wherein the pH is about -26.

6.

5. CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells (1) use the following formula: [006] [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: [0070] [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.],

6. Y 3-1 is about 4.42, and Y 3-2 The method of claim 5, wherein the β-amino acid salt is about 11.

7.

7. CD8 in tumor tissue or blood of patients with malignant tumors + T cells and Foxp3 + T cells (1) express the following formula: [0080] [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 following formula: [0090] [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.],

8. Y 4-1 is about 1.18, and Y 4-2 The method of claim 7, wherein the β-amino acid is about 2.

74.

9. Foxp3 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula: [0010] [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.],

10. Y 5-1 The method of claim 9, wherein the .alpha.-methyl-.alpha.-phenylalanine is about -54.

4.

11. Treg cells (Fr. II) and CD8 in tumor tissues or blood of patients with malignant tumors + T cells (1) express the following formula: ##EQU00011## [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: ##EQU00012## [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.],

12. Y 6-1 is about 31.8, and Y 6-2 The method of claim 11, wherein the .alpha.-amino acid salt is about -48.

2.

13. CD4 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells (1) express the following formula: ##EQU00013## [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 numerical value from about -13.9 to about 4.03; or (2) the condition represented by the following formula: ##EQU14## [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 about 58.2, and the other symbols have the same meanings as above.],

14. Y 7-1 is approximately -6.56, and Y 7-2 The method of claim 13, wherein the pH is about -93.

5.

15. CD3 in tumor tissue or blood of patients with malignant tumors + cells, Treg cells (Fr. II) and CD4 + T cells express the following formula: ##EQU00015## [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 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 number between about 0.939 and about 1.37; Y 8-2 represents any numerical value from about -6.98 to about -0.654.],

16. Y 8-1 is about 1.17, and Y 8-2 The method of claim 15, wherein the pH is about -4.

10.

17. Foxp3 in tumor tissue or blood of patients with malignant tumors + T cells and CD8 + T cells express the following formula: ##EQU00016## [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.] is administered to a patient with a malignant tumor who satisfies the condition represented by the above formula (1).

18. a 9 The method of claim 17, wherein the pH is about -208.

19. Treg cells (Fr. II) and CD8 in tumor tissues or blood of patients with malignant tumors + T cells express the following formula: ##EQU00017## [In the formula, Y 10-1 represents the MFI of PD-1 expression in 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.],

20. a 10 The method of claim 19, wherein the pH is about -131.

21. The agent according to any one of claims 1 to 20, wherein the malignant tumor patient is a patient prior to administration of a drug containing the immune checkpoint inhibitor as an active ingredient.

22. The agent according to any one of claims 1 to 21, 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.

23. 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 claim 22, which is 754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 or CX-188.

24. 23. The agent of claim 22, 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.

25. The method of claim 22, wherein the anti-CTLA-4 antibody is Ipilimumab, Zalifrelimab, Nurulimab or Tremelimumab.

26. The agent according to any one of claims 1 to 25, wherein the malignant tumor is a solid cancer or a blood cancer.

27. The agent according to claim 26, wherein the solid cancer is one or more cancers selected from malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell carcinoma, clear cell renal cell carcinoma, breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal cancer, uterine cancer, anal cancer, colorectal cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophago-gastric junction cancer, small intestine cancer, pancreatic cancer, urothelial carcinoma, prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer, testicular cancer, vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, brain tumor, squamous cell carcinoma, bone and soft tissue sarcoma, and Kaposi's sarcoma.

28. The agent according to any one of claims 1 to 27, wherein the malignant tumor patient has no history of treatment with other anti-malignant tumor drugs.

29. The agent according to any one of claims 1 to 28, wherein TPS or CPS is less than 50%, less than 25%, less than 10%, less than 5% or less than 1%.

30. The agent according to any one of claims 1 to 29, wherein the malignant tumor does not have MSI-H and / or dMMR.

31. The agent according to any one of claims 1 to 30, wherein the malignant tumor has a low TMB frequency.

32. (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 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 values ​​of said ratios.

33. Flow cytometry or immunohistochemistry revealed that Treg cells (Fr.III) and CD8 + The number of T cells and the number of PD-1 expressing cells were measured, and the Treg cells (Fr.III) and the CD8 + A method for identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors by determining the percentage (%) of PD-1 expressing cells in each T cell and based on the combination of these two percentages (%).

34. (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 immune checkpoint inhibitors, 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, by determining the MFI ratio of PD-1 expression in T cells.

35. (1) CD8 in samples derived from tumor tissue or blood of patients with malignant tumors, using flow cytometry or immunohistochemistry + T cells and Foxp3 + (2) PD-1 expression on T cells and the corresponding CD8 + (1a) measuring the number of T cells and the number of PD-1-expressing cells among the T cells, + 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 identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors, by determining the percentage (%) of PD-1 expressing cells in T cells and based on said ratio or a combination of said ratio and the square root of said ratio and said percentage (%).

36. Foxp3 in samples derived from tumor tissue or blood of patients with malignant tumors by flow cytometry or immunostaining + 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 identifying malignant tumor patients who are likely to benefit from immune checkpoint inhibitors by determining the percentage (%) of PD-1 expressing cells in each T cell and based on the combination of these two percentages (%).

37. Flow cytometry or immunohistochemistry was used to measure the expression of Treg cells (Fr. II) 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 were measured, and the Treg cells (Fr. II) and the CD8 + A method for identifying malignant tumor patients who are likely to benefit from immune checkpoint inhibitors by determining the percentage (%) of PD-1 expressing cells in each T cell and based on the combination of these two percentages (%).

38. CD4 counts in samples derived from tumor tissue or blood of patients with malignant tumors by flow cytometry or immunostaining + 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 identifying malignant tumor patients who are likely to benefit from immune checkpoint inhibitors by determining the percentage (%) of PD-1 expressing cells in each T cell and based on the combination of these two percentages (%).

39. (1) CD3 in samples derived from tumor tissue or blood of patients with malignant tumors, using flow cytometry or immunohistochemistry + (1) MFI of PD-1 expression in Treg cells (Fr.II) and (2) MFI of PD-1 expression in the same sample + The number of T cells and the number of PD-1 expressing cells among them 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 the cells and the CD4 + A method for identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors, by determining the percentage (%) of PD-1 expressing cells in T cells and based on said ratio or a combination of said ratio and the square root of said ratio and said percentage (%).

40. Foxp3 in samples derived from tumor tissue or blood of patients with malignant tumors by flow cytometry or immunostaining + T cells and CD8 in the same sample + 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 identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors based on said value.

41. Flow cytometry or immunostaining was used to measure the number of Treg cells (Fr. II) in samples derived from tumor tissue or blood of patients with malignant tumors, and the number of 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 identifying malignant tumor patients who are more likely to benefit from immune checkpoint inhibitors based on said value.

42. The method according to any one of claims 32 to 41, wherein the malignant tumor patient is a patient prior to administration of the immune checkpoint inhibitor.

43. (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 efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors.

44. (1) (i) The percentage (%) of PD-1 expressing cells in Treg cells (Fr.III) in tumor tissue or blood of malignant tumor patients; (ii) Foxp3 derived from the same + 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 T cells expressing PD-1 (%) (iv) The percentage (%) of PD-1 expressing cells in Treg cells (Fr. II) derived from the same mouse, and (v) CD4 + any one selected from the percentage (%) of PD-1 expressing cells in T cells, and (2) CD8 + Use of a combination of the percentage (%) of PD-1 expressing cells in T cells as a biomarker for predicting the efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence and / or treating malignant tumors.

45. (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 43.

46. The Treg cells (Fr.III) and CD8 + The use of a combination of each percentage (%) of PD-1 expressing cells in each T cell as a biomarker as described in claim 44.

47. (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 43.

48. (1) The CD8 + Foxp3 versus MFI of PD-1 expression in T cells + (2) the ratio of MFI of PD-1 expression on T cells or the square root of the ratio and the CD8 + The use of a combination of the percentage (%) of PD-1 expressing cells in T cells as a biomarker as described in claim 44.

49. Foxp3 + T cells and CD8 + The use of a combination of each percentage (%) of PD-1 expressing cells in each T cell as a biomarker as described in claim 44.

50. The Treg cells (Fr. II) and CD8 + The use of a combination of each percentage (%) of PD-1 expressing cells in each T cell as a biomarker as described in claim 44.

51. The CD4 + T cells and CD8 + The use of a combination of each percentage (%) of PD-1 expressing cells in each T cell as a biomarker as described in claim 44.

52. (1) MFI of PD-1 expression on Treg cells (Fr. II) in tumor tissue or blood of patients with malignant tumors versus CD3 + (2) the MFI ratio of PD-1 expression in cells or the square root of the ratio, and (3) CD4 + Use of the percentage (%) of PD-1 expressing cells in T cells as a biomarker for predicting the efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors.

53. Foxp3 in tumor tissue or 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 the efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors.

54. 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 the efficacy of immune checkpoint inhibitors in inhibiting progression, inhibiting recurrence, and / or treating malignant tumors.

55. The use according to any one of claims 43 to 54, wherein the malignant tumor patient is a patient prior to administration of the immune checkpoint inhibitor.

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