TW202021617A - Biomarker for predicting efficacy of immune checkpoint inhibitor - Google Patents

Abstract

The purpose of the present invention is to utilize blood PD-1 concentration as a biomarker for predicting a therapeutic effect of an immune checkpoint inhibitor on cancer, for evaluating cancer progression, or for predicting cancer recurrence. The present invention pertains to an agent for arresting cancer progression, for suppressing cancer recurrence, and/or for cancer treatment, the agent being characterized by containing an immune checkpoint inhibitor as an active ingredient and by being administered to cancer patients having a blood PD-1 concentration level less than a predetermined cutoff value.

Description

Biomarkers used to predict the effectiveness of immune checkpoint blocking drugs

The present invention relates to a biomarker for predicting the effectiveness of immune checkpoint blocking drugs for cancer patients, a biomarker for evaluating the progression of cancer, and a biomarker for patients with a high risk of recurrence of specific cancers.

Nowadays, the incidence of cancer in Japan is relatively high, and with this, the number of cases that eventually become advanced cancers and require comprehensive treatment of multiple disciplines has also increased. In recent years, as a treatment for advanced cancer, there are antibody medicines that use antibodies. However, because they are novel treatments, they are expensive and may cause adverse reactions to a certain degree. Therefore, it is desirable to be able to predict the effect of antibody medicine to a certain extent before administration. Currently, antibody medicines are conducting research to determine the expression levels of factors that become their targets in pathological tissues or blood, and to predict and determine their effects.

The anti-tumor effect of nivolumab, which is an anti-PD-1 (programmed death-1) antibody, has been demonstrated in multiple types of cancer tumors (refer to Patent Document 1), but whether it is judged according to the case The effective benchmark has not yet been established. It also implies that the expression of PD-L1 (PD-1 ligand) in cancer tissues may be related to the effect of nivolumab, but there is no definite conclusion. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2006-340714

[Problems to be solved by the invention]

The purpose of the present invention is to use the PD-1 present in the blood (hereinafter sometimes abbreviated as "PD-1 in the blood") as a predictor of the effectiveness of immune checkpoint blocking drugs for cancer patients, to evaluate the progress of cancer, or Biomarkers for predicting the risk of cancer recurrence. [Technical means to solve the problem]

The inventors of the present invention have conducted intensive research and found that the concentration of PD-1 in blood can be used as the above-mentioned biomarker, thus completing the present invention.

That is, the present invention is as follows. [1] A cancer progression inhibitor, recurrence inhibitor, and/or therapeutic agent, which is characterized in that it contains an immune checkpoint inhibitor as an active ingredient and treats cancer patients whose blood PD-1 concentration does not reach a predetermined threshold Vote. [2] The agent as described in [1] above, wherein the PD-1 in the blood is free PD-1 (hereinafter sometimes abbreviated as "sPD-1"). [3] The agent as described in [1] above, wherein PD-1 in the blood is PD-1 present in exosome (hereinafter sometimes abbreviated as "exosome PD-1") and sPD-1 . [4] The agent as described in any one of [1] to [3], wherein the critical value is any value ranging from 55 to 75 pg/mL. [5] The agent according to any one of [1] to [3] above, wherein the critical value is any value ranging from 55 to 70 pg/mL. [6] The agent according to any one of [1] to [3] above, wherein the critical value is any value ranging from 55 to 65 pg/mL. [7] The agent as described in any one of [1] to [3], wherein the critical value is any value from 60 to 65 pg/mL. [8] The agent according to any one of [1] to [3], wherein the critical value is any value from 55 to 60 pg/mL. [9] The agent according to any one of [1] to [3], wherein the cut-off value is about 75 pg/mL. [10] The agent according to any one of [1] to [3], wherein the cut-off value is about 70 pg/mL. [11] The agent according to any one of [1] to [3], wherein the cut-off value is about 65 pg/mL. [12] The agent according to any one of [1] to [3], wherein the cut-off value is about 60 pg/mL. [13] The agent according to any one of [1] to [3], wherein the cut-off value is about 55 pg/mL. [14] The agent as described in any one of [1] to [13], wherein the immune checkpoint blocking substance is an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, a PD-L1/ VISTA (V-domain Ig suppressor of T cell activation, T cell activation suppressor immunoglobulin variable domain domain) antagonist, PD-L1/TIM3 (T cell immunoglobulin domain and mucin domain 3, T cell immunoglobulin domain and mucin domain 3) Mucin domain molecule 3) Antagonist, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 (Cytotoxic T-lymphocyte associated antigen 4, cytotoxic T lymphocyte associated antigen 4) Antibodies, anti-LAG-3 (Lymphocyte-activation gene 3) antibodies, LAG-3 fusion protein, anti-Tim3 antibodies, anti-KIR (Killer cell immunoglobulin-like receptors, killer cell immunoglobulin-like receptors) Antibody, anti-BTLA (B and T Lymphocyte Attenuator, B/T lymphocyte attenuator) antibody, anti-TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains, T cell immune receptor containing Ig and ITIM domains) antibody, anti-VISTA Antibodies, anti-CSF-1R (Colony stimulating factor 1 receptor) antibodies or CSF-1R inhibitors. [15] The agent according to any one of [1] to [13] above, wherein the immune checkpoint blocking substance is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody. [16] The agent as described in any one of [1] to [13], wherein the immune checkpoint blocking substance is an anti-PD-1 antibody. [17] The agent according to any one of [1] to [13] above, wherein the immune checkpoint blocking substance is an anti-PD-L1 antibody. [18] The agent according to any one of [1] to [13] above, wherein the immune checkpoint blocking substance is an anti-CTLA-4 antibody. [19] The agent according to any one of the preceding items [14] to [16], wherein the anti-PD-1 antibody is Nivolumab, Cemiplimab, Pembrolizumab Anti (Pembrolizumab), Spartalizumab (Spartalizumab), Tislelizumab (Tislelizumab), AMP-514, Dostarlimab (Dostarlimab), Toripalimab (Toripalimab), Carrier Camrelizumab (Camrelizumab), Genolimzumab (Genolimzumab), Sintilimab (Sintilimab), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105 , AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188, JNJ-63723283 or AB122. [20] The agent described in any one of [14] to [16] and [19], which recognizes PD-1 in blood by the anti-PD-1 antibody administered to a cancer patient. [21] The agent as described in any one of [14] to [16] and [19], which measures blood levels by using the same antibody measurement system as the anti-PD-1 antibody administered to cancer patients The concentration of PD-1. [22] The agent as described in the preceding paragraph [21], wherein the measurement system is an ELISA that uses the same antibody as the anti-PD-1 antibody administered to the cancer patient as the capture antibody. [23] The agent as described in the preceding paragraph [14], [15] or [17], wherein the anti-PD-L1 antibody is atezolizumab (Atezolizumab), Avelumab (Avelumab), Duvalu Monoclonal antibody (Durvalumab), BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT- 502, JS003 or CX-072. [24] The agent as described in the preceding item [14], [15] or [18], wherein the anti-CTLA-4 antibody is Ipilimumab, AGEN1884 or Tremelimumab. [25] The agent according to any one of [1] to [24], wherein the cancer is solid cancer or blood cancer. [26] The agent as described in the preceding paragraph [25], wherein the solid cancer is selected from malignant melanoma (e.g., malignant melanoma of the skin, oral mucosal epithelium, or intraocular socket), 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 (for example, oral cavity cancer, upper pharynx cancer, middle pharynx cancer, lower pharynx cancer, laryngeal cancer, salivary gland cancer and tongue cancer), kidney Cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal cancer, uterine cancer (e.g., cervical cancer, endometrial cancer, and uterine body cancer ), anal cancer (for example, anal cancer), colorectal cancer (for example, high-frequency microsatellite instability (hereinafter abbreviated as "MSI-H") and/or mismatch repair defects (hereinafter abbreviated as "dMMR") positive Colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small bowel cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer , Urethral cancer, renal pelvis 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 (blastoma), 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 glioma) and medulla), squamous cell carcinoma, bone/soft tissue sarcoma (e.g., Ewing’s sarcoma, pediatric rhabdomyosarcoma, pediatric rhabdomyosarcoma, Leiomyosarcoma of the uterus, chondrosarcoma, pulmonary sarcoma, osteosarcoma and congenital fibrosarcoma) and Kaposi’s sarcoma. [27] The agent according to the preceding paragraph [25], wherein the blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin’s lymphoma (e.g., filtering lymphoma, precursor B-cell lymphoblastic Lymphoma, chronic B lymphoid leukemia, nodal border zone B cell lymphoma, diffuse large cell B cell lymphoma, MALT (mucosa-associated lymphoid tissue, gastric mucosa-associated lymphoid tissue) lymphoma, primary spleen Marginal zone B-cell lymphoma, hairy cell leukemia, primary mediastinal large cell B-cell lymphoma, Burch's lymphoma, mantle cell lymphoma, mycosis fungoides, Sezary syndrome, Chronic or acute lymphocytic leukemia, precursor T cell lymphoblastic lymphoma, chronic T lymphocytic leukemia, T cell large granular lymphocytic leukemia, NK cell large granular lymphocytic leukemia, peripheral T cell lymphoma, nodule External NK/T cell lymphoma, adult T cell leukemia, angiocentral lymphoma, intestinal T cell lymphoma, Hodgkin-like/Hodgkin-related undifferentiated large cell lymphoma, B-cell lymphoblastic Leukemia, T-cell lymphoblastic leukemia and lymphoplasmacytic lymphoma) and Hodgkin’s lymphoma (for example, classical Hodgkin’s lymphoma and nodular lymphocyte-based Hodgkin’s lymphoma)), leukemia (For example, acute myelogenous leukemia and chronic myelogenous leukemia), primary malignant lymphoma of the central nervous system, myelodysplastic syndrome, or myelodysplastic syndrome. [28] The agent according to any one of [1] to [24], wherein the cancer is pediatric cancer or cancer of unknown primary. [29] The agent as described in any one of [1] to [28] in the preceding paragraph, wherein the cancer is a cancer whose therapeutic effect by other anticancer agents is insufficient or insufficient. [30] The agent as described in any one of [1] to [28], wherein the cancer is a cancer that has deteriorated after treatment with other anticancer agents. [31] The agent as described in any one of [1] to [28], wherein the cancer patient is a patient who has no history of treatment with other anticancer agents. [32] The agent described in any one of [1] to [31] in the preceding paragraph, which is a prescription for postoperative adjuvant therapy or preoperative adjuvant therapy. [33] The agent according to any one of [1] to [32], wherein the cancer is incurable or resectable, metastatic, recurrent, refractory, and/or distant metastatic. [34] The agent according to any one of [1] to [33], wherein the proportion of tumor cells expressing PD-L1 in the tumor cells in the tumor tissue of the cancer (hereinafter abbreviated as "TPS" ) Or the number of PD-L1 positive cells (tumor cells, lymphocytes and macrophages) divided by the total number of tumor cells and multiplied by 100 (hereinafter abbreviated as "CPS") is less than 50%, less than 25%, Less than 10%, less than 5%, or less than 1%. [35] The agent described in any one of [1] to [34], wherein the cancer does not have MSI-H and/or dMMR, or has low-frequency microsatellite instability (hereinafter abbreviated as "MSI-L "). [36] The agent described in the previous item [26], wherein the malignant melanoma or non-small cell lung cancer is BRAF (v-raf murine sarcoma viral oncogene homolog B1, murine sarcoma virus oncogene homolog B1) V600 wild type. [37] The agent described in the previous item [26], wherein the non-small cell lung cancer is EGFR (Epidermal growth factor receptor, epidermal growth factor receptor) gene mutation negative and/or ALK (Anaplastic lymphoma kinase, anaplastic lymphoma kinase) fusion Gene negative. [38] according to item [1] to [37] the agent according to any one of claims, wherein the tumor of the cancer mutation load (hereinafter referred to as "TMB") Number (per ¹⁰⁶ mutated bases is a low frequency of less than 10). [39] The agent described in any one of [1] to [38] above, which is further used in combination with other anticancer agents. [40] The agent according to any one of [29] to [31] or [39], wherein the other anticancer agent is selected from alkylating drugs, platinum preparations, metabolic antagonists (for example, folic acid metabolism antagonist Drugs, pyridine metabolism inhibitors, purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule assembly inhibitors, microtubule disassembly inhibitors, anti- One or more drugs among tumor antibiotics, cytokine preparations, antihormonal drugs, molecular targeted drugs and cancer immunotherapy drugs. [41] The agent described in any one of [1] to [40] above, which is for intravenous injection. [42] The agent described in any one of [1] to [40] above, which is for intravenous drip. [43] The agent according to any one of [14] to [16] in the preceding paragraph, wherein the anti-PD-1 antibody system is administered in the following manner: (i) 3 mg/kg (body weight) once, every 2 weeks Or 2 mg/kg (body weight) once, intravenous drip every 3 weeks, 4 times; (ii) 200 mg once, every 3 weeks or 240 mg, every 2 weeks or 480 mg, every Intravenous infusion once every 4 weeks, 4 times in total; or (iii) 1 mg/kg (body weight) once, intravenous infusion once every 3 weeks, 4 times in total; thereafter, 3 mg/kg (body weight) every time Intravenous drip once every 2 weeks. [44] The agent as described in the preceding paragraph [14], [15] or [17], wherein the anti-PD-L1 antibody system is administered as follows: (i) 10 mg/kg (body weight) once, every 2 weeks Intravenous drip once; (ii) 1200 mg once, intravenous drip every 3 weeks; or (iii) 840 mg once, intravenous drip every 2 weeks. [45] The agent as described in the preceding paragraph [14], [15] or [18], wherein the anti-CTLA-4 antibody system is administered at 1 or 3 mg/kg (body weight) once a day, intravenously every 3 weeks, A total of 4 times. [46] The agent according to any one of [1] to [45], wherein the concentration of PD-1 in the blood is the concentration before the immune checkpoint blocking substance is administered. [1-1] A method for cancer progression inhibition, recurrence inhibition and/or treatment, which comprises administering an effective amount of an immune checkpoint inhibitor to cancer patients whose blood PD-1 concentration does not reach a predetermined threshold. [2-1] An immune checkpoint blocking substance used to inhibit and/or treat the progression and/or recurrence of cancer in cancer patients whose blood PD-1 concentration does not reach a predetermined threshold. [3-1] Use of an immune checkpoint blocking substance for the manufacture of cancer progression inhibition, recurrence inhibition and/or cancer patients whose blood PD-1 concentration does not reach a predetermined threshold value. Or therapeutic agent. [4-1] A method for identifying cancer patients who can expect the effects of immune checkpoint blocking drugs, or cancer patients who cannot expect the effects of immune checkpoint blocking drugs, is to measure PD- in blood collected from cancer patients The concentration of 1 is based on this concentration to identify cancer patients who can expect the effect of the immune checkpoint blocking drug, or cancer patients who cannot expect the effect of the immune checkpoint blocking drug. [4-2] The method described in the preceding paragraph [4-1], wherein the PD-1 in the blood is sPD-1. [4-3] The method described in the preceding paragraph [4-1], wherein the PD-1 in the blood is sPD-1 and extracellular PD-1. [4-4] The method described in any one of [4-1] to [4-3] in the preceding paragraph, wherein patients whose blood PD-1 concentration does not reach a predetermined threshold are specified as being more likely to expect immune examination Cancer patients who have the effect of blocking drugs, or patients whose blood PD-1 concentration is higher than a predetermined threshold are specified as cancer patients who cannot expect the effects of immune checkpoint blocking drugs. [4-5] The method described in the previous item [4-4], wherein the cut-off value is about 75 pg/mL. [4-6] The method described in the previous item [4-4], wherein the cut-off value is about 70 pg/mL. [4-7] The method described in the previous item [4-4], wherein the cut-off value is about 65 pg/mL. [4-8] The method described in the previous item [4-4], wherein the cut-off value is about 60 pg/mL. [4-9] The method described in the previous item [4-4], wherein the cut-off value is about 55 pg/mL. [4-10] The method according to any one of [4-1] to [4-9] in the preceding paragraph, wherein the active ingredient of the immune checkpoint inhibitor is anti-PD-1 antibody, anti-PD-L1 antibody, PD -1 Antagonist, PD-L1/VISTA antagonist, PD-L1/TIM3 antagonist, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody , LAG-3 fusion protein, anti-Tim3 antibody, anti-KIR antibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-CSF-1R antibody or CSF-1R inhibitor. [4-11] The method as described in the previous item [4-10], wherein the anti-PD-1 antibody is nivolizumab, seprolizumab, pembrolizumab, spartizumab, or Relizumab, AMP-514, Dotalizumab, Teriprizumab, Carrelizumab, Genovumab, Sintilizumab, STI-A1110, ENUM 388D4, ENUM 244C8 , GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188, JNJ-63723283 or AB122. [4-12] The method described in [4-10] in the preceding paragraph, wherein the anti-PD-1 antibody recognizes the PD-1 in the blood by administering the anti-PD-1 antibody to cancer patients who are more likely to expect the effect of the immune checkpoint inhibitor . [4-13] The method described in the preceding paragraph [4-10], wherein the same antibody as the anti-PD-1 antibody administered to cancer patients who are more likely to expect the effect of immune checkpoint inhibitors is used The measurement system measures the concentration of PD-1 in the blood. [4-14] The method described in the preceding paragraph [4-13], wherein the measurement system is the same as the anti-PD-1 antibody administered to cancer patients who are more likely to expect the effects of immune checkpoint inhibitors The antibody is used as a capture antibody for ELISA. [4-15] The method as described in the preceding item [4-10], wherein the anti-PD-L1 antibody is atelizumab, aviruzumab, duvaluzumab, BMS-936559, STI-1014 , KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 or CX-072. [4-16] The method as described in the previous item [4-10], wherein the anti-CTLA-4 antibody is ipilimumab, AGEN1884 or tremelimumab. [4-17] The method according to any one of the preceding items [4-1] to [4-16], wherein the cancer is solid cancer or blood cancer. [4-18] The method described in the preceding paragraph [4-17], wherein the solid cancer is selected from malignant melanoma (e.g., malignant melanoma in the skin, oral mucosal epithelium or in the eye socket), 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 (e.g. oral cancer, upper pharynx cancer, middle pharynx cancer, lower pharynx cancer, laryngeal cancer, salivary gland cancer and tongue Cancer), renal cell carcinoma (for example, clear cell renal cell carcinoma), breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal head cancer, uterine cancer (for example, cervical cancer, endometrial cancer) And uterine body cancer), anal cancer (for example, anal canal cancer), colorectal cancer (for example, MSI-H and/or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, Gastric cancer, esophagus-gastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, urethral cancer, renal pelvis cancer and urethral cancer), prostate cancer, fallopian tube cancer, primary Peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (blastoma), vaginal cancer, vulvar cancer , Penile cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumors, brain tumors (e.g., gliomas (e.g., glioblastoma and glioma sarcoma) and medulla) , Squamous cell carcinoma, bone/soft tissue sarcoma (e.g., Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine body leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma) and one of Kaposi's sarcoma Cancer of the above. [4-19] The method described in the preceding paragraph [4-17], wherein the blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin’s lymphoma (e.g., filtering lymphoma, precursor B cell) Lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone B-cell lymphoma, diffuse large-cell B-cell lymphoma, MALT lymphoma, splenic primary marginal zone B-cell lymphoma, hair Cell leukemia, primary mediastinal large cell B-cell lymphoma, Burch's lymphoma, mantle cell lymphoma, mycosis fungoides, Sezari syndrome, chronic or acute lymphocytic leukemia, precursor T cells Lymphoblastic lymphoma, chronic T lymphocytic leukemia, T cell large granular lymphocytic leukemia, NK cell large granular lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T cell Leukemia, angiocentric lymphoma, intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-associated undifferentiated large cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, and lymphoplasm Cellular lymphoma) and Hodgkin’s lymphoma (for example, classical Hodgkin’s lymphoma and nodular lymphocyte-based Hodgkin’s lymphoma), leukemia (for example, acute myelogenous leukemia and chronic myelogenous leukemia) ), primary malignant lymphoma of the central nervous system, myelodysplastic syndrome or myelodysplastic syndrome. [4-20] The method according to any one of [4-1] to [4-19], wherein the concentration of PD-1 in the blood is the concentration before the immune checkpoint blocking drug is administered. [5-1] A use of PD-1 in blood as a biomarker for predicting the effectiveness of immune checkpoint inhibitors in cancer progression inhibition, recurrence inhibition and/or treatment. [5-2] The use as described in the preceding paragraph [5-1], wherein the PD-1 concentration in the blood is used as an indicator to predict the effectiveness of the immune checkpoint blocking drug in cancer progression inhibition, recurrence inhibition and/or treatment. [5-3] The use as described in the preceding item [5-1] or [5-2], wherein the PD-1 in the blood is sPD-1. [5-4] The use as described in the preceding item [5-1] or [5-2], wherein the PD-1 in the blood is sPD-1 and extracellular PD-1. [5-5] The use as described in any one of [5-1] to [5-4], wherein the active ingredient of the immune checkpoint inhibitor is anti-PD-1 antibody, anti-PD-L1 antibody, PD -1 Antagonist, PD-L1/VISTA antagonist, PD-L1/TIM3 antagonist, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody , LAG-3 fusion protein, anti-Tim3 antibody, anti-KIR antibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-CSF-1R antibody or CSF-1R inhibitor. [5-6] The use as described in the previous item [5-5], wherein the anti-PD-1 antibody is nivolizumab, ceprizumab, pembrolizumab, spartalizumab, and Relizumab, AMP-514, Dotalizumab, Teriprizumab, Carrelizumab, Genovumab, Sintilizumab, STI-A1110, ENUM 388D4, ENUM 244C8 , GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188, JNJ-63723283 or AB122. [5-7] The use as described in the preceding paragraph [5-5], wherein the anti-PD-1 antibody administered to a cancer patient recognizes PD-1 in the blood. [5-8] The use as described in the preceding paragraph [5-5], wherein the blood PD-1 concentration is measured by a measurement system using the same antibody as the anti-PD-1 antibody administered to cancer patients. [5-9] The use as described in the preceding paragraph [5-8], wherein the measurement system is an ELISA that uses the same antibody as the anti-PD-1 antibody administered to the cancer patient as the capture antibody. [5-10] The use as described in the previous item [5-5], wherein the anti-PD-L1 antibody is atelizumab, aviruzumab, duvaluzumab, BMS-936559, STI-1014 , KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 or CX-072. [5-11] The use as described in the previous item [5-5], wherein the anti-CTLA-4 antibody is ipilimumab, AGEN1884 or tremelimumab. [5-12] The use according to any one of [5-1] to [5-11], wherein the cancer is solid cancer or blood cancer. [5-13] The use as described in the preceding paragraph [5-12], wherein the solid cancer is selected from malignant melanoma (for example, malignant melanoma in the skin, oral mucosal epithelium or in the eye socket), 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 (e.g. oral cancer, upper pharynx cancer, middle pharynx cancer, lower pharynx cancer, laryngeal cancer, salivary gland cancer and tongue Cancer), renal cell carcinoma (for example, clear cell renal cell carcinoma), breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal head cancer, uterine cancer (for example, cervical cancer, endometrial cancer) And uterine body cancer), anal cancer (for example, anal canal cancer), colorectal cancer (for example, MSI-H and/or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, Gastric cancer, esophagus-gastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, urethral cancer, renal pelvis cancer and urethral cancer), prostate cancer, fallopian tube cancer, primary Peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (blastoma), vaginal cancer, vulvar cancer , Penile cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumors, brain tumors (e.g., gliomas (e.g., glioblastoma and glioma sarcoma) and medulla) , Squamous cell carcinoma, bone/soft tissue sarcoma (for example, Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine body leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma) and one of Kaposi's sarcoma Cancer of the above. [5-14] The use as described in the preceding paragraph [5-12], wherein the blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin’s lymphoma (e.g., filtering lymphoma, precursor B cell) Lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone B-cell lymphoma, diffuse large-cell B-cell lymphoma, MALT lymphoma, splenic primary marginal zone B-cell lymphoma, hair Cell leukemia, primary mediastinal large cell B-cell lymphoma, Burch's lymphoma, mantle cell lymphoma, mycosis fungoides, Sezari syndrome, chronic or acute lymphocytic leukemia, precursor T cells Lymphoblastic lymphoma, chronic T lymphocytic leukemia, T cell large granular lymphocytic leukemia, NK cell large granular lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T cell Leukemia, angiocentric lymphoma, intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-associated undifferentiated large cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, and lymphoplasm Cellular lymphoma) and Hodgkin’s lymphoma (for example, classical Hodgkin’s lymphoma and nodular lymphocyte-based Hodgkin’s lymphoma), leukemia (for example, acute myelogenous leukemia and chronic myelogenous leukemia) ), primary malignant lymphoma of the central nervous system, myelodysplastic syndrome or myelodysplastic syndrome. [5-15] The use according to any one of [5-2] to [5-14], wherein the concentration of PD-1 in the blood is the concentration before the immune checkpoint blocking drug is administered. [6-1] A method for patients with a high risk of recurrence of a specific cancer, which is to measure the concentration of PD-1 in blood collected from a cancer patient, based on the concentration, and a patient with a high risk of recurrence of the specific cancer. [6-2] The method as described in the previous item [6-1], wherein the PD-1 in the blood is sPD-1. [6-3] The method as described in the preceding paragraph [6-1], wherein the PD-1 in the blood is sPD-1 and extracellular PD-1. [6-4] The method described in any one of [6-1] to [6-3] in the preceding paragraph, wherein the patient whose blood PD-1 concentration is above a predetermined threshold is specified as the risk of cancer recurrence High patient. [6-5] The method described in the preceding paragraph [6-4], wherein the critical value is any value ranging from 30 to 40 pg/mL. [6-6] The method described in the preceding paragraph [6-4], wherein the critical value is any value ranging from 30 to 35 pg/mL. [6-7] The method described in the previous item [6-4], wherein the cut-off value is about 33 pg/mL. [6-8] The method according to any one of [6-1] to [6-7], wherein the cancer is solid cancer or blood cancer. [6-9] The method described in the preceding paragraph [6-8], wherein the solid cancer is selected from malignant melanoma (for example, malignant melanoma in the skin, oral mucosal epithelium, or in the eye socket), 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 (e.g. oral cancer, upper pharynx cancer, middle pharynx cancer, lower pharynx cancer, laryngeal cancer, salivary gland cancer and tongue Cancer), renal cell carcinoma (for example, clear cell renal cell carcinoma), breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal head cancer, uterine cancer (for example, cervical cancer, endometrial cancer) And uterine body cancer), anal cancer (for example, anal canal cancer), colorectal cancer (for example, MSI-H and/or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, Gastric cancer, esophagus-gastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, urethral cancer, renal pelvis cancer and urethral cancer), prostate cancer, fallopian tube cancer, primary Peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary cancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma), testicular cancer (blastoma), vaginal cancer, vulvar cancer , Penile cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumors, brain tumors (e.g., gliomas (e.g., glioblastoma and glioma sarcoma) and medulla) , Squamous cell carcinoma, bone/soft tissue sarcoma (e.g., Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine body leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, and congenital fibrosarcoma) and one of Kaposi's sarcoma Cancer of the above. [6-10] The method according to the preceding item [6-8], wherein the blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin’s lymphoma (e.g., filtering lymphoma, precursor B cell) Lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone B-cell lymphoma, diffuse large-cell B-cell lymphoma, MALT lymphoma, splenic primary marginal zone B-cell lymphoma, hair Cell leukemia, primary mediastinal large cell B-cell lymphoma, Burch's lymphoma, mantle cell lymphoma, mycosis fungoides, Sezari syndrome, chronic or acute lymphocytic leukemia, precursor T cells Lymphoblastic lymphoma, chronic T lymphocytic leukemia, T cell large granular lymphocytic leukemia, NK cell large granular lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T cell Leukemia, angiocentric lymphoma, intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-associated undifferentiated large cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, and lymphoplasm Cellular lymphoma) and Hodgkin’s lymphoma (for example, classical Hodgkin’s lymphoma and nodular lymphocyte-based Hodgkin’s lymphoma), leukemia (for example, acute myelogenous leukemia and chronic myelogenous leukemia) ), primary malignant lymphoma of the central nervous system, myelodysplastic syndrome or myelodysplastic syndrome. [7-1] A test kit for measuring the concentration of PD-1 in the blood, comprising an anti-PD-1 antibody, used for (1) predicting immune checkpoint inhibitors in cancer progression inhibition, recurrence inhibition and/or treatment (2) Specific cancer patients who can expect the effect of immune checkpoint blocking drugs, or cancer patients who cannot expect the effect of immune checkpoint blocking drugs; (3) Assess and determine the progress of cancer; (4) Predict The risk of cancer recurrence; or (5) Patients with a high risk of recurrence of specific cancer. [7-2] The set as described in the preceding paragraph [7-1], wherein the active ingredient of the immune checkpoint blocking drug is an anti-PD-1 antibody. [7-3] The kit as described in the previous item [7-2], wherein the anti-PD-1 antibody is nivolizumab, seprolizumab, pembrolizumab, spartizumab, Tilelizumab, AMP-514, Dotalizumab, Teriplizumab, Carrelizumab, Genozumab, Sintilizumab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591 , CX-188, JNJ-63723283 or AB122. [7-4] The kit according to the preceding paragraph [7-2], wherein the anti-PD-1 antibody constituting the kit is the same antibody as the anti-PD-1 antibody administered to the cancer patient. [7-5] The kit described in the preceding paragraph [7-2], which uses the same antibody as the anti-PD-1 antibody administered to cancer patients as a capture antibody kit for ELISA. [7-6] The set as described in any one of [7-1] to [7-5], wherein the PD-1 in the blood is sPD-1. [7-7] The set as described in any one of [7-1] to [7-5], wherein the PD-1 in the blood is sPD-1 and extracellular PD-1. [7-8] The set according to any one of [7-1] to [7-7], wherein the cancer is solid cancer or blood cancer. [7-9] The set described in the preceding paragraph [7-8], wherein the solid cancer is selected from malignant melanoma (for example, malignant melanoma in the skin, oral mucosal epithelium or in the eye socket), 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, upper pharynx cancer, middle pharynx cancer, lower pharynx cancer, laryngeal cancer, salivary gland cancer and Tongue cancer), renal cell carcinoma (for example, clear cell renal cell carcinoma), breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal cancer, uterine cancer (for example, cervical cancer, endometrial cancer) Cancer and uterine body cancer), anal cancer (e.g., anal canal cancer), colorectal cancer (e.g., MSI-H and/or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma , Gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (e.g. bladder cancer, upper urinary tract cancer, urethral 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 melanoma and Merkel cell carcinoma), testicular cancer (blastoma), vaginal cancer, vulva Cancer, penile cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, spinal tumor, brain tumor (e.g., glioma (e.g., glioblastoma and glioma) and medulla ), squamous cell carcinoma, bone/soft tissue sarcoma (for example, Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine body leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma and congenital fibrosarcoma) and Kaposi’s sarcoma More than one type of cancer. [7-10] The set according to the preceding paragraph [7-8], wherein the blood cancer is multiple myeloma, malignant lymphoma (e.g., non-Hodgkin’s lymphoma (e.g., filtering lymphoma, precursor B) Cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal border zone B cell lymphoma, diffuse large cell B cell lymphoma, MALT lymphoma, splenic primary marginal zone B cell lymphoma, Hairy cell leukemia, primary mediastinal large cell B-cell lymphoma, Burch's lymphoma, mantle cell lymphoma, mycosis fungoides, Sezary's syndrome, chronic or acute lymphocytic leukemia, precursor T -Cell lymphoblastic lymphoma, chronic T lymphocytic leukemia, T cell large granular lymphocytic leukemia, NK cell large granular lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T Cell leukemia, angiocentric lymphoma, intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-associated undifferentiated large cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, and lymph Plasma cell lymphoma) and Hodgkin’s lymphoma (for example, classical Hodgkin’s lymphoma and nodular lymphocyte-based Hodgkin’s lymphoma), leukemia (for example, acute myeloid leukemia and chronic myelogenous Leukemia), primary malignant lymphoma of the central nervous system, myelodysplastic syndrome or myelodysplastic syndrome. [7-11] The kit described in any one of [7-1] to [7-10] in the preceding paragraph, which measures the PD-1 concentration in the blood before the immune checkpoint blocking drug is administered.

This specification contains the disclosure content of Japanese Patent Application No. 2018-152032 which is the basis of the priority of this case. [Effect of invention]

By measuring the concentration of PD-1 in the blood of cancer patients, the effectiveness of using immune checkpoint blocking drugs for cancer treatment can be predicted. In addition, the PD-1 concentration in the blood of cancer patients can be used as an indicator to evaluate the progress of cancer and predict the risk of cancer recurrence.

Hereinafter, the present invention will be described in detail.

The present invention relates to a cancer progression inhibitor, recurrence inhibitor and/or therapeutic agent, which contains an immune checkpoint inhibiting substance as an active ingredient, and has an effect on the concentration of PD-1 present in the blood (hereinafter sometimes referred to as "blood PD- 1 Concentration") to be administered to cancer patients who have not reached a predetermined value.

The so-called "PD-1 in blood" (PD-1 in blood) in this manual refers to PD-1 that can be detected in blood by existing assays including the following methods. The main target is The form of PD-1 is PD-1 in the blood. Here, the so-called "free PD-1" refers to PD-1 that is free in the blood due to the absence of the cell membrane permeable area. It is also called soluble PD-1, sometimes abbreviated as sPD-1. In addition, the PD-1 in the blood also includes PD-1 in the form of exosome freed into the blood.

The present invention is based on the knowledge that the PD-1 concentration in the blood of cancer patients can be used as an index to predict the effectiveness of immune checkpoint inhibitors. That is, based on the following insights: when using immune checkpoint blocking drugs for cancer patients, the PD-1 concentration in the blood of cancer patients can be used as an indicator to predict the effectiveness of immune checkpoint blocking drugs for cancer patients, more specifically In other words, when the measured PD-1 concentration in the blood of a cancer patient does not reach a predetermined value, it can be predicted that the immune checkpoint blocking drug can be expected to treat the cancer patient.

In the method of the present invention, the concentration of PD-1 in the blood is measured, and whole blood, serum or plasma can be used as the specimen.

The method for measuring the concentration of PD-1 in blood is not limited, and it is preferably measured by immunological measurement using antibodies or mass spectrometry. Examples of immunological assays using antibodies include: immunoblotting method, enzyme immunoassay (for example, EIA (Enzyme Immunoassay), ELISA, CLEIA (Chemiluminescent Enzyme Immunoassay, chemiluminescent enzyme immunoassay), CLIA (Chemiluminescent Immunoassay, Chemiluminescence Immunoassay) and ELISPOT (Enzyme-Linked ImmunoSpot, Enzyme-Linked ImmunoSpot, etc.), radioimmunoassay (for example, RIA (Radioimmunoassay, Radioimmunoassay), IRMA (Immunoradiometric assay, Immunoradiation Quantitative analysis), RRA (Radioreceptor Assay, radioreceptor analysis) and CPBA (Competitive Protein Binding Assay, Competitive Protein Binding Assay, etc.), fluorescent antibody method (for example, FA (Fluorescent antibody, fluorescent antibody), FIA ( Fluoroimmunoassay, Fluoroimmunoassay), TR-FIA (Time-resolved Fluoroimmunoassay, Time-resolved Fluoroimmunoassay, and IFA (Indirect fluorescent antibody), etc.), methods using agglutination, immunochromatography, etc. . Among them, the sandwich immunological assay is preferred, and the ELISA (Enzyme Linked Immunosorbent Assay) that can easily obtain the correct measurement value is preferred.

This sandwich immunoassay is a method of measuring PD-1 to be measured by sandwiching two kinds of antibodies like a sandwich. In this method, the capture anti-PD-1 antibody (primary antibody, immobilized antibody) used to capture PD-1 is immobilized on a culture plate, etc., and is subjected to horseradish peroxidase (HRP) or alkali Anti-PD-1 antibody (secondary antibody) is used for detection of enzymes such as phosphatase (ALP), fluorescent substances such as FITC (Fluorescein isothiocyanate), or biotin labeling. In the case of using a biotin-labeled antibody (biotin-conjugated antibody), avidin or streptavidin labeled with the above-mentioned enzyme or fluorescent substance may be used. The capture antibody or detection antibody used to measure PD-1 is also referred to as an antibody for measurement.

The ELISA that can be carried out in the present invention can be carried out by the following procedure, for example.

First, add a sample to a microtiter plate made of polystyrene or the like with anti-PD-1 antibody for capture immobilized, and form a solid-phased anti-PD-1 antibody and assay by the antigen-antibody reaction. The PD-1 complex in the body. Furthermore, an anti-PD-1 antibody for detection labeled with enzymes, etc. is added to bind to the PD-1 captured by the immobilized antibody to form an immobilized anti-PD-1 antibody for capture on the culture plate: Specimen PD-1 in the middle: a complex of anti-PD-1 antibodies labeled with enzymes for detection (":" means binding). After washing, make it react with enzyme to develop color and measure absorbance. The concentration of PD-1 in bleeding can be calculated based on the calibration curve made using the dilution series of PD-1 with known concentration. The calibration curve can be made in advance, or it can be made by measuring the dilution series of PD-1 with a known concentration while measuring the sample.

In this ELISA, add the capture anti-PD-1 antibody solution to the wells of the ELISA culture plate at a concentration of hundreds of ng to tens of μg/well, and incubate for 1 hour to ten hours, preferably 1 to several hours Adsorb it, thereby solidifying. The amount of sample added to the solid-phased well is several μL to several tens of μL. The binding reaction between the antibody and the antigen may be carried out at 4°C to 45°C, preferably 20°C to 40°C, and more preferably 25°C to 38°C. In addition, the reaction time is about 10 minutes to tens of hours, more preferably 10 minutes to several hours, and still more preferably about 30 minutes to 1 hour.

The PD-1 concentration in the blood is preferably measured by a measurement system using the same antibody as the anti-PD-1 antibody actually administered to the cancer patient. For example, when Nivolumab is used in cancer treatment, the PD-1 concentration in the blood of cancer patients is measured by an immunological assay using Nivolumab as an antibody for measurement.

In this sandwich immunoassay method, a capture antibody (immobilized antibody) and a detection antibody are used. For example, an anti-PD-1 antibody that is actually used for cancer treatment may be used as the capture antibody.

Regarding the reference value of the blood PD-1 concentration as an indicator for judging whether or not to administer the cancer progression inhibition, recurrence inhibition and/or therapeutic agent of the present invention to a cancer patient, it can be measured before the administration of the immune checkpoint inhibitor The PD-1 concentration in the blood of the patient is then administered with the immune checkpoint blocking drug, divided into effective groups and non-effective groups, and predetermined based on the blood PD-1 concentration before each administration. The effectiveness of the anticancer agent can be determined based on the effectiveness of the anticancer agent. For example, when the cancer is a solid cancer, it should be based on the RECIST guideline (Response Evaluation Criteria in Solid Tumor, 2000) showing the effect of the anticancer agent. It can be divided into complete response (Complete Response: CR), partial response (Partial Response: PR), progress (Progressive Disease: PD), and stable (Stable Disease: SD). Among them, for example, there are situations: if it is fully effective (CR), partially effective (PR), or stable (SD), it can be judged as effective, and if it is progressing (PD), it can be judged as non-effective. For example, from the start of treatment by the administration of the immune checkpoint blocking drug to the 12th month, preferably to the 10th month, more preferably to the 8th month, and then It is preferable to make a judgment based on the standard until the 6th month. In addition, it is also possible to judge whether it is effective or not based on the overall performance efficiency (ORR), progression-free survival (PFS), overall survival (OS), survival rate, or the median value of survival. The above-mentioned reference value can be set as a cut-off value or threshold for evaluating the effectiveness of immune checkpoint blocking drugs. When the PD-1 concentration in the blood of cancer patients does not reach the cut-off value, it can be predicted that the immune checkpoint can be expected When the therapeutic effect of the blocking drug is above the threshold, it can be predicted that the therapeutic effect of the blocking drug at the immune checkpoint cannot be expected.

The critical value can be determined by, for example, ROC (receiver operating characteristic curve) analysis. Regarding ROC analysis, the PD-1 concentration in the blood of the cancer patient before the immune checkpoint blocking drug is administered as the sample is measured, and then the immune checkpoint blocking drug is administered, divided into effective groups and non-effective groups, and calculated The sensitivity and specificity at each critical value are plotted on the coordinates with the horizontal axis as the specificity and the vertical axis as the sensitivity. In addition, the 95% reliability interval of the effective group and the non-effective group is calculated, and the critical value can be set based on the upper limit or the lower limit of the 95% reliability interval. When predicting a situation where the 95% reliability interval of the two groups clearly deviates, a critical value can be set in the deviation area of the 95% reliability interval of the two groups. For example, any value from the upper limit of the 95% reliability interval of the effective group to the lower limit of the 95% reliability interval of the non-effective group can be set as the critical value. When the 95% reliability interval of the two groups does not deviate, when selecting patients who can expect the therapeutic effect of the immune checkpoint blocking drug, for example, the value exceeding the upper limit of the 95% reliability interval of the effective group can be set as the critical value.

With the method of the present invention, the effectiveness of anti-PD-1 antibodies for cancer treatment can be predicted. The cut-off value of the blood PD-1 concentration used to predict the effectiveness of the anti-PD-1 antibody is, for example, any value from 55 to 75 pg/mL, preferably any value from 55 to 70 pg/mL, and more It is preferably any value from 55 to 65 pg/mL, more preferably any value from 60 to 65 pg/mL, and still more preferably any value from 55 to 60 pg/mL. Moreover, it is about 75 pg/mL, preferably about 70 pg/mL, more preferably about 65 pg/mL, still more preferably about 60 pg/mL, and still more preferably about 55 pg/mL. It is sufficient to administer the progression inhibitor, recurrence inhibitor and/or therapeutic agent of the present invention to cancer patients whose blood PD-1 concentration does not reach the above-mentioned critical value. The cut-off value is preferably a value measured by ELISA.

With this method, when it is predicted that the therapeutic effect of the immune checkpoint blocking drug on a cancer patient can be expected, the immune checkpoint blocking drug may be administered to the cancer patient for cancer treatment. For example, when it is predicted that the therapeutic effect of an anti-PD-1 antibody (for example, nivolumab) on a cancer patient can be expected, the anti-PD-1 antibody may be administered to the cancer patient for cancer treatment.

The so-called "immune checkpoint inhibitory substance" in this specification includes, for example, anti-PD-1 antibodies (e.g., nivolumab, seprolizumab (REGN-2810), pembrolizumab (MK- 3475), Spartizumab (PDR-001), Tilelizumab (BGB-A317), AMP-514 (MEDI0680), Dotalizumab (ANB011/TSR-042), Terip Lizumab (JS001), Carrelizumab (SHR-1210), Genovumab (CBT-501), Sintilizumab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188 , JNJ-63723283 and AB122, etc.), anti-PD-L1 antibodies (e.g., Atelizumab (RG7446/MPDL3280A), Avirulumab (PF-06834635/MSB0010718C), Duvaluzumab (MEDI4736) , BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001 (WBP3155), MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502( TQB2450), JS003 and CX-072, etc.), PD-1 antagonists (for example, AUNP-12, BMS-M1-BMS-M10 compounds (refer to 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 and BMS-1166 (refer to WO2015/034820, WO2015/160641, WO2017/066227 and Oncotarget. 2017 Sep 22; 8(42): 72167-72181.), Incyte-1～Incyte-6 compounds (refer to WO2017/070089, WO2017/087777, WO2017/106634, WO2017/112730, WO2017/192961 and WO2017/205464), CAMC-1～CAMC-4 (Refer to WO2017/202273, WO2017/202274, WO2017/202275 and WO2017/202276), RG_1 (refer to WO2017/118762) and DPPA-1 (refer to Angew. Chem. Int. Ed. 2015, 54, 11760-11764) etc.) , PD-L1/VISTA antagonist (for example, CA-170, etc.), PD-L1/TIM3 antagonist (for example, CA-327, etc.), anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein (E.g., AMP-224, etc.), anti-CTLA-4 antibodies (e.g., Ipilimumab (MDX-010), AGEN1884 and tremelimumab, etc.), anti-LAG-3 antibodies (e.g., riralizumab (Relatlimab) (BMS-986016), LAG525, REGN3767, and MK-4280, etc.), LAG-3 fusion proteins (e.g., IMP321, etc.), anti-Tim3 antibodies (e.g., MBG453 and TSR-022, etc.), anti-KIR antibodies (e.g. , Lirilumab (BMS-986015), IPH2101, LY3321367 and MK-4280, etc.), anti-BTLA antibodies, anti-TIGIT antibodies (e.g., Tiragolumab and BMS-986207), anti-VISTA antibodies (e.g., JNJ-61610588, etc.), and anti-CSF- 1R antibody or CSF-1R inhibitor (e.g., Cabiralizumab (FPA008/BMS-986227), Emactuzumab, LY3022855, MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945, ARRY-382, etc.) Wait. In addition, in this specification, drugs containing these immune checkpoint inhibitory substances as active ingredients are referred to as "immune checkpoint inhibitory drugs". Furthermore, nivolumab can be manufactured according to the method described in WO2006/121168, pembrolizumab can be manufactured according to the method described in WO2008/156712, BMS-936559 can be manufactured according to the method described in WO2007/005874, Pimumab can be manufactured according to the method described in WO2001/014424.

As the "immune checkpoint blocking substance" in the present invention, anti-PD-1 antibodies and anti-PD-L1 antibodies are preferred, and particularly preferred anti-PD-1 antibodies include: Nivolumab, Sepp Lizumab, pembrolizumab, spartizumab, tislelizumab and carrelizumab, as better anti-PD-L1 antibodies, include: atelizumab, Aviruzumab, Duvaluzumab and BMS-936559.

In this specification, the concentration of PD-1 in the blood is preferably the concentration before the administration of the immune checkpoint blocking substance.

The term "pre-administration of immune checkpoint blocking substance" or "pre-administration of immune checkpoint blocking drug" in this manual includes: cases where there is no previous treatment history of the immune checkpoint blocking drug and it is completely the first administration, And the situation before the administration of the drug when there has been a history of treatment with the immune checkpoint blocking drug or other anticancer agents (also including immune checkpoint blocking drugs other than the immune checkpoint blocking drug).

In this specification, the so-called "about" used in the numerical value of the blood PD-1 concentration means that it can be changed within a range of 10% lower or 10% higher than the stated value. [Applicable diseases and patients] In the present invention, solid cancers or blood cancers can be cited as target cancers. Examples of solid cancers include: selected from malignant melanomas (for example, malignant melanomas in the skin, oral mucosal epithelium, or intraocular sockets) , 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 cavity cancer, upper pharynx cancer, middle pharynx cancer, lower pharynx cancer, larynx Cancer, salivary gland cancer and tongue cancer), renal cell carcinoma (e.g., clear cell renal cell carcinoma), breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma, nasopharyngeal carcinoma, uterine cancer (e.g., cervical Cancer, endometrial cancer and uterine body cancer), anal cancer (e.g., anal cancer), colorectal cancer (e.g., MSI-H and/or dMMR positive colorectal cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophagus Cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer (for example, bladder cancer, upper urinary tract cancer, urethral cancer, renal pelvis 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 melanoma and Merkel cell carcinoma), testicular cancer (blastoma), Vaginal cancer, vulvar cancer, penile cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, spine tumor, brain tumor (e.g., glioma (e.g., glioblastoma and glioma) ) And medulla), squamous cell carcinoma, bone/soft tissue sarcoma (for example, Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine body leiomyosarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma and congenital fibrosarcoma) and card More than one type of cancer in Posey's sarcoma. Furthermore, pediatric cancer and unidentified primary cancer can also be cited. Furthermore, the so-called "cancer" in the present invention is used as a concept including all malignant tumors.

In the present invention, the target blood cancers include: multiple myeloma, malignant lymphoma (e.g., non-Hodgkin’s lymphoma (e.g., filtrating lymphoma, precursor B-cell lymphoblastic lymphoma) , Chronic B lymphocytic leukemia, nodal border zone B cell lymphoma, diffuse large cell B cell lymphoma, MALT lymphoma, splenic primary marginal zone B cell lymphoma, hairy cell leukemia, primary Large mediastinal B-cell lymphoma, Burch's lymphoma, mantle cell lymphoma, mycosis fungoides, Sezary's syndrome, chronic or acute lymphocytic leukemia, precursor T-cell lymphoblastic lymphoma , Chronic T lymphocytic leukemia, T cell large granular lymphocytic leukemia, NK cell large granular lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T cell leukemia, angiocentric lymphoma Tumor, intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-related undifferentiated large cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemia, and lymphoplasmacytic lymphoma) and Hodgkin’s lymphoma (for example, classical Hodgkin’s lymphoma and nodular lymphocyte-based Hodgkin’s lymphoma), leukemia (for example, acute myelogenous leukemia and chronic myelogenous leukemia), central nervous system Malignant lymphoma, myelodysplastic syndrome and myelodysplastic syndrome, etc.

These cancers can be incurable or resectable, metastatic, recurrent, refractory, and/or distant metastatic.

In addition, cancers to be targeted include cancers whose therapeutic effects are insufficient or insufficient with other anticancer agents, and cancers that have worsened after treatment with other anticancer agents.

In this specification, the term "cancer treatment" includes, for example, (i) treatment for slowing down the proliferation of cancer cells, (ii) treatment for reducing symptoms caused by cancer, and (iii) treatment for improving cancer Treatment based on the patient’s quality of life, (iv) used to reduce the dosage of other anticancer agents or cancer therapy adjuvants that have been administered, and/or (v) used to prolong the survival of cancer patients The treatment performed; the so-called "inhibition of cancer progression" means slowing the progression of cancer, stabilizing cancer-related symptoms and alleviating symptoms. In addition, the so-called "cancer recurrence suppression" means preventively inhibiting the recurrence of cancer in patients whose cancerous lesions have been completely or substantially eliminated or removed by cancer treatment or cancer resection.

The presence of the medicament of the present invention is more required to meet the blood PD-1 concentration conditions of the present invention, and further to the following cancer patients, namely (a) cancer patients without a history of treatment with other anticancer agents, (b) TPS or CPS less than 50%, less than 25%, less than 10%, less than 5%, or less than 1% of cancer patients, (c) do not have MSI-H and/or dMMR, or have MSI-L Cancer patients, (d) BRAF V600 wild-type malignant melanoma or non-small cell lung cancer patients, (e) EGFR gene mutation negative and/or ALK fusion gene negative non-small cell lung cancer patients, or (f) TMB (mutated tumor load) of a low frequency (per ¹⁰⁶ bases of less than 10 mutations) of cancer patient of the prescription opened. Furthermore, the medicament of the present invention can also be used as a postoperative adjuvant therapy for preventively inhibiting recurrence or metastasis after surgical resection of cancer, or preoperative adjuvant therapy performed before surgical resection.

Here, as the above-mentioned "other anticancer agents", the following anticancer agents listed in the related items of [Combination and Formulation], namely, as alkylating drugs, platinum preparations, metabolic antagonists (for example, folic acid) Metabolic antagonists, pyridine metabolism inhibitors, purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule assembly inhibitors, microtubule disassembly inhibitors , Anti-tumor antibiotics, cytokine preparations, anti-hormonal drugs, molecular targeted drugs and cancer immunotherapy drugs are exemplified respectively. In addition, the so-called "insufficient or insufficient therapeutic effect of anticancer agents" can be exemplified in RECIST, where at least progression (PD) is judged even after treatment with anticancer agents. [prescription] The dosage of the immune checkpoint blocking substance as the active ingredient of the medicament of the present invention varies according to age, weight, symptoms, therapeutic effect, administration method, treatment time, etc. Generally, it is 1 ng per person per adult To be administered once to several times a day in the range of 1000 mg, or once to several times a day non-orally administered in the range of 0.1 ng to 1200 mg per adult, or 30 minutes a day It is continuously administered intravenously by intravenous injection in the range of 24 hours. Of course, as mentioned above, the amount to be injected varies according to various conditions. Therefore, there are cases where the amount is less than the above-mentioned injection amount is sufficient, and there are cases where it is necessary to over-range the injection amount.

For example, in the case of nivolumab as an anti-PD-1 antibody, it is administered according to the following usage and dosage. That is, for patients with malignant melanoma, as nivolumab, 3 mg/kg (body weight), intravenous drip every 2 weeks, or 2 mg/kg (body weight), intravenous drip every 3 weeks One-time administration; for each patient with non-small cell lung cancer, renal cell carcinoma, classical Hodgkin’s lymphoma, head and neck cancer and gastric cancer, as nivolumab, 3 mg/kg (body weight) per time It is administered by intravenous drip every 2 weeks. Also, regarding other usage and dosage, for example, for malignant melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, MSI-H or dMMR positive colorectal cancer (including children over 12 years old), gastric cancer For each patient with hepatocellular carcinoma, small cell lung cancer, and malignant pleural mesothelioma, as nivolumab, 240 mg once every 2 weeks or 480 mg every 4 weeks Vote in one time. Furthermore, regarding other usages and dosages, for example, there are cases where for patients with malignant melanoma, when combined with ipilimumab, as nivolumab, 1 mg/kg (body weight) once, intravenously every 3 weeks Instilled once for 4 times. After that, as nivolumab, 3 mg/kg (body weight) once, intravenously every 2 weeks; or, as nivolumab, 80 mg once every 2 weeks Infusion was given once every 3 weeks for a total of 4 times. Thereafter, as nivolumab, 240 mg was given once every 2 weeks. In addition, for example, for patients with renal cell carcinoma, when combined with ipilimumab, nivolumab is given 240 mg once every 3 weeks by intravenous drip for a total of 4 times. Thereafter, As nivolumab, 240 mg is given by intravenous drip every 2 weeks.

Also, in the same way, in the case of pembrolizumab as an anti-PD-1 antibody, it is administered according to the following usage and dosage. That is, for malignant melanoma, non-small cell lung cancer, classical Hodgkin’s lymphoma, head and neck cancer, MSI-H or dMMR positive solid cancer or colorectal cancer, urothelial cancer, cervical cancer, primary mediastinal B cell Patients with lymphoma, hepatocellular carcinoma, gastric cancer, and Merkel cell carcinoma were administered as pembrolizumab at 200 mg once every 3 weeks by intravenous infusion. Furthermore, regarding other usages and dosages, for example, for each patient with classical Hodgkin's lymphoma, MSI-H or dMMR positive solid cancer or colorectal cancer and primary mediastinal B-cell lymphoma in children over 2 years old, it is regarded as Pembrolizumab is administered at a dose of 2 mg/kg (body weight) once (up to 200 mg once), intravenously every 3 weeks.

In addition, with regard to avirulumab as an anti-PD-L1 antibody, for each patient of Merkel cell carcinoma and urothelial carcinoma, as avirulumab, 10 mg/kg (body weight) once, every 2 It is administered by intravenous drip once a week. Regarding atelizumab, which is also a PD-L1 antibody, for each patient with non-small cell lung cancer and urothelial cancer, as atelizumab, 1200 mg once, intravenous drip every 3 weeks For patients with triple-negative breast cancer, when combined with paclitaxel, atelizumab is administered as an intravenous infusion of 840 mg once every 2 weeks. Furthermore, with regard to duvaluzumab, which is also a PD-L1 antibody, for each patient with non-small cell lung cancer and urothelial cancer, the dose of duvaluzumab is 10 mg/kg (body weight) once, every 2 It is administered by intravenous drip once a week.

In addition, in the case of ipilimumab as an anti-CTLA-4 antibody, for patients with malignant melanoma, when used alone or in combination with nivolumab, as ipilimumab, 3 mg once a day kg (body weight), intravenous drip every 3 weeks, 4 times in total; for renal cell carcinoma, and MSI-H or dMMR positive colorectal cancer patients, when combined with nivolumab, as ipilimumab Anti-, 1 mg/kg (body weight) once a day, intravenous drip every 3 weeks, 4 times in total. [Combined use and blending agent] The medicament of the present invention (1) is to enhance cancer progression inhibition and/or therapeutic effect, (2) to reduce the dosage of other drugs used in combination, and/or (3) to reduce the amount of other drugs used in combination The side effects can be used in combination with one or more other drugs (mainly anti-cancer drugs) used for the purpose of cancer treatment. In the present invention, the administration form when the prescription is combined with other medicines may be in the form of a two-component formulation in one preparation, or may be a form of administration as a separate preparation. When the medicament of the present invention is administered separately from other medicaments, the medicament of the present invention may be administered first, and then the other medicaments may be administered after its administration, or the other medicament may be administered first and then administered to the medicament of the present invention In addition, in the above-mentioned administration, the medicament may also exist during the period of simultaneous administration of two medicaments within a certain period of time. In addition, the administration method of each medicine may be the same or different. According to the nature of the medicine, it can also be provided in the form of a kit containing the medicine of the present invention and other medicines. Here, the dosage of other drugs can be appropriately selected based on the clinically used dosage. In addition, other drugs may be administered in combination of any two or more at an appropriate ratio. In addition, the above-mentioned other drugs include not only those who have been discovered so far, but also those who may be discovered in the future.

The main examples of other drugs used in combination include anticancer agents, such as alkylating drugs (for example, dacarbazine, Nimustine, Temozolomide, Temozolomide). Fotemustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil, and Procarbazine, etc.), platinum preparations (e.g., Cisplatin, Carboplatin, Nedaplatin and oxaliplatin, etc.), metabolic antagonists (e.g., Folic acid metabolism antagonists (for example, Pemetrexed (Pemetrexed), leucovorin and methotrexate, etc.), pyridine metabolism inhibitors (for example, TS-1 (registered trademark), 5 -Fluorouracil (fluorouracil), UFT (UFT), Carmofur (Carmofur), Doxifluridine, 5-fluoro-2'-deoxyuridine (FdUrd, 5-fluoro-2'-deoxyuridine) ), Cytarabine and Capecitabine, etc.), purine metabolism inhibitors (for example, Fludarabine, Cladribine, Nelarabine, etc.) , Ribonucleotide reductase inhibitors, nucleotide analogs (for example, gemcitabine (Gemcitabine), etc.), topoisomerase inhibitors (for example, Irinotecan, Nogitecan, and Etoposide ), etc.), microtubule assembly inhibitors (for example, vinblastine (Vinblastine), vincristine (Vincristine), vindesine (Vindesine), vinorelbine (Vinorelbine), Eribulin (Eribulin), etc.), micro Tube disassembly inhibitors (for example, Docetaxel and Paclitaxel), antitumor antibiotics (for example, Bleomycin, Mitomycin C, Doxorubicin Doxorubicin (Doxorubicin), Zorubicin (Daunorubicin), Idarubicin (Idarubicin), Etoposide, Mitoxantrone (Mitoxantrone), Vinblastine, Vincristine, Pelomycin (Pepl omycin), Amrubicin (Amrubicin), Aclarubicin (Aclarubicin) and Epirubicin (Epirubicin), cytokine preparations (for example, IFN (Interferon, interferon)-α2a, IFN-α2b, PEG IFN (Pegylated Interferon, Pegylated Interferon)-α2b, natural IFN-β and interleukin-2, etc.), antihormonal drugs (for example, Tamoxifen (Tamoxifen), Fulvestrant (Fulvestrant) , Goserelin, Leuprorelin, Anastrozole, Letrozole, Exemestane, etc.), molecular targeted drugs, cancer immunotherapy drugs And other antibody medicines.

Here, as molecular targeted drugs, for example, ALK inhibitors (for example, Crizotinib, Ceritinib, Ensartinib, Alectinib) And Lorlatinib), BCR-ABL inhibitors (e.g., Imatinib and Dasatinib), EGFR inhibitors (e.g., Erlotinib, EGF816, Afatinib (Afatinib), Osimertinib mesylate (Osimertinib), Gefitinib (Gefitinib) and Rociletinib (Rociletinib), B-Raf blockers (for example, Sorafenib (Sorafenib) ), Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and BGB-3111), VEGFR inhibitors (for example, bevacizumab (Bevacizumab), Apatinib, Lenvatinib, Aflibercept and Axitinib), FGFR blockers (e.g., AZD4547, B-701, FGF401 and INCB05482), c-Met inhibitors (for example, Savolitinib, merestinib, Capmatinib, INC280 and Glesatinib), Axl inhibitors (for example, ONO-7475 and BGB324 ), Mek inhibitors (e.g., Cobimetinib, Binimetinib, Selumetinib and Trametinib), CDK inhibitors (e.g., Dinasceril ( Dinaciclib), Abemaciclib, Palbociclib and trilaciclib), Btk blockers (for example, ONO-4059, Ibrutinib and Acalabrutinib), PI3K-δ /γ inhibitors (for example, TGR-1202, INCB050465 and IPI-549), JAK-1/2 inhibitors (for example, Itacitinib and Ruxolitinib), ERK inhibitors (for example, SCH 900353), TGFbR1 Blockers (eg, Galunisertib), cancer cell stemness (Cancer c ell stemness) Kinase inhibitor (for example, Amcasertib), FAK inhibitor (for example, Defactinib), Syk/FLT3 dual inhibitor (for example, TAK-659), ATR inhibitor (E.g., AZD6738), Wee1 kinase inhibitors (e.g., AZD1775), multi-target tyrosine kinase inhibitors (e.g., sunitinib (Sunitinib), pazopanib (Pazopanib), cabozantinib) ), Regorafenib, Nintedanib, Sitravatinib and Midostaurin (Midostaurin), mTOR inhibitors (e.g., Temsirolimus, Everolimus (Everolimus) ), Vistusertib, Irinotecan), HDAC inhibitors (e.g., Vorinostat, Romidepsin, Entinostat, Sidar The amine (Chidamide), Mocetinol (Mocetinostat), Citarinostat, Pabirestat (Panobinostat), Valproate (Valproate)), PARP inhibitors (e.g., Niraparib (Niraparib), Olapa Olaparib, Veliparib, Rucaparib, Beigene-290), aromatase inhibitors (e.g., Exemestane, Letrozole), EZH2 Inhibitors (for example, tazemetostat), galectin-3 inhibitors (for example, GR-MD-02), STAT3 inhibitors (for example, Napabucasin), DNMT inhibitors (for example, azacytosis Glycoside (Azacitidine), SMO inhibitors (e.g., Vismodegib), Hsp90 inhibitors (e.g., XL888), γ-tubulin-specific inhibitors (e.g., Glaziovianin A, Primbulin ( Plinabulin), HIF2α inhibitors (for example, PT2385), glutamine amidase inhibitors (for example, CB-839), E3 ligase inhibitors (for example, Avadomide), Nrf2 activators (for example, Omaveloxolone), refined Aminase inhibitors (for example, CB-1158), cell cycle inhibitors (for example, Trabectedin (Trabectedin)), Ephrin B4 inhibitors (for example, sEph B4-HAS), IAP antagonists (e.g., Birinapant), anti-Her2 antibodies (e.g., rastuzumab, trastuzumab-maytan new conjugate (Trastuzumab) emtansine), Pertuzumab and Margetuximab), anti-EGFR antibodies (e.g., Cetuximab, Panitumumab, Necitumumab and Nituximab) Nimotuzumab), anti-VEGF antibody (e.g., bevacizumab), anti-VEGFR2 antibody (e.g., Ramucirumab (Ramucirumab)), anti-CD20 antibody (e.g., Rituximab (Rituximab) ), Ofatumumab, Ublituximab and Obinutuzumab), anti-CD30 antibodies (for example, Brentuximab Vedotin) ), anti-CD38 antibody (for example, Daratumumab), anti-DR5 antibody (for example, DS-8273a), anti-CA125 antibody (for example, Oregovomab), anti-DLL4 antibody (for example , Demcizumab (Demcizumab)), anti-fucosyl GM1 antibody (e.g., BMS-986012), anti-gpNMB antibody (e.g., Glembatumumab vedotin (Glembatumumab vedotin)), anti-intermediate Mesothelin antibody (for example, BMS-986148), anti-MMP9 antibody (for example, Andecaliximab (Andecaliximab)), anti-GD2 antibody (for example, Dinutuximab (Dinutuximab)-β), Anti-c-Met antibody (e.g., ABT-399), anti-FOLR1 antibody (e.g., mivetuximab soravtansine conjugate (Mirvetuximab soravtansine)), anti-Ang2-VEGF bispecific antibody (e.g., Van Nosizumab (Vanucizumab), anti-CD30-CD16A bispecific antibody (e.g., AFM13), anti-CD79b antibody (e.g., Polatuzumab Vedotin), anti-FAP antibody/IL -2 fusion protein (for example, RO6874281), anti-CEA antibody/IL-2 fusion protein (for example, Cergutuzumab amunaleukin), anti-CEA-CD3 bispecific antibody (for example, RO6958688), anti-DLL3 antibody (for example, Rovalpit uzumab tesirine), anti-CD3-CD19 bispecific antibodies (for example, Blinatumomab), and anti-CD20-CD3 bispecific antibodies (for example, REGN1979).

In addition, as cancer immunotherapeutics, for example, anti-PD-1 antibodies (for example, nivolumab, seprolizumab (REGN-2810), pembrolizumab (MK-3475), sparta Daclizumab (PDR-001), tislelizumab (BGB-A317), AMP-514 (MEDI0680), dotalizumab (ANB011/TSR-042), teriprizumab (JS001) ), Carrelizumab (SHR-1210), Genovumab (CBT-501), Sintilizumab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003 , BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188, JNJ-63723283, AB122, etc. ), anti-PD-L1 antibodies (e.g., Atelizumab (RG7446/MPDL3280A), Aviruzumab (PF-06834635/MSB0010718C), Duvaluzumab (MEDI4736), BMS-936559, STI- 1014, KN035, LY3300054, SHR-1316, CS1001 (WBP3155), MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502 (TQB2450), JS003 or CX-072, etc. ), PD-L1/VISTA antagonist (e.g., CA-170, etc.), PD-L1/TIM3 antagonist (e.g., CA-327, etc.), anti-PD-L2 antibody, anti-CTLA-4 antibody (e.g., Ipi Monoclonal antibodies (MDX-010), AGEN1884 and tremelimumab, etc.), anti-LAG-3 antibodies (e.g., riralimab (BMS-986016), LAG525, REGN3767 and MK-4280, etc.), LAG-3 Fusion proteins (e.g., IMP321, etc.), anti-Tim3 antibodies (e.g., MBG453 and TSR-022, etc.), anti-KIR antibodies (e.g., Lirilumab (BMS-986015), IPH2101, LY3321367, and MK-4280 Etc.), anti-BTLA antibodies, anti-TIGIT antibodies (for example, Tiragolumab (Tiragolumab) and BMS-986207), anti-VISTA antibodies (for example, JNJ-61610588, etc.), anti-CD 137 antibody (for example, Urelumab (BMS-663513) and Utomilumab (PF-05082566), etc.), anti-CSF-1R antibody or CSF-1R inhibitor (for example, Cabiralizumab (FPA008/BMS-986227), Emactuzumab, LY3022855, MCS-110, IMC-CS4, AMG820, Pixidatinib, BLZ945 and ARRY-382, etc.), anti-OX40 antibodies (e.g., MEDI6469, PF-04518600, MEDI0562, MEDI6383, Efizonerimod, GSK3174998, BMS-986178, MOXR0916, etc.), anti-HVEM antibodies, anti-CD27 antibodies (e.g., Varlilumab (CDX-1127), etc.), anti-GITR antibodies (e.g., MK-4166 , INCAGN01876, GWN323 and TRX-518, etc.), anti-CD28 antibodies, anti-CCR4 antibodies (e.g., Mogamulizumab, etc.), anti-B7-H3 antibodies (e.g., Enoblituzumab, etc.), anti-ICOS agonist antibodies (E.g., JTX-2011 and GSK3359609, etc.), anti-CD4 antibodies (e.g., MTRX-1011A, TRX-1, Ibalizumab, huB-F5, Zanolimumab, 4162W94, Gram Reximab (Clenoliximab), Keliximab (Keliximab), AD-519, PRO-542, Cedelizumab (Cedelizumab), TNX-355, Dacetuzumab (Dacetuzumab), Trigalizumab Anti-Tregalizumab, Priliximab, MDX-CD4, CAMPATH-9 and IT1208, etc.), anti-DEC-205 antibody/NY-ESO-1 fusion protein (e.g., CDX-1401, etc.), anti-SLAMF7 Antibodies (e.g., Elotuzumab, etc.), anti-CD73 antibodies (e.g., Oleclumab and BMS-986179, etc.), anti-CD122 antibodies (e.g., NKTR-214, etc.), anti-CD40 agonist antibodies (e.g. , ABBV-428, APX005M and RO7009789, etc.), IDO blockers (e.g., Epacadostat, Indoximod and BMS-986205, etc.), TLR agonists (e.g., Motoli Motolimod, CMP-0 01, G100, IMO-2125, SD-101 and MEDI9197, etc.), adenosine A2A receptor antagonists (e.g., Preladenant, AZD4635, PBF 509 and CPI-444, etc.), anti-NKG2A antibodies (e.g. , Monalizumab (Monalizumab, etc.), anti-CSF-1 antibodies (for example, PD0360324, etc.), immune enhancers (for example, PV-10, etc.), IL-15 super agonists (for example, ALT-803, etc.) ), soluble LAG3 (for example, IMP321, etc.), CD47 antagonists (for example, ALX148, etc.) and IL-12 antagonists (for example, M9241, etc.).

Furthermore, examples of other antibody medicines include anti-IL-1β antibodies (for example, Canakinumab, etc.) and anti-CCR2 antibodies (for example, Palolizumab (Plozalizumab), etc.). [preparation] When the immune checkpoint blocking substance or immune checkpoint blocking drug of the present invention is administered alone or when these are administered together with other drugs, it can be used as an internally administered solid or internally administered liquid for oral administration. Use of sustained-release preparations, controlled-release preparations for oral administration or injections, external preparations, inhalants or suppositories for parenteral administration.

Examples of solid forms for oral administration include tablets, pills, capsules, powders and granules. Capsules include hard capsules and soft capsules.

In such internally administered solid form, one or more active substances are directly or in combination with excipients (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binding agents (for example, hydroxyl Propyl cellulose, polyvinylpyrrolidone, aluminum magnesium silicate, etc.), disintegrants (for example, calcium cellulose glycolate, etc.), lubricants (for example, magnesium stearate, etc.), stabilizers, dissolution aids (For example, glutamic acid, aspartic acid, etc.), etc. are mixed and formulated and used according to a conventional method. Furthermore, if necessary, it may be coated with a coating agent (for example, sugar, gelatin, hydroxypropyl cellulose, hypromellose phthalate, etc.), or may be coated with two or more layers. Furthermore, capsules of absorbable substances such as gelatin are also included.

Internal liquids for oral administration include pharmacologically acceptable liquids, suspensions, emulsions, syrups and elixirs. In this liquid, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol, or a mixture of these, etc.). Furthermore, the liquid formulation may contain a wetting agent, a suspending agent, an emulsifier, a sweetener, a flavor, an aromatic, a preservative, or a buffer, etc.

In addition, sustained-release preparations in oral administration are also effective. The so-called colloidal substance used in these sustained-release preparations refers to a substance that contains a solvent and swells, and its colloidal particles are connected to each other to form a three-dimensional network structure and lose fluidity, thereby forming a jelly-like object. It is mainly used as binding agent, viscosity increasing agent and slow-release base agent in preparation. For example, gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, guar gum, gelatin, hydroxypropyl can be used Methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose or hydroxyethyl methyl cellulose, etc.

When used as an injection or infusion for infusion, the injection or infusion can be in any form of aqueous solution, suspension or emulsion, and it can also be dissolved by adding a solvent when used , Suspension or Emulsion, together with a pharmaceutically acceptable carrier to prepare a solid dosage form. As a solvent used in injections or intravenous infusions, for example, distilled water for injection, physiological saline, glucose solution and isotonic solution (for example, sodium chloride, potassium chloride, glycerol, mannitol, sorbitol, boric acid , Borax, propylene glycol and other solutions) and so on.

Here, examples of pharmaceutically acceptable carriers include stabilizers, dissolution aids, suspending agents, emulsifiers, analgesics, buffers, preservatives, preservatives, pH adjusters, antioxidants, and the like. As stabilizers, for example, various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sodium bisulfite, thiosulfate can be used. Sodium sulfate, sodium ethylenediaminetetraacetate, sodium citrate, dibutylhydroxytoluene, etc. As the dissolution aid, for example, alcohols (for example, ethanol, etc.), polyols (for example, propylene glycol, polyethylene glycol, etc.), nonionic surfactants (for example, Polysorbate 20 (registered trademark), Polysorbate 80 ( Registered trademark), HCO-50, etc.) etc. As the suspending agent, for example, glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate, etc. can be used. As the emulsifier, for example, gum arabic, sodium alginate, tragacanth, etc. can be used. As an analgesic, for example, benzyl alcohol, chlorobutanol, sorbitol, etc. can be used. As a buffer, for example, phosphate buffer, acetic acid buffer, boric acid buffer, carbonic acid buffer, citrate buffer, Tris buffer (tris buffer), glutamine buffer, ε-aminocaproic acid buffer, etc. As a preservative, for example, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, chlorobutanol, benzyl alcohol, benzalkonium chloride, and Sodium hydrogen acetate, sodium ethylenediaminetetraacetate, boric acid, borax, etc. As the preservative, for example, benzalkonium chloride, p-hydroxybenzoic acid, chlorobutanol, etc. can be used. As the pH adjuster, for example, acid, sodium hydroxide, phosphoric acid, acetic acid, etc. can be used. As an antioxidant, for example, water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc. can be used, (2) ascorbyl palmitate, butyl Oil-soluble antioxidants such as hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, α-tocopherol, etc., and (3) citric acid, ethylenediaminetetraacetic acid, sorbose Metal chelating agents such as alcohol, tartaric acid, phosphoric acid, etc.

Especially when the active ingredient of the medicament of the present invention is nivolumab, as a pharmaceutically acceptable carrier, for example: D-mannitol, sodium citrate hydrate, sodium chloride, diethylene triamine Pentaacetic acid, Polysorbate 80 and pH regulator. In addition, when the active ingredient of the medicament of the present invention is pembrolizumab, as a pharmaceutically acceptable carrier, for example, L-histidine, L-histidine hydrate, refined sugar and Polysorbate are used. 80.

Injections or intravenous infusions can be manufactured by sterilizing or aseptic operations in the final step, for example, filtering and sterilizing with a filter or the like, and then filling them into a sterile container. In addition, injections or intravenous infusions can also be used by dissolving the sterile powder (powder that may contain a pharmaceutically acceptable carrier) obtained through vacuum drying and freeze drying in a suitable solvent.

Dosage forms for parenteral administration of external preparations include, for example, sprays, inhalants, sprays, aerosols, ointments, gels, creams, dressings, patches, liniments and nose drops剂 etc. These active substances containing one or more of them are prepared according to known methods or where they are commonly used.

In addition to the commonly used diluents, sprays, inhalants and sprays can also contain stabilizers such as sodium bisulfite and buffers that impart isotonicity, such as sodium chloride, sodium citrate or citric acid Such isotonic agents. The manufacturing method of the spray is described in detail in, for example, US Patent No. 2868691 and No. 3095355.

As an inhalant for parenteral administration, it includes aerosol, powder for inhalation or liquid for inhalation. The liquid for inhalation can also be dissolved or suspended in water or other suitable medium during use. And the form of use.

These inhalants can be manufactured according to known methods. For example, in the case of a liquid for inhalation, preservatives (for example, benzalkonium chloride, parabens, etc.), coloring agents, and buffering agents (for example, sodium phosphate, sodium acetate, etc.) are appropriately selected as necessary. ), isotonic agents (for example, sodium chloride, concentrated glycerin, etc.), thickeners (for example, carboxyvinyl polymer, etc.), absorption promoters, etc.

In the case of powders for inhalation, lubricants (for example, stearic acid and its salts, etc.), binding agents (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.) ), colorants, preservatives (for example, benzalkonium chloride, parabens, etc.) or absorption enhancers.

When administering a liquid for inhalation, a nebulizer (for example, a nebulizer, nebulizer, etc.) is usually used, and when administering a powder for inhalation, an inhalation dispenser for powdered medicine is usually used.

The ointment can be manufactured according to the known or commonly used method. For example, it is prepared by mixing or melting one or more active substances into the base. The ointment base can be selected from known or commonly used ones. For example, it can be selected from higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate, myristate, palmitate, stearin Acid esters, oleates, etc.), waxes (for example, beeswax, spermaceti, ozokerite, etc.), surfactants (for example, polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (for example, cetyl alcohol, Stearyl alcohol, cetearyl alcohol, etc.), silicone oil (for example, dimethyl polysiloxane, etc.), hydrocarbons (for example, hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols ( For example, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, Macrogol, etc.), vegetable oils (for example, castor oil, olive oil, sesame oil, turpentine, etc.), animal oils (for example, mink oil, egg butter, dogfish One of alkane, squalene, etc.), water, absorption enhancer, or anti-rash agent is used alone or as a mixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a fragrance agent, etc. may also be contained.

The gel can be produced according to known or usual usage. For example, it is prepared by dissolving one or more active substances into the base. The gel base can be selected from known or commonly used ones. For example, it can be selected from lower alcohols (for example, ethanol, isopropanol, etc.), gelling agents (for example, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.) , Neutralizers (for example, triethanolamine, diisopropanolamine, etc.), surfactants (for example, polyethylene glycol monostearate, etc.), rubbers, water, absorption enhancers and anti-rash agents These can be used alone or in a mixture of two or more. Furthermore, preservatives, antioxidants, fragrances, etc. may also be included.

The cream can be manufactured according to known or usual usage. For example, it can be manufactured by melting or emulsifying one or more active substances into the base. The cream base can be selected from known or commonly used ones. For example, it can be selected from higher fatty acid esters, lower alcohols, hydrocarbons, polyols (for example, propylene glycol, 1,3-butanediol, etc.), higher alcohols (for example, 2-hexyldecanol, cetyl alcohol, etc.) , Emulsifiers (for example, polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, and anti-rash agents are used alone or in combination of two or more. Furthermore, preservatives, antioxidants, fragrances, etc. may also be included.

The cataplasm can be manufactured according to the known or commonly used methods. For example, one or more active materials can be melted into the base to prepare a kneaded product and spread on the support. The wet cloth base can be selected from known or commonly used ones. For example, it can be selected from the group consisting of thickeners (for example, polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (for example, urea, glycerin, propylene glycol, etc.), fillers (For example, kaolin, zinc oxide, talc, calcium, magnesium, etc.), water, dissolution aid, adhesion imparting agent, and anti-rash agent are used alone or in combination of two or more. Furthermore, preservatives, antioxidants, fragrances, etc. may also be included.

The patch can be manufactured according to known or commonly used methods. For example, one or more active substances can be melted into the base, and then spread and coated on the support. The base for patch preparations can be selected from known or commonly used ones. For example, one selected from the group consisting of polymer bases, oils and fats, higher fatty acids, adhesion-imparting agents, and anti-rash agents can be used alone or as a mixture of two or more. Furthermore, preservatives, antioxidants, fragrances, etc. may also be included.

The rubbing agent can be manufactured according to the known or commonly used methods. For example, dissolving, suspending or emulsifying one or more actives to a single selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier and suspending agent, etc. One type or two or more types are prepared. Furthermore, preservatives, antioxidants, fragrances, etc. may also be included.

Other compositions for parenteral administration include suppositories for intrarectal administration and pessaries for intravaginal administration that contain one or more active substances and are prescribed according to conventional methods.

In addition, the present invention also includes the following inventions. which is, (1) A cancer progression inhibition, recurrence inhibition and/or treatment method, which comprises administering an effective amount of an immune checkpoint blocking substance to cancer patients whose blood PD-1 concentration does not reach a predetermined value; (2) An immune checkpoint blocking substance for inhibiting and/or treating cancer progression and/or recurrence in cancer patients whose blood PD-1 concentration does not reach a predetermined value; (3) The use of an immune checkpoint blocking substance for the manufacture of cancer progression inhibition, recurrence inhibition and/or treatment for administering cancer patients whose blood PD-1 concentration does not reach a predetermined value Agent.

Furthermore, the present invention also includes an invention related to a specific method, which measures the concentration of PD-1 in the blood of cancer patients, and based on this concentration, specifies cancer patients who can more expect the effect of immune checkpoint inhibitors, or who cannot expect immune examination Some cancer patients who hinder the effect of the medicine. That is, a cancer patient whose blood PD-1 concentration does not reach a predetermined reference value (cutoff value) can be specified as a patient who can expect the effect of the immune checkpoint blocking drug. On the other hand, for the predetermined Cancer patients whose concentration is above the reference value can be specified as patients who cannot expect the effect of immune checkpoint blocking drugs.

For example, the concentration of PD-1 in the blood may be less than any value of 55-75 pg/mL, preferably less than any value of 55-70 pg/mL, and more preferably less than 55-65 pg/mL. Any value of mL, more preferably less than any value of 60 to 65 pg/mL, and more preferably less than any value of 55 to 60 pg/mL, is specified for patients who are more likely to expect immune checkpoint hindrance Cancer patients with the effect of drugs (for example, anti-PD-1 antibodies); on the other hand, the concentration of PD-1 in the blood can be set to 55-75 pg/mL or more, preferably 55-70 pg/mL. Any value of mL or more, more preferably 55 to 65 pg/mL or more, more preferably 60 to 65 pg/mL or more, more preferably 55 to 60 pg A patient with an arbitrary value of /mL or more is specified as a cancer patient who cannot expect the effect of an immune checkpoint inhibitor (for example, anti-PD-1 antibody). In addition, the concentration of PD-1 in the blood can be less than about 75 pg/mL, preferably less than about 70 pg/mL, more preferably less than about 65 pg/mL, and more preferably less than about 60 pg/mL. pg/mL, and preferably less than about 55 pg/mL, are specified as cancer patients who can expect the effect of immune checkpoint blocking drugs (for example, anti-PD-1 antibodies); the blood PD-1 concentration can be determined It is about 75 pg/mL or more, preferably 70 pg/mL or more, more preferably 65 pg/mL or more, more preferably 60 pg/mL or more, and more preferably 55 pg/mL or more for patients Cancer patients who cannot expect the effects of immune checkpoint blocking drugs (for example, anti-PD-1 antibodies).

Furthermore, the present invention also includes an invention related to the use of PD-1 in the blood, using the PD-1 in the blood as a drug for predicting the effectiveness of immune checkpoint inhibitors in cancer progression inhibition, recurrence inhibition and/or treatment Of biomarkers. That is, as described above, it is possible to predict the effectiveness of the immune checkpoint inhibitory substance using the concentration of PD-1 in the blood of cancer patients as an index.

In addition, the PD-1 concentration in the blood of cancer patients can be used as an index to evaluate and judge the progress of cancer. Here, the degree of progression of cancer refers to, for example, the distinction between early cancer, advanced cancer, and terminal cancer. Moreover, the so-called progression of cancer refers to the stage of cancer. The stages of cancer can be classified into stages 0 to 4 as shown below. Stage 0: The cancer cells stay in the mucosa or epithelial cells and have not metastasized to the lymph nodes. Stage 1: The cancer has spread slightly but only stays in the muscle layer without metastasis to the lymph nodes. Stage 2: The cancer cells have not metastasized to the lymph nodes, but infiltrated beyond the muscle layer. Maybe the cancer has spread, but it has slightly spread to the lymph nodes. Stage 3: Cancer cells have spread to lymph nodes. Stage 4: Cancer cells have metastasized to other organs.

The more the cancer progresses, the more the PD-1 concentration in the blood rises. The PD-1 concentration in the blood of cancer patients at each stage is determined in advance, and the PD-1 concentration in the blood is correlated with the progression of cancer, so that the progression of cancer can be evaluated based on the PD-1 concentration in the blood.

For example, the PD-1 concentration in the blood of cancer patients can be measured regularly, and the progression of cancer can be evaluated based on the changes in the blood PD-1 concentration. When the concentration of PD-1 in the blood decreases relative to the previously measured value, it can be judged that the cancer is being eliminated, cured, radically cured or alleviated. On the other hand, when the PD-1 concentration in the blood increases relative to the previously measured value, it can be judged that the cancer has progressed and worsened. By measuring the concentration of PD-1 in the blood of cancer patients who are already under treatment, the therapeutic effect can also be evaluated.

In addition, the PD-1 concentration in the blood of cancer patients can be used as an indicator to predict the risk of cancer recurrence. Here, the so-called recurrence of cancer refers to the recurrence of cancer after the treatment is completed in patients whose cancer has been cured, radically cured or remissioned, and the cancer has been eliminated. Recurrence also includes recurrence caused by metastasis to other organs. The higher the concentration of PD-1 in the blood, the higher the risk of cancer recurrence. By measuring the concentration of PD-1 in the blood of a patient whose cancer is temporarily eliminated, the risk of cancer recurrence in the patient can be predicted. The PD-1 concentration in the blood of cancer patients who have received cancer treatment is measured, and the patient is also regularly diagnosed thereafter. The patients are classified into cancer patients with recurrence and cancer patients without recurrence, and the PD- in the blood of the two groups is measured. 1 Concentration, the cut-off value is set based on the blood PD-1 concentration at the time of each group measurement. When the blood PD-1 concentration is lower than the cut-off value, the risk of cancer recurrence can be predicted to be lower, and the In the case of this threshold, it can be predicted that the risk of cancer recurrence is high. For example, when the concentration of PD-1 in blood is 30-40 pg/mL or more, preferably 30-35 pg/mL or more, and more preferably about 33 pg/mL or more , It can be judged that the risk of cancer recurrence is high. This value is preferably the value when measured by ELISA.

By predicting the risk of cancer recurrence, patients with high risk of cancer recurrence can be identified. The present invention also includes methods for patients with a high risk of recurrence of specific cancers.

The present invention also includes a test kit for determining the concentration of PD-1 in blood. This test kit can be used as a kit for predicting the effectiveness of anti-PD-1 antibodies and other immune checkpoint blocking drugs in cancer progression inhibition, recurrence inhibition and/or treatment, and can be used for specific anti-PD-1 A set of cancer patients whose immune checkpoint blocking drugs such as antibodies are effective, or a set of cancer patients who cannot expect the effects of immune checkpoint blocking drugs such as anti-PD-1 antibodies, a set used to evaluate the progress of cancer, and used for prediction Use of kits for cancer recurrence risk, kits for specific cancer patients with high recurrence risk, etc.

The test kit is a kit for immunological assays containing anti-PD-1 antibodies as the antibodies for the assay. The immunoassay kit can be based on, for example, immunoblotting method, enzyme immunoassay (for example, EIA, ELISA, CLEIA, CLIA and ELISPOT, etc.), radioimmunoassay (for example, RIA, IRMA, RRA and CPBA) Etc.), fluorescent antibody methods (for example, FA, FIA, TR-FIA, IFA, etc.), methods using agglutination, immunochromatography, etc. Among them, a kit based on a sandwich immunological assay, etc. is preferred, and a kit for ELISA (enzyme-bound immunosorbent assay) that can easily obtain a correct measurement value is more preferred. The anti-PD-1 antibody for measurement used in the examination kit is preferably the same antibody as the anti-PD-1 antibody actually administered to the cancer patient. For example, when Nivolumab is used in cancer treatment, the antibody for measurement included in the above-mentioned examination kit is Nivolumab. In addition, in the sandwich immunoassay method, a capture antibody (immobilized antibody) and a detection antibody are used. For example, an anti-PD-1 antibody that is actually used for cancer treatment is included in the above inspection kit as the capture antibody. can.

The above-mentioned inspection kit may also include reagents such as a specimen collection instrument, a specimen processing solution, and a color-developing substrate, and may further include equipment required for the test or instructions for use. In the case of a sandwich immunoassay kit, it contains a carrier such as a microtiter plate immobilized with anti-PD-1 antibody.

In this specification, the contents of all patent documents and non-patent documents or references cited in the disclosure can be cited here as part of this specification. [Example]

The present invention is explained in more detail with the following examples, but the scope of the present invention is not limited thereto. The industry can make various changes and modifications based on the description of the present invention, and these changes and modifications are also included in the present invention. [method] (1) Collection of samples Serum was collected from healthy volunteers and kidney cancer patients with consent, and stored at -80 degrees before use. (2) Preparation of culture plate for Nivolumab immobilized ELISA The Ab-Match Universal kit (Code No.5310) of MBL was used to prepare a culture plate for ELISA with nivolumab immobilized. Use the coating buffer of the kit to dilute nivolumab according to the attached instructions, and make 100 ng/μL of nivolumab solution, and then dispense 100 μL per well to the attached 96-well culture plate. The reaction was carried out overnight at 4°C, and nivolumab was immobilized onto the culture plate. After that, the culture plate was washed twice with physiological saline, 200 μL of the blocking agent was added to each well, and the reaction was performed at room temperature for 1 hour to perform blocking. (3) Determination of PD-1 concentration in serum The PD-1 concentration in the serum was measured using Invitrogen's Human PD-1 ELISA kit (Catalog No. BMS2214). As a culture plate for anti-PD-1 antibody immobilized ELISA, use the culture plate prepared in (2) with immobilized nivolumab, and use anti-PD other than immobilized nivolumab The culture plate of the above set of -1 antibody was used as a control. In addition, as a labeled antibody for detection, a set of biotin-conjugated anti-PD-1 antibody was used. Add 50 μL of sample dilution buffer, 50 μL of serum and 50 μL of biotin-conjugated anti-PD-1 antibody to the wells of the culture plate, and react for 2 hours at room temperature. Then wash, add streptavidin-HRP (Horseradish peroxidase, horseradish peroxidase), use TMB (3,3',5,5'-Tetramethylbenzidine, tetramethylbenzidine) matrix for color development, Determine absorbance. [result] (1) Comparison of PD-1 concentration in serum by ELISA using nivolumab and other anti-PD-1 antibodies As described in methods (2) and (3), use ELISA that uses nivolumab as immobilized antibody and ELISA that uses anti-PD-1 antibodies other than nivolumab as immobilized antibody , Measure the PD-1 concentration in serum of healthy normal people and renal cancer patients. Figure 2 shows the value of PD-1 in the serum measured by the previous ELISA and the PD-1 concentration of the same sample measured by the ELISA using nivolumab as the immobilized antibody. cont1 and cont2 represent specimens of healthy normal people, and the others represent specimens of kidney cancer patients. Although the sensitivity of nivolumab ELISA is slightly lower, it has a lower background under the PD-1 concentration of healthy normal people, and it can be separated from kidney cancer patients well. In ELISA using other anti-PD-1 antibodies, even if it is a healthy normal person, PD-1 shows a high value, which is difficult to distinguish from cancer patients. It is believed that this system is affected by the specificity of other anti-PD-1 antibodies to PD-1 or the affinity with the antibody used for detection. The results show that nivolumab is more useful for distinguishing specimens from cancer patients. In the case of normal subjects, the background is low, so the reliability of the examination system is high. (2) The concentration of PD-1 in the serum of renal cancer patients in the ELISA measurement system of nivolumab Using ELISA using nivolumab as the immobilized antibody, the PD-1 concentration in the serum of 23 healthy normal people, 30 kidney cancer patients without metastasis, and 20 kidney cancer patients with metastasis or recurrence were measured respectively. . As shown in Figure 3, the average serum PD-1 concentration is 28.31 pg/mL in healthy normal people (Cont), 28.95 pg/mL in non-metastasis kidney cancer (Met(-)), and For renal cancer with metastasis or recurrence (Met(+)/Rec), it was 51.8 pg/mL. Through one-way analysis of variance (one-way ANNOVA analysis), significant differences were confirmed among the three groups. That is to say, the concentration of PD-1 in the serum increases significantly in the case of advanced renal cancer. Based on the above results, it shows the possibility that the increase in serum PD-1 concentration can be used as a biomarker for cancer progression in a measurement system using nivolumab. (3) The relationship between serum PD-1 concentration and cancer recurrence rate in the ELISA measurement system of nivolumab To study the recurrence of renal cancer patients without metastasis. The results are shown in Figure 4. The results showed that among the cases without metastasis shown in (2), cases with a higher serum PD-1 concentration (33.0 pg/mL or more) had a higher recurrence rate of cancer. It can be seen that the concentration of PD-1 in serum measured by the ELISA measurement system of Nivolumab can be used as an indicator of the recurrence rate. (4) The relationship between the concentration of PD-1 in serum in the ELISA measurement system of nivolumab and the therapeutic effect of nivolumab The correlation between the concentration of PD-1 in the blood before the administration of nivolumab and the therapeutic effect of nivolumab in the ELISA measurement system of nivolumab was studied. As the case of nivolumab administration, 6 cases were used, and according to the RECIST guidelines, it was judged whether there was any effect within 6 months after the administration of nivolumab. The results are shown in Fig. 5. In addition, in Table 1, for the patient group of patients with PR or SD, or each group of patients with PD, the average value, standard deviation and 95% reliability of the blood PD-1 concentration are shown for the effect of nivolumab Interval. As shown in Figure 5 and Table 1, in the case of the use of nivolumab for renal cancer recurrence, patients with low serum PD-1 concentration before the administration of nivolumab showed signs of PR or SD effect. On the other hand, patients with a higher concentration of PD-1 in serum are PD. That is to say, the effect of nivolumab is lower in patients with higher serum PD-1 concentration, and the effect is higher in patients with lower serum PD-1 concentration.

[Table 1]

Based on the above results, it is shown that in patients with low serum PD-1 concentration when measured by the ELISA measurement system using nivoliuximab, the therapeutic effect of nivoliuximab is higher, thus indicating that the serum PD-1 The -1 concentration can be used as a biomarker for the effectiveness of nivolumab.

In addition, the cut-off value of PD-1 concentration in serum used for effectiveness determination can be set based on the 95% confidence interval in Table 1. [Industrial availability]

With the method of the present invention, immune checkpoint blocking drugs (for example, anti-PD-1 antibodies) can be used efficiently.

All publications, patents and patent applications cited in this specification are directly incorporated into this specification by reference.

Figure 1 is a diagram showing the principle of PD-1 assay ELISA using nivolumab as the immobilized antibody. Fig. 2 is a graph showing the comparison of the results of the previous ELISA using anti-PD-1 antibody and the ELISA using nivolumab as the immobilized antibody. Fig. 3 is a graph showing the comparison of the PD-1 concentration in the serum of healthy normal people and patients with kidney cancer by ELISA using nivolumab as the immobilized antibody. Figure 4 is a graph showing the correlation between serum PD-1 concentration and recurrence in cases of renal cancer without metastasis. Fig. 5 is a graph showing the relationship between the serum PD-1 concentration and the therapeutic effect of nivolumab in cases of renal cancer recurrence.

Claims (41)

A cancer progression inhibitor, recurrence inhibitor and/or therapeutic agent, which is characterized in that it contains an immune checkpoint blocking substance as an active ingredient, and is administered to cancer patients whose blood PD-1 concentration does not reach a predetermined threshold. Such as the agent of claim 1, wherein the PD-1 in the blood is free PD-1. Such as the agent of claim 1, wherein the PD-1 in the blood is PD-1 and free PD-1 present in extracellular bodies. Such as the agent of any one of claims 1 to 3, wherein the critical value is any value ranging from 55 to 75 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the threshold value is any value ranging from 55 to 70 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the critical value is any value ranging from 55 to 65 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the threshold value is any value ranging from 60 to 65 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the critical value is any value ranging from 55 to 60 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the cut-off value is about 75 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the cut-off value is about 70 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the cut-off value is about 65 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the cut-off value is about 60 pg/mL. Such as the agent of any one of claims 1 to 3, wherein the cut-off value is about 55 pg/mL. The agent according to any one of claims 1 to 13, wherein the immune checkpoint blocking substance is anti-PD-1 antibody, anti-PD-L1 antibody, PD-1 antagonist, PD-L1/VISTA antagonist, PD-L1 /TIM3 antagonist, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody, LAG-3 fusion protein, anti-Tim3 antibody, anti-KIR antibody, anti BTLA antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-CSF-1R antibody or CSF-1R inhibitor. The agent according to any one of claims 1 to 13, wherein the immune checkpoint blocking substance is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody. The agent according to claim 15, wherein the anti-PD-1 antibody is nivolizumab, seprolizumab, pembrolizumab, spartizumab, tislelizumab, AMP-514 , Dotalizumab, Teriplizumab, Carrelizumab, Genolizumab, Sintilizumab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188, JNJ-63723283 or AB122. The agent of claim 14 or 15, which recognizes PD-1 in blood by the anti-PD-1 antibody administered to cancer patients. For the agent of claim 14 or 15, it measures PD-1 in the blood by using the same antibody measurement system as the anti-PD-1 antibody administered to the cancer patient. The agent of claim 18, wherein the measurement system is an ELISA that uses the same antibody as the anti-PD-1 antibody administered to the cancer patient as the capture antibody. Such as the agent of claim 15, wherein the anti-PD-L1 antibody is atelizumab, aviruzumab, duvaluzumab, BMS-936559, STI-1010, STI-1011, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK104, ZKAB001, FAZ053, CBT-502, JS003 or CX-072. The agent of claim 15, wherein the anti-CTLA-4 antibody is ipilimumab, AGEN1884 or tremelimumab. The agent according to any one of claims 1 to 21, wherein the cancer is solid cancer or blood cancer. The agent of claim 22, wherein the solid cancer is selected from malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell carcinoma, breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma , Nasopharyngeal head cancer, uterine cancer, anal cancer, colorectal cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophageal gastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer , Prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary cancer, skin cancer, testicular cancer (blastoma), vaginal cancer, vulvar cancer, penile cancer, One of small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, spinal tumor, brain tumor, glioblastoma, glioma sarcoma, squamous cell carcinoma, bone/soft tissue sarcoma, and Kaposi's sarcoma Cancer of the above. The agent of claim 23, wherein the solid cancer is renal cell carcinoma. The agent of claim 22, wherein the blood cancer is multiple myeloma, malignant lymphoma, leukemia, primary malignant lymphoma of the central nervous system, myelodysplastic syndrome or myelodysplastic syndrome. The agent according to any one of claims 1 to 25, wherein the concentration of PD-1 present in the blood is the concentration before the immune checkpoint blocking substance is administered. A use of PD-1 in blood, which is used as a biomarker for predicting the effectiveness of immune checkpoint inhibitors in cancer progression inhibition, recurrence inhibition and/or treatment. Such as the use of claim 27, wherein the PD-1 concentration in the blood is used as a biomarker to predict the effectiveness of the immune checkpoint inhibitor in cancer progression inhibition, recurrence inhibition and/or treatment. Such as the use of claim 27 or 28, wherein the PD-1 in the blood is sPD-1. Such as the use of claim 27 or 28, wherein the blood PD-1 is sPD-1 and extracellular PD-1. Such as the use of any one of claim 27 to 30, wherein the active ingredient of the immune checkpoint blocking drug is anti-PD-1 antibody, anti-PD-L1 antibody, PD-1 antagonist, PD-L1/VISTA antagonist, PD-L1/TIM3 antagonist, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody, LAG-3 fusion protein, anti-Tim3 antibody, anti-KIR Antibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-CSF-1R antibody, or CSF-1R inhibitor. Such as the use of claim 31, wherein the anti-PD-1 antibody is nivolizumab, seprolizumab, pembrolizumab, spartizumab, tislelizumab, AMP-514 , Dotalizumab, Teriplizumab, Carrelizumab, Genolizumab, Sintilizumab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF-06801591, CX-188, JNJ-63723283 or AB122 . The use of claim 31, wherein the PD-1 in the blood is recognized by the anti-PD-1 antibody administered to the cancer patient. The use of claim 31, wherein the PD-1 concentration in the blood is measured by a measurement system using the same antibody as the anti-PD-1 antibody administered to the cancer patient. The use of claim 34, wherein the measurement system uses the same antibody as the anti-PD-1 antibody administered to the cancer patient as an ELISA for the capture antibody. Such as the use of claim 31, wherein the anti-PD-L1 antibody is atelizumab, aviruzumab, duvaluzumab, BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR- 1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 or CX-072. The use of claim 31, wherein the anti-CTLA-4 antibody is ipilimumab, AGEN1884 or tremelimumab. The use of any one of claims 27 to 37, wherein the cancer is solid cancer or blood cancer. The use of claim 38, wherein the solid cancer is selected from malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell carcinoma, breast cancer, ovarian cancer, serous ovarian cancer, ovarian clear cell adenocarcinoma , Nasopharyngeal head cancer, uterine cancer, anal cancer, colorectal cancer, rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophageal gastric junction cancer, small intestine cancer, pancreatic cancer, urothelial cancer , Prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, bile duct cancer, biliary tract cancer, skin cancer, testicular cancer, vagina 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/soft tissue sarcoma and Kaposi's sarcoma. The use of claim 38, wherein the blood cancer is multiple myeloma, malignant lymphoma, leukemia, primary malignant lymphoma of the central nervous system, myelodysplastic syndrome or myelodysplastic syndrome. The use of any one of claims 28 to 40, wherein the concentration of PD-1 in the blood is the concentration before the immune checkpoint blocking drug is administered.

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