Cancer treatment methods and medicines

Abstract

The present disclosure provides a composition, a combination product, a medical device and the like for treating or preventing cancer or a tumor or preventing the recurrence of the cancer or the tumor. The present disclosure provides a composition, a combination product and a medical device for treating or preventing cancer or a tumor or preventing the recurrence of the cancer or the tumor, each of which comprises an immune checkpoint inhibitor and a dendritic cell direct activator or means. In another aspect, the present disclosure provides: a novel cancer treatment method which comprises carrying out a treatment of cancer by employing a combination of a treatment by the administration of an immune checkpoint inhibitor and a treatment for improving the sensitivity to the immune checkpoint inhibitor and, therefore, can be used as an immunotherapy that can be expected to have an excellent therapeutic effect; and a medicine which can be used for the cancer treatment method.

Description

[Technical Field]

[0001] The present disclosure relates to methods for treating cancer, combinations and compositions for use in cancer treatment, and programs for use in cancer treatment, particularly to immunotherapy-based cancer treatment methods, combinations, compositions, and programs. The present disclosure also relates to novel techniques for activating dendritic cells. [Background technology]

[0002] Currently, the most common cancer treatments are known to be surgical therapy (removal of cancer tissue through surgery), chemotherapy (administration of anticancer drugs, including molecular targeted drugs), radiation therapy (irradiation of cancer tissue), immunotherapy (enhancement of the patient's immune function), and combinations of these.

[0003] Among these, immunotherapy is a treatment that utilizes the immune system, an ability that everyone is born with to eliminate foreign substances that enter the body, and aims to treat cancer by enhancing this immune system. While surgical therapy, chemotherapy, and radiation therapy treat cancer using external factors (surgery, anticancer drugs, radiation), immunotherapy primarily utilizes the immune system (immune cells) that an individual naturally possesses to treat cancer. Summary of the Invention [Means for solving the problem]

[0004] The present inventors provide a novel technology for treating or preventing cancer.

[0005] For example, the present disclosure provides the following as representative aspects. [Item 1] a) Immune checkpoint inhibitors and b) a direct dendritic cell activator or means; wherein a) and b) are administered at different times or simultaneously, for treating, preventing, or preventing the recurrence of cancer or tumor. [Item 2] A composition or medical device for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising a direct dendritic cell activator or means, wherein the composition or medical device is administered or used in combination with an immune checkpoint inhibitor. [Item 3] A composition for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising an immune checkpoint inhibitor, wherein the composition is administered in combination with a direct dendritic cell activator or means. [Item 4] The combination, composition or medical device according to any of the preceding items, wherein the dendritic cell direct activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item 5] The combination, composition, or medical device described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item 6] The combination, composition, or medical device described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item 7] The combination, composition or medical device according to any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item 8] The combination, composition or medical device according to any of the preceding items, wherein the cancer expresses PD-L1. [Item 9] The combination, composition, or medical device described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item 10] The combination, composition or medical device according to any of the preceding items, wherein the cancer is lung cancer. [Item 11] The combination, composition or medical device according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item 12] The combination, composition or medical device described in any of the above items, wherein the treatment, prevention or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item 13] The combination, composition, or medical device described in any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item 14] The combination, composition, or medical device described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject for whom treatment with an immune checkpoint inhibitor has been determined to be ineffective. [Item 15] The combination, composition, or medical device described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been treated with an immune checkpoint inhibitor and has been effectively treated, but has subsequently developed progressive disease (PD). [Item 16] The combination, composition or medical device described in any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item 17] The subject has a CD8 + T cells low The combination, composition or medical device according to any of the preceding items, wherein the subject is a patient of the above-mentioned category. [Item 18] A composition for directly activating dendritic cells, comprising an immune adjuvant. [Item 19] The composition according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item 20] The composition according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item 21] a) Immune checkpoint inhibitors and b) immune adjuvants and wherein a) and b) are administered at different times or simultaneously, for treating, preventing, or preventing the recurrence of cancer or tumor. [Item 22] A composition for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising an immune adjuvant, wherein the composition is administered in combination with an immune checkpoint inhibitor. [Item 23] A composition for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising an immune checkpoint inhibitor, wherein the composition is administered in combination with an immune adjuvant. [Item 24] The combination or composition according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item 25] The composition described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item 26] The combination or composition according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item 27] A combination, composition or medical device for activating dendritic cells, comprising the composition according to any of the preceding items and a means for providing radiation therapy. [Item 28] The combination, composition or medical device according to any of the preceding items, wherein the means for providing radiation therapy comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device and a radioactive substance. [Item 29] 10. The combination, composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item 30] 10. The combination, composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate in an abscopal manner. [Item 31] 10. The combination, composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the target lesion. [Item 32] The combination, composition or medical device according to any of the preceding items, further comprising a regulatory T cell inhibitor. [Item 33] The combination, composition or medical device according to any of the preceding items, wherein the regulatory T cell suppressor comprises a COX-2 inhibitor. [Item 34] The combination, composition or medical device according to any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen and lornoxicam. [Item 35] A composition or medical device for activating dendritic cells, including a means for delivering radiation therapy. [Item 36] The composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive substance. [Item 37] The composition or medical device described in any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item 38] 10. The composition or medical device of any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item 39] 10. The composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate in an abscopal manner. [Item 40] 2. The composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the target lesion. [Item 41] A program for use in treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an immune checkpoint inhibitor and / or a dendritic cell activator or procedure; identifying an optimal treatment program based on the patient's response; A program characterized by executing the following. [Item 42] The program according to any of the above items, wherein the patient's response is a predetermined change in the patient's medical image and the measurement value of the patient's tumor marker. [Item 43] A medicament for preventing or treating cancer in a patient, comprising: The pharmaceutical comprises a combination of an immune checkpoint and a dendritic cell activator or means, and is characterized in that the dosage and administration method for a therapeutically or prophylactically effective combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on optimized specific markers for the combination obtained from the patient, and the pharmaceutical is administered based on the specified dosage and administration method. [Item 44] A pharmaceutical or device for treating, preventing, or preventing recurrence of cancer, cancer, or tumor in a subject with a specific regimen, comprising: The medicament comprises a combination of an immune checkpoint and a dendritic cell activator or means, and the regimen comprises: a) administering an immune checkpoint inhibitor, and b) administering a dendritic cell activator A medicine or device comprising: [Item 45] The pharmaceutical or device described in any of the above items, wherein the subject has not received treatment with an immune checkpoint inhibitor, or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item 46] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; A medicament or device according to any of the above items. [Item 47] The particular regimen comprises: c) administering radiation therapy The medicament or device according to any of the above items, further comprising: [Item 48] The pharmaceutical or device according to any of the preceding items, wherein the radiotherapy is palliative irradiation for purposes other than brain metastasis, and is performed by irradiating 10 times with 3 Gy or 20 to 25 times with 2 Gy. [Item 49] The dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week. [Item A1] The subject a) an effective amount of an immune checkpoint inhibitor; b) an effective amount of a direct dendritic cell activator or means; A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering at different times or simultaneously. [Item A2] A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering or using to the subject an effective amount of a direct dendritic cell activator or means, wherein the administration of the direct dendritic cell activator or means is administered or used in combination with an effective amount of an immune checkpoint inhibitor. [Item A3] A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering to the subject an effective amount of an immune checkpoint inhibitor, wherein the administration of the immune checkpoint inhibitor is administered or used in combination with an effective amount of a direct dendritic cell activator or means. [Item A4] The method according to any one of the preceding items, wherein the dendritic cell direct activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item A5] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item A6] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item A7] The method of any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item A8] The method of any of the preceding items, wherein the cancer expresses PD-L1. [Item A9] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item A10] The method according to any of the preceding items, wherein the cancer is lung cancer. [Item A11] The method according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item A12] The method according to any of the preceding items, administered to a subject undergoing treatment with a tyrosine kinase inhibitor. [Item A13] The method of any of the preceding items, administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item A14] The method according to any one of the preceding items, which is administered to a subject who has been determined to be ineffective in treatment with an immune checkpoint inhibitor. [Item A15] The method according to any of the preceding items, which is administered to a subject who has been treated with an immune checkpoint inhibitor and has subsequently experienced progressive disease (PD). [Item A16] The method according to any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item A17] The subject has a CD8 + T cells lowThe method according to any of the preceding items, wherein the subject is a [Item A18] A method for directly activating dendritic cells in a subject, comprising administering to the subject an effective amount of an immune adjuvant. [Item A19] The method according to any one of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item A20] The method according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item A21] The subject a) an effective amount of an immune checkpoint inhibitor; b) an effective amount of an immune adjuvant; A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering at different times or simultaneously. [Item A22] 1. A method for treating, preventing, or preventing the recurrence of cancer or a tumor in a subject, comprising administering to the subject an effective amount of an immune adjuvant, wherein the immune adjuvant is administered in combination with an effective amount of an immune checkpoint inhibitor. [Item A23] 1. A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering to the subject an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered in combination with an immune adjuvant. [Item A24] The method according to any one of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item A25] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item A26] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item A27] A method for activating dendritic cells, wherein radiation therapy delivery means is further used. [Item A28] The method according to any one of the preceding items, wherein the radiation therapy providing means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item A29] 10. The method of any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item A30] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item A31] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the lesion of interest. [Item A32] The method according to any of the preceding items, wherein a regulatory T cell inhibitor is further administered. [Item A33] The method according to any one of the preceding items, wherein the regulatory T cell inhibitor comprises a COX-2 inhibitor. [Item A34] The method according to any one of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam. [Item A35] A method for activating dendritic cells comprising administering to a subject a means for delivering radiation therapy. [Item A36] The method according to any one of the preceding items, wherein the radiation therapy providing means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item A37] The method according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item A38] 10. The method of any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item A39] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item A40] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the lesion of interest. [Item A41] 1. A method for treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an effective amount of an immune checkpoint inhibitor and / or an effective amount of a dendritic cell activator or means; identifying an optimal treatment program based on the patient's response; The method includes: [Item A42] A method according to any of the preceding items, wherein the patient's response is a predetermined change in the patient's medical images and in the measurement values ​​of the patient's tumor markers. [Item A43] 1. A method for preventing or treating cancer in a patient, comprising: administering a combination of an effective amount of an immune checkpoint and an effective amount of a dendritic cell activator or means; A method of identifying the dosage and administration of a therapeutically or prophylactically effective combination of the immune checkpoint and the dendritic cell activator or means based on information on the optimization-specific markers for the combination obtained from the patient, and administering the combination based on the identified dosage and administration. [Item A44] 1. A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject with a particular regimen, comprising: administering a combination of an effective amount of an immune checkpoint and an effective amount of a dendritic cell activator or means, the regimen comprising: a) administering an effective amount of an immune checkpoint inhibitor, and b) administering an effective amount of a dendritic cell activator. A method comprising: [Item A45] The method according to any of the preceding items, wherein the subject has never received treatment with an immune checkpoint inhibitor, or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item A46] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; A method according to any of the above items. [Item A47] The particular regimen comprises: c) administering radiation therapy The method according to any one of the preceding items, further comprising: [Item A48] The method according to any of the preceding items, wherein the radiotherapy is palliative irradiation for other than brain metastasis, and is administered at 3 Gy in 10 fractions or at 2 Gy in 20 to 25 fractions. [Item A49] The method according to any of the preceding items, wherein the dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week. [Item B1] 1. Use of a) an immune checkpoint inhibitor and b) a direct dendritic cell activator or means in the manufacture of a medicament for treating, preventing, or preventing the recurrence of cancer or tumors. [Item B2] 1. Use of a direct dendritic cell activator or means in the manufacture of a medicament for use in combination with an immune checkpoint inhibitor to treat, prevent or prevent recurrence of cancer or tumor in a subject. [Item B3] 1. Use of an immune checkpoint inhibitor in the manufacture of a medicament for use in combination with a direct dendritic cell activator or means for treating, preventing, or preventing recurrence of cancer or tumor in a subject. [Item B4] The use according to any of the preceding items, wherein the direct dendritic cell activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item B5] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item B6] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item B7] The use of any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item B8] The use of any of the preceding items, wherein the cancer expresses PD-L1. [Item B9] The use described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item B10] The use according to any of the preceding items, wherein the cancer is lung cancer. [Item B11] The use according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item B12] The use according to any of the preceding items, wherein the treatment, prevention or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item B13] The use described in any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item B14] The use described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject for whom treatment with an immune checkpoint inhibitor has been determined to be ineffective. [Item B15] The use according to any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been treated with an immune checkpoint inhibitor and has been responsive to the treatment, but has subsequently developed progressive disease (PD). [Item B16] The use according to any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item B17] The subject has a CD8 + T cells low The use according to any of the preceding items, wherein the subject is a [Item B18] Use of an immune adjuvant in the manufacture of a medicament for directly activating dendritic cells. [Item B19] The use according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item B20] The use according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item B21] 1. Use of a) an immune checkpoint inhibitor and b) an immune adjuvant in the manufacture of a medicament for treating, preventing, or preventing the recurrence of cancer or a tumor. [Item B22] 1. Use of an immune adjuvant in the manufacture of a medicament for use in combination with an immune checkpoint inhibitor to treat, prevent, or prevent recurrence of cancer or tumors. [Item B23] 1. Use of an immune checkpoint inhibitor in the manufacture of a medicament for use in combination with an immune adjuvant to treat, prevent, or prevent the recurrence of cancer or tumors. [Item B24] The use according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item B25] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item B26] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item B27] The use according to any of the preceding items, characterized in that a means for providing radiation therapy is further used on the subject. [Item B28] The use according to any of the preceding items, wherein the radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item B29] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item B30] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item B31] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions present other than the lesion of interest. [Item B32] The use according to any of the preceding items, wherein a regulatory T cell inhibitor is further administered to the subject. [Item B33] The use according to any of the preceding items, wherein the regulatory T cell inhibitor comprises a COX-2 inhibitor. [Item B34] The use according to any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam. [Item B35] 10. Use of a radiotherapy delivery means in the manufacture of a medicament for activating dendritic cells. [Item B36] The use according to any of the preceding items, wherein the radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item B37] The use according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item B38] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item B39] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item B40] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions present other than the lesion of interest. [Item B41] A program for use in treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an immune checkpoint inhibitor and / or a dendritic cell activator or procedure; identifying an optimal treatment program based on the patient's response; A program characterized by executing the following. [Item B42] The program according to any of the above items, wherein the patient's response is a predetermined change in the patient's medical image and the measurement value of the patient's tumor marker. [Item B43] 1. Use of a combination of an immune checkpoint and a dendritic cell activator or means in the manufacture of a medicament for preventing or treating cancer in a patient, comprising: The pharmaceutical is characterized in that the dosage and administration method for a therapeutic or prophylactic combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on the optimized specific markers for the combination obtained from the patient, and the pharmaceutical is administered based on the specified dosage and administration method. [Item B44] Use of an immune checkpoint inhibitor and a dendritic cell activator in the manufacture of a medicament for treating, preventing or preventing recurrence of cancer or tumor in a subject with a specific regimen. [Item B45] The use according to any of the preceding items, wherein the subject has not received treatment with an immune checkpoint inhibitor or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item B46] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; Use according to any of the above items. [Item B47] The particular regimen comprises: c) administering radiation therapy The use according to any of the above items further includes: [Item B48] The use according to any of the preceding items, wherein the radiotherapy is palliative irradiation for treatment other than brain metastasis, and is administered at 3 Gy in 10 fractions or at 2 Gy in 20 to 25 fractions. [Item B49] The use according to any of the preceding items, wherein the dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week. [Item C1] An immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer or tumor, characterized in that it is used in combination with a direct dendritic cell activator or means. [Item C2] A direct dendritic cell activator or means for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item C3] An immune checkpoint inhibitor for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with a direct dendritic cell activator or means. [Item C4] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the direct dendritic cell activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item C5] The immune checkpoint inhibitor or dendritic cell direct activator or means according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item C6] The immune checkpoint inhibitor or dendritic cell direct activator or means according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item C7] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item C8] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the cancer expresses PD-L1. [Item C9] The immune checkpoint inhibitor according to any one of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. checkpoint inhibitors, or direct dendritic cell activators or means. [Item C10] The immune checkpoint inhibitor or dendritic cell direct activator or means according to any of the preceding items, wherein the cancer is lung cancer. [Item C11] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item C12] The immune checkpoint inhibitor, or direct dendritic cell activator or means according to any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item C13] The immune checkpoint inhibitor, or direct dendritic cell activator or means according to any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item C14] The immune checkpoint inhibitor, or direct dendritic cell activator or means according to any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject for whom treatment with an immune checkpoint inhibitor has been determined to be ineffective. [Item C15] The immune checkpoint inhibitor or direct dendritic cell activator or means described in any of the above items is administered to a subject who has been treated with an immune checkpoint inhibitor and has been effective, but has subsequently developed progressive disease (PD). [Item C16] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item C17] The subject has a CD8 + T cells low The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the subject is a patient of the above-mentioned category. [Item C18] An immune adjuvant for direct activation of dendritic cells. [Item C19] 2. The immune adjuvant according to any of the preceding items, comprising a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item C20] The immune adjuvant according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item C21] An immune checkpoint inhibitor for treating, preventing, or preventing the recurrence of cancer or tumor, characterized in that it is administered in combination with an immune adjuvant. [Item C22] An immune adjuvant for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item C23] An immune checkpoint inhibitor for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune adjuvant. [Item C24] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item C25] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item C26] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item C27] The immune adjuvant or immune checkpoint inhibitor described in any of the above items, further comprising the administration of a radiation therapy delivery means. [Item C28] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the radiation therapy delivery means includes at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive substance. [Item C29] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item C30] The immune adjuvant or immune checkpoint inhibitor described in any of the preceding items, characterized in that the radiation therapy delivery means is configured to irradiate in an abscopal manner. [Item C31] The immune adjuvant or immune checkpoint inhibitor described in any of the preceding items, characterized in that the radiation therapy delivery means is configured to irradiate measurable lesions present other than the target lesion. [Item C32] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, further comprising a regulatory T cell suppressor. [Item C33] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the regulatory T cell suppressor comprises a COX-2 inhibitor. [Item C34] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam. [Item C35] A means of providing radiation therapy to activate dendritic cells. [Item C36] The radiation therapy providing means according to any of the preceding items, comprising at least one selected from the group consisting of a radiation sensitizer, a radiation irradiation device, and a radioactive substance. [Item C37] The method of providing radiotherapy according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression of CD80 / 86 on the surface of dendritic cells in the presence of the immunoadjuvant compared to in the absence of the immunoadjuvant. [Item C38] 10. The radiation therapy delivery means of any of the preceding items, configured to provide palliative radiation. [Item C39] 10. The radiation therapy delivery means according to any of the preceding items, configured to deliver radiation in an abscopal manner. [Item C40] 10. The radiation therapy delivery means of any of the preceding claims, configured to irradiate measurable lesions other than the lesion of interest. [Item C41] A program for use in treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an immune checkpoint inhibitor and / or a dendritic cell activator or procedure; identifying an optimal treatment program based on the patient's response; A program characterized by executing the following. [Item C42] The program according to any of the above items, wherein the patient's response is a predetermined change in the patient's medical image and the measurement value of the patient's tumor marker. [Item C43] An immune checkpoint inhibitor for preventing or treating cancer in a patient, wherein the immune checkpoint inhibitor is administered in combination with a dendritic cell activator or means, and the dosage and administration method for a therapeutic or preventively effective combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on optimization-specific markers for the combination obtained from the patient, and the immune checkpoint inhibitor is administered based on the specified dosage and administration method. [Item C43A] A dendritic cell activator or means for preventing or treating cancer in a patient, wherein the dendritic cell activator or means is administered in combination with an immune checkpoint inhibitor, and the dosage and administration method for a therapeutic or preventively effective combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on optimization-specific markers for the combination obtained from the patient, and the dendritic cell activator or means is administered based on the specified dosage and administration method. [Item C44] 1. An immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer, a cancer, or tumor in a subject with a particular regimen, the regimen comprising administering the immune checkpoint inhibitor in combination with a dendritic cell activator. [Item C44A] A dendritic cell activator for treating, preventing, or preventing recurrence of cancer, cancer, or tumor in a subject with a particular regimen, the regimen comprising administering the dendritic cell activator in combination with an immune checkpoint inhibitor. [Item C45] The immune checkpoint inhibitor or dendritic cell activator described in any of the preceding items, wherein the subject has never received treatment with an immune checkpoint inhibitor, or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item C46] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; The immune checkpoint inhibitor or dendritic cell activator according to any of the preceding items. [Item C47] The particular regimen comprises: c) administering radiation therapy The immune checkpoint inhibitor or dendritic cell activator according to any of the preceding items, further comprising: [Item C48] The immune checkpoint inhibitor or dendritic cell activator described in any of the above items, characterized in that the radiation therapy is palliative irradiation for purposes other than brain metastasis, and is administered in 10 doses of 3 Gy or 20 to 25 doses of 2 Gy. [Item C49] The immune checkpoint inhibitor or dendritic cell activator according to any of the preceding items, wherein the dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week.

[0006] The present disclosure also provides: [Item X1] a) Immune checkpoint inhibitors and b) a direct dendritic cell activator or means; wherein a) and b) are administered at different times or simultaneously, for treating, preventing, or preventing the recurrence of cancer or tumor. [Item X2] A composition or medical device for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising a direct dendritic cell activator or means, wherein the composition or medical device is administered or used in combination with an immune checkpoint inhibitor. [Item X3] A composition for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising an immune checkpoint inhibitor, wherein the composition is administered in combination with a direct dendritic cell activator or means. [Item X4] The combination, composition or medical device according to any of the preceding items, wherein the dendritic cell direct activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item X5] The combination, composition or medical device according to any of the preceding items, wherein the direct dendritic cell activator or means comprises a radiotherapy delivery means and an immune adjuvant. [Item X6] The combination, composition, or medical device described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item X7] The combination, composition, or medical device described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item X8] The combination, composition or medical device according to any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item X9] The combination, composition or medical device according to any of the preceding items, wherein the cancer expresses PD-L1. [Item X10] The combination, composition, or medical device described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item X11] The combination, composition or medical device according to any of the preceding items, wherein the cancer is lung cancer. [Item X12] The combination, composition or medical device according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item X13] The combination, composition or medical device described in any of the above items, wherein the treatment, prevention or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item X14] The combination, composition, or medical device described in any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item X15] The combination, composition, or medical device described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject for whom treatment with an immune checkpoint inhibitor has been determined to be ineffective. [Item X16] The combination, composition, or medical device described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been treated with an immune checkpoint inhibitor and has been effectively treated, but has subsequently developed progressive disease (PD). [Item X17] The combination, composition, or medical device described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has effectively received treatment with a tyrosine kinase inhibitor and treatment with an immune checkpoint inhibitor but has subsequently developed progressive disease (PD). [Item X18] The combination, composition or medical device described in any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item X19] The subject has a CD8 + T cells low The combination, composition or medical device according to any of the preceding items, wherein the subject is a patient of the above-mentioned category. [Item X20] A composition for directly activating dendritic cells, comprising an immune adjuvant. [Item X21] The composition according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item X22] The composition according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item X23] a) Immune checkpoint inhibitors and b) immune adjuvants and wherein a) and b) are administered at different times or simultaneously, for treating, preventing, or preventing the recurrence of cancer or tumor. [Item X24] A composition for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising an immune adjuvant, wherein the composition is administered in combination with an immune checkpoint inhibitor. [Item X25] A composition for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising an immune checkpoint inhibitor, wherein the composition is administered in combination with an immune adjuvant. [Item X26] The combination or composition according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item X27] The composition described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item X28] The combination or composition according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item X29] A combination, composition or medical device for activating dendritic cells, comprising the composition according to any of the preceding items and a means for providing radiation therapy. [Item X30] The combination, composition or medical device according to any of the preceding items, wherein the means for providing radiation therapy comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device and a radioactive substance. [Item X31] 10. The combination, composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item X32] 10. The combination, composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate in an abscopal manner. [Item X33] 10. The combination, composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the target lesion. [Item X34] The combination, composition or medical device according to any of the preceding items, further comprising a regulatory T cell inhibitor. [Item X35] The combination, composition or medical device according to any of the preceding items, wherein the regulatory T cell suppressor comprises a COX-2 inhibitor. [Item X36] The combination, composition or medical device according to any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen and lornoxicam. [Item X37] A composition or medical device for activating dendritic cells, including a means for delivering radiation therapy. [Item X38] The composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive substance. [Item X39] The composition or medical device described in any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item X40] 10. The composition or medical device of any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item X41] 10. The composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate in an abscopal manner. [Item X42] 2. The composition or medical device according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the target lesion. [Item X43] A program for use in treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an immune checkpoint inhibitor and / or a dendritic cell activator or procedure; identifying an optimal treatment program based on the patient's response; A program characterized by executing the following. [Item X44] The program according to any of the above items, wherein the patient's response is a predetermined change in the patient's medical image and the measurement value of the patient's tumor marker. [Item X45] A medicament for preventing or treating cancer in a patient, comprising: The pharmaceutical comprises a combination of an immune checkpoint and a dendritic cell activator or means, and is characterized in that the dosage and administration method for a therapeutically or prophylactically effective combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on optimized specific markers for the combination obtained from the patient, and the pharmaceutical is administered based on the specified dosage and administration method. [Item X46] A pharmaceutical or device for treating, preventing, or preventing recurrence of cancer, cancer, or tumor in a subject with a specific regimen, comprising: The medicament comprises a combination of an immune checkpoint and a dendritic cell activator or means, and the regimen comprises: a) administering an immune checkpoint inhibitor, and b) administering a dendritic cell activator A medicine or device comprising: [Item X47] The pharmaceutical or device described in any of the above items, wherein the subject has not received treatment with an immune checkpoint inhibitor, or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item X48] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; A medicament or device according to any of the above items. [Item X49] The particular regimen comprises: c) administering radiation therapy The medicament or device according to any of the above items, further comprising: [Item X50] The pharmaceutical or device according to any of the preceding items, wherein the radiotherapy is palliative irradiation for purposes other than brain metastasis, and is performed by irradiating 10 times with 3 Gy or 20 to 25 times with 2 Gy. [Item X51] The dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week. [Item XA1] The subject a) an effective amount of an immune checkpoint inhibitor; b) an effective amount of a direct dendritic cell activator or means; A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering at different times or simultaneously. [Item XA2] A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering or using to the subject an effective amount of a direct dendritic cell activator or means, wherein the administration of the direct dendritic cell activator or means is administered or used in combination with an effective amount of an immune checkpoint inhibitor. [Item XA3] A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering to the subject an effective amount of an immune checkpoint inhibitor, wherein the administration of the immune checkpoint inhibitor is administered or used in combination with an effective amount of a direct dendritic cell activator or means. [Item XA4] The method according to any one of the preceding items, wherein the dendritic cell direct activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item XA5] The method according to any of the preceding items, wherein the direct dendritic cell activating agent or means includes radiotherapy delivery means and immune adjuvants. [Item XA6] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XA7] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item XA8] The method of any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item XA9] The method of any of the preceding items, wherein the cancer expresses PD-L1. [Item XA10] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item XA11] The method according to any of the preceding items, wherein the cancer is lung cancer. [Item XA12] The method according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item XA13] The method according to any of the preceding items, administered to a subject undergoing treatment with a tyrosine kinase inhibitor. [Item XA14] The method of any of the preceding items, administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item XA15] The method according to any one of the preceding items, which is administered to a subject who has been determined to be ineffective in treatment with an immune checkpoint inhibitor. [Item XA16] The method according to any of the preceding items, which is administered to a subject who has been treated with an immune checkpoint inhibitor and has subsequently experienced progressive disease (PD). [Item XA17] The method according to any of the preceding items, which is administered to a subject who has been effectively treated with a tyrosine kinase inhibitor and an immune checkpoint inhibitor, but has subsequently developed progressive disease (PD). [Item XA18] The method according to any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item XA19] The subject has a CD8 + T cells low The method according to any of the preceding items, wherein the subject is a [Item XA20] A method for directly activating dendritic cells in a subject, comprising administering to the subject an effective amount of an immune adjuvant. [Item XA21] The method according to any one of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XA22] The method according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item XA23] The subject a) an effective amount of an immune checkpoint inhibitor; b) an effective amount of an immune adjuvant; A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering at different times or simultaneously. [Item XA24] 1. A method for treating, preventing, or preventing the recurrence of cancer or a tumor in a subject, comprising administering to the subject an effective amount of an immune adjuvant, wherein the immune adjuvant is administered in combination with an effective amount of an immune checkpoint inhibitor. [Item XA25] 1. A method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, comprising administering to the subject an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered in combination with an immune adjuvant. [Item XA26] The method according to any one of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XA27] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XA28] The method according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item XA29] A method for activating dendritic cells, wherein radiation therapy delivery means is further used. [Item XA30] The method according to any one of the preceding items, wherein the radiation therapy providing means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item XA31] 10. The method of any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item XA32] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item XA33] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the lesion of interest. [Item XA34] The method according to any of the preceding items, wherein a regulatory T cell inhibitor is further administered. [Item XA35] The method according to any one of the preceding items, wherein the regulatory T cell inhibitor comprises a COX-2 inhibitor. [Item XA36] The method according to any one of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam. [Item XA37] A method for activating dendritic cells comprising administering to a subject a means for delivering radiation therapy. [Item XA38] The method according to any one of the preceding items, wherein the radiation therapy providing means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item XA39] The method according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item XA40] 10. The method of any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item XA41] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item XA42] 10. The method of claim 9, wherein the radiation therapy delivery means is configured to irradiate measurable lesions other than the lesion of interest. [Item XA43] 1. A method for treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an effective amount of an immune checkpoint inhibitor and / or an effective amount of a dendritic cell activator or means; identifying an optimal treatment program based on the patient's response; The method includes: [Item XA44] A method according to any of the preceding items, wherein the patient's response is a predetermined change in the patient's medical images and in the measurement values ​​of the patient's tumor markers. [Item XA45] 1. A method for preventing or treating cancer in a patient, comprising: administering a combination of an effective amount of an immune checkpoint and an effective amount of a dendritic cell activator or means; A method of identifying the dosage and administration of a therapeutically or prophylactically effective combination of the immune checkpoint and the dendritic cell activator or means based on information on the optimization-specific markers for the combination obtained from the patient, and administering the combination based on the identified dosage and administration. [Item XA46] 1. A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject with a particular regimen, comprising: administering a combination of an effective amount of an immune checkpoint and an effective amount of a dendritic cell activator or means, the regimen comprising: a) administering an effective amount of an immune checkpoint inhibitor, and b) administering an effective amount of a dendritic cell activator. A method comprising: [Item XA47] The method according to any of the preceding items, wherein the subject has never received treatment with an immune checkpoint inhibitor, or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item XA48] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; A method according to any of the above items. [Item XA49] The particular regimen comprises: c) administering radiation therapy The method according to any one of the preceding items, further comprising: [Item XA50] The method according to any of the preceding items, wherein the radiotherapy is palliative irradiation for other than brain metastasis, and is administered at 3 Gy in 10 fractions or at 2 Gy in 20 to 25 fractions. [Item XA51] The method according to any of the preceding items, wherein the dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week. [Item XB1] 1. Use of a) an immune checkpoint inhibitor and b) a direct dendritic cell activator or means in the manufacture of a medicament for treating, preventing, or preventing the recurrence of cancer or tumors. [Item XB2] 1. Use of a direct dendritic cell activator or means in the manufacture of a medicament for use in combination with an immune checkpoint inhibitor to treat, prevent or prevent recurrence of cancer or tumor in a subject. [Item XB3] 1. Use of an immune checkpoint inhibitor in the manufacture of a medicament for use in combination with a direct dendritic cell activator or means for treating, preventing, or preventing recurrence of cancer or tumor in a subject. [Item XB4] The use according to any of the preceding items, wherein the direct dendritic cell activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item XB5] The use according to any of the preceding items, wherein the direct dendritic cell activating agent or means includes radiotherapy delivery means and immune adjuvants. [Item XB6] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XB7] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item XB8] The use of any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item XB9] The use of any of the preceding items, wherein the cancer expresses PD-L1. [Item XB10] The use described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item XB11] The use according to any of the preceding items, wherein the cancer is lung cancer. [Item XB12] The use according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item XB13] The use according to any of the preceding items, wherein the treatment, prevention or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item XB14] The use described in any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item XB15] The use described in any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject for whom treatment with an immune checkpoint inhibitor has been determined to be ineffective. [Item XB16] The use according to any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been treated with an immune checkpoint inhibitor and has been responsive to the treatment, but has subsequently developed progressive disease (PD). [Item XB17] The use according to any of the above items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been effectively treated with a tyrosine kinase inhibitor and an immune checkpoint inhibitor, but has subsequently developed progressive disease (PD). [Item XB18] The use according to any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item XB19] The subject has a CD8 + T cells low The use according to any of the preceding items, wherein the subject is a [Item XB20] Use of an immune adjuvant in the manufacture of a medicament for directly activating dendritic cells. [Item XB21] The use according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XB22] The use according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item XB23] 1. Use of a) an immune checkpoint inhibitor and b) an immune adjuvant in the manufacture of a medicament for treating, preventing, or preventing the recurrence of cancer or a tumor. [Item XB24] 1. Use of an immune adjuvant in the manufacture of a medicament for use in combination with an immune checkpoint inhibitor to treat, prevent, or prevent recurrence of cancer or tumors. [Item XB25] 1. Use of an immune checkpoint inhibitor in the manufacture of a medicament for use in combination with an immune adjuvant to treat, prevent, or prevent the recurrence of cancer or tumors. [Item XB26] The use according to any of the preceding items, wherein the immunoadjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XB27] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XB28] The use according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item XB29] The use according to any of the preceding items, characterized in that a means for providing radiation therapy is further used on the subject. [Item XB30] The use according to any of the preceding items, wherein the radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item XB31] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item XB32] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item XB33] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions present other than the lesion of interest. [Item XB34] The use according to any of the preceding items, wherein a regulatory T cell inhibitor is further administered to the subject. [Item XB35] The use according to any of the preceding items, wherein the regulatory T cell inhibitor comprises a COX-2 inhibitor. [Item XB36] The use according to any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam. [Item XB37] 10. Use of a radiotherapy delivery means in the manufacture of a medicament for activating dendritic cells. [Item XB38] The use according to any of the preceding items, wherein the radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive material. [Item XB39] The use according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item XB40] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item XB41] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to deliver radiation in an abscopal manner. [Item XB42] 10. The use according to any of the preceding items, wherein the radiation therapy delivery means is configured to irradiate measurable lesions present other than the lesion of interest. [Item XB43] A program for use in treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an immune checkpoint inhibitor and / or a dendritic cell activator or procedure; identifying an optimal treatment program based on the patient's response; A program characterized by executing the following. [Item XB44] The program according to any of the above items, wherein the patient's response is a predetermined change in the patient's medical image and the measurement value of the patient's tumor marker. [Item XB45] 1. Use of a combination of an immune checkpoint and a dendritic cell activator or means in the manufacture of a medicament for preventing or treating cancer in a patient, comprising: The pharmaceutical is characterized in that the dosage and administration method for a therapeutic or prophylactic combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on the optimized specific markers for the combination obtained from the patient, and the pharmaceutical is administered based on the specified dosage and administration method. [Item XB46] Use of an immune checkpoint inhibitor and a dendritic cell activator in the manufacture of a medicament for treating, preventing or preventing recurrence of cancer or tumor in a subject with a specific regimen. [Item XB47] The use according to any of the preceding items, wherein the subject has not received treatment with an immune checkpoint inhibitor or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item XB48] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; Use according to any of the above items. [Item XB49] The particular regimen comprises: c) administering radiation therapy The use according to any of the above items further includes: [Item XB50] The use according to any of the preceding items, wherein the radiotherapy is palliative irradiation for treatment other than brain metastasis, and is administered at 3 Gy in 10 fractions or at 2 Gy in 20 to 25 fractions. [Item XB51] The use according to any of the preceding items, wherein the dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week. [Item XC1] An immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer or tumor, characterized in that it is used in combination with a direct dendritic cell activator or means. [Item XC2] A direct dendritic cell activator or means for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item XC3] An immune checkpoint inhibitor for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with a direct dendritic cell activator or means. [Item XC4] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the direct dendritic cell activator or means comprises at least one selected from the group consisting of a radiotherapy delivery means and an immune adjuvant. [Item XC5] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the direct dendritic cell activator or means comprises a radiotherapy delivery means and an immune adjuvant. [Item XC6] The immune checkpoint inhibitor or dendritic cell direct activator or means according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XC7] The immune checkpoint inhibitor or dendritic cell direct activator or means according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item XC8] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the cancer or tumor expresses an immune checkpoint factor. [Item XC9] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the cancer expresses PD-L1. [Item XC10] The immune checkpoint inhibitor according to any one of the preceding items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. checkpoint inhibitors, or direct dendritic cell activators or means. [Item XC11] The immune checkpoint inhibitor or dendritic cell direct activator or means according to any of the preceding items, wherein the cancer is lung cancer. [Item XC12] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item XC13] The immune checkpoint inhibitor, or direct dendritic cell activator or means according to any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item XC14] The immune checkpoint inhibitor, or direct dendritic cell activator or means according to any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item XC15] The immune checkpoint inhibitor, or direct dendritic cell activator or means according to any of the preceding items, wherein the treatment, prevention, or recurrence prevention is administered to a subject for whom treatment with an immune checkpoint inhibitor has been determined to be ineffective. [Item XC16] The immune checkpoint inhibitor or direct dendritic cell activator or means described in any of the above items is administered to a subject who has been treated with an immune checkpoint inhibitor and has been effective, but has subsequently developed progressive disease (PD). [Item XC17] The immune checkpoint inhibitor, or direct dendritic cell activator or means described in any of the above items is administered to a subject who has effectively received treatment with a tyrosine kinase inhibitor and treatment with an immune checkpoint inhibitor but has subsequently developed progressive disease (PD). [Item XC18] The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the subject is CXCL10 positive in the tumor. [Item XC19] The subject has a CD8 + T cells low The immune checkpoint inhibitor or direct dendritic cell activator or means according to any of the preceding items, wherein the subject is a patient of the above-mentioned category. [Item XC20] An immune adjuvant for direct activation of dendritic cells. [Item XC21] 2. The immune adjuvant according to any of the preceding items, comprising a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XC22] The immune adjuvant according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to in the absence of the immune adjuvant. [Item XC23] An immune checkpoint inhibitor for treating, preventing, or preventing the recurrence of cancer or tumor, characterized in that it is administered in combination with an immune adjuvant. [Item XC24] An immune adjuvant for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item XC25] An immune checkpoint inhibitor for treating, preventing, or preventing the recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune adjuvant. [Item XC26] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XC27] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor of at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XC28] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. [Item XC29] The immune adjuvant or immune checkpoint inhibitor described in any of the above items, further comprising the administration of a radiation therapy delivery means. [Item XC30] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the radiation therapy delivery means includes at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive substance. [Item XC31] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the radiation therapy delivery means is configured to provide palliative radiation. [Item XC32] The immune adjuvant or immune checkpoint inhibitor described in any of the preceding items, characterized in that the radiation therapy delivery means is configured to irradiate in an abscopal manner. [Item XC33] The immune adjuvant or immune checkpoint inhibitor described in any of the preceding items, characterized in that the radiation therapy delivery means is configured to irradiate measurable lesions present other than the target lesion. [Item XC34] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, further comprising a regulatory T cell suppressor. [Item XC35] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the regulatory T cell suppressor comprises a COX-2 inhibitor. [Item XC36] The immune adjuvant or immune checkpoint inhibitor according to any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam. [Item XC37] A means of providing radiation therapy to activate dendritic cells. [Item XC38] The radiation therapy providing means according to any of the preceding items, comprising at least one selected from the group consisting of a radiation sensitizer, a radiation irradiation device, and a radioactive substance. [Item XC39] The method of providing radiotherapy according to any of the preceding items, wherein the activation is determined by measuring an increase in the expression of CD80 / 86 on the surface of dendritic cells in the presence of the immunoadjuvant compared to in the absence of the immunoadjuvant. [Item XC40] 10. The radiation therapy delivery means of any of the preceding items, configured to provide palliative radiation. [Item XC41] 10. The radiation therapy delivery means according to any of the preceding items, configured to deliver radiation in an abscopal manner. [Item XC42] 10. The radiation therapy delivery means of any of the preceding claims, configured to irradiate measurable lesions other than the lesion of interest. [Item XC43] A program for use in treating or preventing cancer in a patient, comprising: On the computer, administering to the patient a first treatment with an immune checkpoint inhibitor and / or a dendritic cell activator or procedure; identifying an optimal treatment program based on the patient's response; A program characterized by executing the following. [Item XC44] The program according to any of the above items, wherein the patient's response is a predetermined change in the patient's medical image and the measurement value of the patient's tumor marker. [Item XC45] An immune checkpoint inhibitor for preventing or treating cancer in a patient, wherein the immune checkpoint inhibitor is administered in combination with a dendritic cell activator or means, and the dosage and administration method for a therapeutic or preventively effective combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on optimization-specific markers for the combination obtained from the patient, and the immune checkpoint inhibitor is administered based on the specified dosage and administration method. [Item XC45A] A dendritic cell activator or means for preventing or treating cancer in a patient, wherein the dendritic cell activator or means is administered in combination with an immune checkpoint inhibitor, and the dosage and administration method for a therapeutic or preventively effective combination of the immune checkpoint and the dendritic cell activator or means is specified based on information on optimization-specific markers for the combination obtained from the patient, and the dendritic cell activator or means is administered based on the specified dosage and administration method. [Item XC46] 1. An immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer, a cancer, or tumor in a subject with a particular regimen, the regimen comprising administering the immune checkpoint inhibitor in combination with a dendritic cell activator. [Item XC46A] A dendritic cell activator for treating, preventing, or preventing recurrence of cancer, cancer, or tumor in a subject with a particular regimen, the regimen comprising administering the dendritic cell activator in combination with an immune checkpoint inhibitor. [Item XC47] The immune checkpoint inhibitor or dendritic cell activator described in any of the preceding items, wherein the subject has never received treatment with an immune checkpoint inhibitor, or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective. [Item XC48] In said particular regimen, said immune checkpoint inhibitor is i) Nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks; The immune checkpoint inhibitor or dendritic cell activator according to any of the preceding items. [Item XC49] The particular regimen comprises: c) administering radiation therapy The immune checkpoint inhibitor or dendritic cell activator according to any of the preceding items, further comprising: [Item XC50] The immune checkpoint inhibitor or dendritic cell activator described in any of the above items, characterized in that the radiation therapy is palliative irradiation for purposes other than brain metastasis, and is administered in 10 doses of 3 Gy or 20 to 25 doses of 2 Gy. [Item XC51] The immune checkpoint inhibitor or dendritic cell activator according to any of the preceding items, wherein the dendritic cell activator or means comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week.

[0007] In one embodiment, the cancer treatment method disclosed herein is a method for treating cancer, characterized by combining treatment with an immune checkpoint inhibitor with treatment to increase sensitivity to the immune checkpoint inhibitor.

[0008] In one embodiment, the cancer treatment method disclosed herein is a method for treating cancer in a patient, characterized by comprising a first step of administering an immune checkpoint inhibitor to the patient, and a second step of administering a treatment to the patient to increase sensitivity to the immune checkpoint inhibitor.

[0009] In one embodiment, the cancer treatment method according to the present disclosure is characterized in that the second step is carried out simultaneously or at a different time from the first step.

[0010] In one embodiment, the cancer treatment method according to the present disclosure is characterized in that the immune checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab.

[0011] In one embodiment, the medicament according to the present disclosure is a medicament for treating cancer, which comprises an immune checkpoint inhibitor and is used in a regimen of being administered in combination with radiation therapy, wherein the regimen increases sensitivity to the immune checkpoint inhibitor by irradiating the cancer with radiation.

[0012] In one embodiment, the medicament disclosed herein is a medicament for treating cancer, comprising an immune checkpoint inhibitor and Extract Z, and used in a regimen in which the immune checkpoint inhibitor and Extract Z are administered at different times or simultaneously, wherein the regimen is characterized in that the administration of Extract Z increases sensitivity to the immune checkpoint inhibitor.

[0013] In one embodiment, the program disclosed herein is a program used for treating cancer in a patient, and is characterized by causing a computer to execute the steps of: specifying a first period during which the patient will be administered either a first treatment using an immune checkpoint inhibitor or a second treatment for increasing sensitivity to the immune checkpoint inhibitor; and specifying a second period during which the patient will be administered one or both of the first treatment and the second treatment when test results for the patient show a predetermined change.

[0014] In one embodiment, the program according to the present disclosure is characterized in that the predetermined change is a predetermined change in a medical image of the patient and a measurement value of a tumor marker of the patient.

[0015] In one embodiment, the program according to the present disclosure is characterized in that the second treatment includes at least one of radiation exposure, administration of Extract Z, and a combination of radiation exposure.

[0016] In one embodiment, the program of the present disclosure is characterized in that the immune checkpoint inhibitor is nivolumab, pembrolizumab, or atezolizumab.

[0017] In one embodiment, the present disclosure provides cancer treatment that combines a treatment with an immune checkpoint inhibitor (first treatment) with a treatment to increase sensitivity to the immune checkpoint inhibitor (second treatment), and the synergistic effect of the two treatments eliminates or reduces cancer tissue.

[0018] In one embodiment, the present disclosure provides a treatment (second treatment) for increasing sensitivity to immune checkpoint inhibitors before or during treatment with an immune checkpoint inhibitor (first treatment), thereby efficiently increasing sensitivity to the immune checkpoint inhibitor.

[0019] In one embodiment, the present disclosure specifies a first period during which either a first treatment using an immune checkpoint inhibitor or a second treatment for increasing sensitivity to the immune checkpoint inhibitor is administered, and specifies a second period during which either or both of the first treatment and the second treatment are administered when the patient's test results show a predetermined change (for example, when imaging diagnosis shows that the cancer tissue does not shrink and the measured value of the tumor marker increases).

[0020] In one embodiment, the present disclosure provides a treatment for increasing sensitivity to immune checkpoint inhibitors, which may involve radiation therapy, administration of Extract Z and radiation therapy, either alone or in combination, to improve sensitivity to immune checkpoint inhibitors.

[0021] In one embodiment, the present disclosure uses nivolumab, pembrolizumab, or atezolizumab, which are antibodies against PD-1 on T cells, as an immune checkpoint inhibitor to inhibit the immune checkpoint between T cells and cancer cells.

[0022] It is contemplated that one or more of the above features may be provided in combinations other than those explicitly stated. Further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. [Effects of the Invention]

[0023] The present disclosure can unexpectedly activate dendritic cells. The present disclosure can also provide a method for effectively treating or preventing cancer or tumors using an immune adjuvant or the like. [Brief explanation of the drawings]

[0024] [Figure 1] 1 is a block diagram showing a configuration of a system that uses a program according to an embodiment of the present invention. [Figure 2] 10 is a flowchart showing a treatment procedure according to the present embodiment. [Figure 3] FIG. 1 is a diagram illustrating the time course of a treatment method in Example 1. [Figure 4] FIG. 10 is a diagram illustrating the time course of a treatment method in Example 2. [Figure 5] FIG. 10 is a diagram illustrating the time course of tumor marker measurement values ​​and treatment methods in Example 3. [Figure 6]FIG. 10 is a diagram illustrating the time course of tumor marker measurement values ​​and treatment methods in Example 4. [Figure 7] FIG. 13 shows the enhancement of CXCL10 production by immune adjuvants in Example 13. [Figure 8] FIG. 11 shows the effect of promoting the infiltration of CD8+ T cells into tumors in Example 15. [Figure 9] FIG. 10 shows the expression of PD-L1 in cultured Sq-1979 cells in Example 20. [Figure 10] FIG. 10 is a diagram illustrating the time course of the treatment method in Example 23. [Figure 11] FIG. 10 is a diagram illustrating the time course of tumor marker measurement values ​​and treatment methods in Example 23. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present disclosure will be described below, illustrating some of the best modes. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0026] (definition) The terms used in this specification are explained below.

[0027] As used herein, "immune checkpoint inhibitors" refer to substances that bind to immune checkpoint molecules or their ligands, inhibiting the transmission of immunosuppressive signals and thereby relieving the suppression of T cell activation by immune checkpoint molecules. Specifically, these include PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-1, TIM-3, TIM-4, VISTA, BTLA, TIGIT, A2AR, 4-1BB, 4-1BBL, 2B4 (CD244), and KIR family receptors, B7.1, B7.2, B7-H2, B7-H3, B7-H4, B7-H6, BATE, CD39, CD40, CD47, CD48, CD73, CD94 / NKG2A, CD96, CD160, CD200, CD200R, CD274, butyrophilins, CEAC AM1, CSF-1R, DcR3, EDO, Foxpl, GARP, GITR, gp49B, HHLA2, HVEM, ICOS, IDO, ILT-2, ILT-4, LAIR-1, MAFB, MICA. / B, NKG2A / HLA-E, NR4A2, OCT-2, OX-40, PIR-B, Rara (retinoic acid receptor These include inhibitors of PD-1, PD-L1, TDO, TLR3, and TNFR, with preferred inhibitors being PD-1, PD-L1, and CTLA-4. Anti-PD-1 antibodies, a type of PD-1 inhibitor, bind to PD-1 on T cells and inhibit the binding of PD-1 to PD-L1, thereby blocking the transmission of inhibitory signals and maintaining T cell activation. Anti-PD-L1 antibodies, a type of PD-L1 inhibitor, bind to PD-L1 expressed on cancer cells and antigen-presenting cells, thereby inhibiting the interaction with PD-1 on T cells, thereby inhibiting inhibitory signaling to T cells and maintaining T cell activation. Anti-CTLA-4 antibodies, a type of CTLA-4 inhibitor, compete with CD28 ligand on dendritic cells and block CD28-mediated inhibitory signals from immune cells, thereby maintaining T cell activation.Examples of anti-PD-1 antibodies include nivolumab, pembrolizumab, spartalizumab, and cemiplimab; examples of anti-PD-L1 antibodies include atezolizumab, durvalumab, and avelumab; and examples of anti-CTLA-4 antibodies include ipilimumab and tremelimumab.

[0028] As used herein, "immune checkpoint factors" refer to factors that suppress immune responses against oneself and excessive immune responses in order to maintain immune homeostasis. "Immune checkpoint factors" are originally intended to suppress excessive activation of T cells and prevent self-attack, but during carcinogenesis, they are used by cancer cells to evade attack from the immune system and proliferate. Therefore, inhibition of immune checkpoint factors in cancer cells allows T cells to attack cancer cells. Representative examples of "immune checkpoint factors" include PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, TIM-1, TIM-3, TIM-4, VISTA, BTLA, TIGIT, A2AR, 4-1BB, 4-1BBL, 2B4 (CD244), and the KIR family. receptors, B7.1, B7.2, B7-H2, B7-H3, B7-H4, B7-H6, BATE, CD39, CD40, CD47, CD48, CD73, CD94 / NKG2A, CD96, CD160, CD200, CD200R, CD274, butyrophilins, CEAC AM1, CSF-1R, DcR3, EDO, Foxpl, GARP, GITR, gp49B, HHLA2, HVEM, ICOS, IDO, ILT-2, ILT-4, LAIR-1, MAFB, MICA. / B, NKG2A / HLA-E, NR4A2, OCT-2, OX-40, PIR-B, Rara (retinoic acid receptor alpha), SIRP, TDO, TLR3, and TNFR.

[0029] As used herein, the term "direct dendritic cell activator or device" refers to an agent or device that can activate dendritic cells directly (i.e., without the intervention of other molecules) inside or outside the body of a subject. Representative examples of "direct dendritic cell activators or devices" include radiotherapy delivery devices and immune adjuvants. In the present disclosure, whether or not "dendritic cells" are "directly activated" can be determined by the following: as exemplified in the Examples, if the expression of the cell membrane surface marker CD80 / 86 is higher in a candidate target or factor than in the absence of the target or factor (e.g., physiological saline) + control antibody group, the candidate target or factor can be said to be directly activated, and can be determined to be a "direct dendritic cell activator or means (device)."

[0030] As used herein, the term "radiation therapy delivery means" refers to methods, apparatus, instruments, agents, devices, etc. for delivering radiation therapy to a subject.

[0031] As used herein, the term "medical device" refers to an object that is inserted into or implanted in a subject or applied to the surface of a subject for the purpose of treatment, prevention, or prevention of recurrence. Common examples of medical devices include any device used in radiation therapy, as well as stents, fasteners, ports, catheters, scaffolds, and grafts.

[0032] As used herein, "EGFR gene mutation" refers to a mutation in the EGFR gene. "EGFR" stands for epidermal growth factor receptor and functions in cell proliferation and growth. When a mutation occurs in the EGFR gene, cell proliferation and growth become constitutively activated, leading to cancer. "EGFR gene mutation" is known to cause non-squamous cell carcinoma, a type of lung cancer.

[0033] As used herein, "tyrosine kinase inhibitor (TKI)" refers to an agent that inhibits tyrosine kinase. Tyrosine kinase inhibitors have the effect of suppressing cancer growth by blocking signaling pathways related to the proliferation of cancer cells. Representative examples of "tyrosine kinase inhibitors" include afatinib, erlotinib, osimertinib (AZD9291), AZD3759, gefitinib, canertinib, lapatinib, cetuximab, zalutumumab, and panitumumab.

[0034] As used herein, the term "immune adjuvant" refers to any agent or factor that assists the immune response, and representative examples include Mycobacterium tuberculosis extracts such as hot water extracts of Mycobacterium tuberculosis, or portions thereof.

[0035] As used herein, "CXCL10" is an abbreviation for C-X-C motif chemokine ligand 10, also known as IP-10, interferon-gamma-inducible protein 10, or small inducible cytokine B10. In humans, the CXCL10 gene encodes a non-glycosylated 8.7 kDa protein consisting of 77 amino acids. It is a chemokine produced in response to IFN-γ treatment in monocytes, endothelial cells, and fibroblasts. IP-10 functions as a chemoattractant for cells expressing the G protein-coupled receptor CXCR3, which is found primarily on activated T cells and NK cells. It is also known as CXCL10, C7, IFI10, INP10, IP-10, SCYB10, crg-2, gIP-10, mob-1, C-X-C motif chemokine ligand 10, and C-X-C motif chemokine 10. Also known as ID NM_001565 (nucleic acid) and NP_001556 (protein).

[0036] As used herein, the term "enhancement of CXCL10 production" refers to an increase in the production (or amount) of CXCL10.

[0037] As used herein, the term "CXCL10-positive cancer or tumor" refers to a cancer or tumor that is positive for CXCL10.

[0038] As used herein, "CXCR3" has the same meaning as commonly used in the art and refers to a member of the CXC chemokine receptor family, a G protein-coupled receptor. It is also known as G protein-coupled receptor 9 (GPR9) or CD183, as well as CD182; CKR-L2; CMKAR3; IP10-R; Mig-R; or MigR. Two variants of CXCR3 are known. One of these, CXCR3-A, binds to the CXC chemokines CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC), while CXCR3-B can also bind to CXCL4. Nucleic acid IDs include NM_001142797 and NM_001504, and protein IDs include NP_001136269 and NP_001495.

[0039] As used herein, "CD8 + T cells low " refers to T cells that are positive for CD8 expression. Herein, CD8-positive T cell infiltration is assessed by counting the number of cells by examining slides using at least three different high-power fields (maximum, 40x objective and 10x eyepiece). The number of cells stained as CD8-positive is recorded, and low infiltration is defined as 5 or fewer cells in three fields, and high infiltration is defined as more than 5 cells.

[0040] As used herein, the term "Mycobacterium tuberculosis hot water extract" refers typically to a substance produced by Mycobacterium tuberculosis, and is a mixture containing polysaccharides composed primarily of arabinose, mannose, and glucose. While the anticancer effects of Mycobacterium tuberculosis hot water extracts have long been studied, the details of their mechanism of action have not been fully elucidated, and they have not been used as prophylactic drugs. In addition, the extract may contain trace components such as proteins, peptides, amino acids, nucleic acids, and lipids (glycolipids), as appropriate. An example of a Mycobacterium tuberculosis hot water extract is Extract Z, which is described herein. Therefore, in the technology of the present disclosure, the Mycobacterium tuberculosis hot water extract may be Extract Z, which is described herein in detail, or any preparation produced using Extract Z as a drug substance.

[0041] A typical method for producing a hot water extract of Mycobacterium tuberculosis is as follows.

[0042] Mycobacterium tuberculosis is cultured in a 37°C incubator for 3–7 weeks, after which the membrane-like cells that form on the medium are filtered and the medium components are removed by washing with water. The wet cells are used as the extraction material. The cells are suspended in distilled water at a volume 15–40 times their wet weight and heated at 90–120°C for 80–180 minutes for extraction. The bacterial residue is removed using a sterilizing filter. The extract is concentrated to less than 60%. Acetone, trichloroacetic acid, ammonium sulfate, or sulfosalicylic acid is added to the extract to a concentration of 0.5–3% (w / v). The mixture is stirred and allowed to stand. The resulting precipitate is removed by centrifugation, and the supernatant is dialyzed under running water. The dialyzed solution is concentrated under reduced pressure to 1 / 20–1 / 4 of its original volume. Sodium chloride is added to the concentrate to a concentration of 0.5–1% (w / v), followed by the addition of 2–4 volumes of ethanol, and the mixture is allowed to stand. The precipitate is then centrifuged and removed. Furthermore, 2 to 6 volumes of ethanol are added to the supernatant, and the mixture is left to stand, followed by centrifugation to collect the precipitated polysaccharides. It will be understood by those skilled in the art that similar products can be obtained even if the above conditions are appropriately changed.

[0043] In the present disclosure, "prevention" refers to the act of administering the active ingredient of the present disclosure to a person who has not developed the target disease, for example, with the purpose of preventing the onset of the disease.

[0044] In the present disclosure, "treatment" refers to the act of administering, for example, an active ingredient of the present disclosure to a person (subject, patient) who has been diagnosed by a physician or equivalent practitioner as having a disease, for the purpose of, for example, alleviating the disease or symptoms, preventing the growth of carcinoma, or restoring the state to a state before the onset of the disease. Furthermore, even if the purpose of administration is to prevent the worsening of the disease or symptoms or the growth of carcinoma, it is still a therapeutic act if the person receiving the administration is a patient.

[0045] As used herein, "radiotherapy" refers to a treatment method using radiation. Examples of radiation include X-rays, gamma rays, electron beams, proton beams, and heavy particle beams. One type of radiation may be used, or two or more types of radiation may be used. In one aspect, the "radiotherapy delivery means" of the present disclosure may include a radiosensitizer, a radiation delivery device, a radioactive substance, and the like. In the present disclosure, the "radiotherapy delivery means" is preferably configured to provide palliative radiation. More preferably, the "radiotherapy delivery means" is configured to irradiate radiation to have an abscopal effect. In yet another embodiment, the "radiotherapy delivery means" is configured to irradiate measurable lesions present other than the target lesion.

[0046] As used herein, the term "regulatory T cell inhibitor" refers to any drug or device that inhibits regulatory T cells. Whether or not regulatory T cells are inhibited can be determined, for example, by the following method: (1) CD4 cells from the spleen or tumor of mice + CD25 + The cells are collected and co-cultured with effector T cells collected and differentiated from mouse spleens to confirm the proliferation of effector T cells. + CD25 +The cells are treated by adding them to the culture. (2) Cancer cells were transplanted into mice and drugs were administered. The tumors were then collected and CD4 + CD25 + FoxP3 in cells + Calculate the cell ratio. (3) Cancer cells are transplanted into mice, and the drug is administered. Tumors are then harvested and FoxP3 gene expression is confirmed to determine whether the tumor is positive or negative. The target animal is not limited to mice, but may be other animals (including humans).) Examples of regulatory T cell inhibitors include, but are not limited to, COX-2 inhibitors.

[0047] As used herein, the term "COX-2 inhibitor" refers to an inhibitor of prostaglandin-endoperoxide synthase 2. Examples include celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen, and lornoxicam.

[0048] As used herein, the term "carrier" refers to a pharmaceutically acceptable substance, composition, or excipient, such as a liquid or solid filler, diluent, additive, solvent, or encapsulating material, which pertains to or enables the carrying or transport of a subject pharmaceutical compound from one organ or part of the body to another. "Pharmaceutically acceptable" means compatible with other ingredients in the formulation and not harmful to the patient. Non-limiting examples of pharmaceutically acceptable carriers, carriers, and / or diluents include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and perfuming agents, preservatives, and antioxidants can also be included in the compositions.

[0049] As used herein, "parenteral administration" refers to any route of administration other than oral administration, and includes any form of administration that provides a dosage in a form and at a level effective for the treatment or prevention of a target disease, such as cancer treatment or prevention. Parenteral administration methods include administration via transdermal or transmucosal absorption, including injection or infusion, and combinations thereof. For example, transdermal or transmucosal administration involves contacting a transdermal formulation, such as a liniment, patch, or spray, with the skin or mucosa, allowing the drug in the formulation to penetrate the body through the skin or mucosa, thereby exerting its effects. Administration via injection or infusion includes intravenous, intradermal, subcutaneous, intramuscular, and enteral (enema) administration, and may be by bolus administration and / or continuous infusion. These may include suspensions, solutions, emulsions, or implants in oily or aqueous media, containing other formulation substances such as suspending agents, stabilizers, and / or dispersants. For enteral (enema) administration, continuous delivery to the proximal small intestine can be achieved using a tube and a portable infusion pump via percutaneous endoscopic gastrostomy. Subcutaneous or intradermal administration is more preferred. Parenteral administration (e.g., transdermal administration) can also be achieved using tapes / patches, powders, sprays, ointments, pastes, creams, lotions, gels, and solutions. Compositions suitable for parenteral administration can comprise at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, implant, or sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0050] DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. It is also understood that the following embodiments of the present disclosure can be used alone or in combination.

[0051] <Direct activation of dendritic cells> In one aspect, the present disclosure provides various agents or means for directly activating dendritic cells. In one embodiment, the present disclosure provides compositions, uses, and methods for directly activating dendritic cells, comprising an immunoadjuvant. In an exemplary embodiment, the immunoadjuvant comprises a Mycobacterium tuberculosis extract, such as a Mycobacterium tuberculosis hot water extract or a portion thereof. In another embodiment, the present disclosure provides a composition or medical device for activating dendritic cells, a use, and a method of using the same, comprising a radiotherapy delivery means. Here, the radiotherapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation irradiation device, and a radioactive substance. For example, the radiotherapy delivery means is configured to provide palliative radiation. In a preferred embodiment, the radiotherapy delivery means is configured to irradiate to have an abscopal effect. In a specific example, the radiotherapy delivery means is configured to irradiate measurable lesions present other than the target lesion.

[0052] In the present disclosure, whether dendritic cells are directly activated can be determined by confirming an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of an immune adjuvant compared to the absence of the immune adjuvant, in an experiment that includes measuring the increase in the expression level in the presence of a substance or factor of interest compared to the absence of the immune adjuvant.

[0053] <Combination of immune checkpoint blockade and direct dendritic cell activation> The present disclosure is based on the discovery that the combined use of an immune checkpoint inhibitor and a direct dendritic cell activator or means exhibits specific and effective therapeutic and preventive effects against malignant neoplasms such as cancer.

[0054] The present disclosure generally provides a combination, a method for treating, preventing, or preventing recurrence of cancer or tumor in a subject by combining an immune checkpoint inhibitor with a direct dendritic cell activator or means, and a combination of an immune checkpoint inhibitor and a direct dendritic cell activator or means for use in treating, preventing, or preventing recurrence of cancer or tumor in a subject. The immune checkpoint inhibitor and the direct dendritic cell activator or means may be administered or provided simultaneously or at different times, and either may be administered first.

[0055] In another aspect, the present disclosure provides a composition, use, or medical device, use, therapy, prophylaxis, or method for treating, preventing, or preventing the recurrence of cancer or tumor in a subject using a direct dendritic cell activator or means, wherein the direct dendritic cell activator or means is administered or used in combination with an immune checkpoint inhibitor. In yet another aspect, the present disclosure provides a composition, use, or medical device, use, therapy, prophylaxis, or method for treating, preventing, or preventing recurrence of cancer or tumor in a subject using an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is administered or used in combination with a direct dendritic cell activator or means.

[0056] In one exemplary aspect, the direct dendritic cell activating agent or means can include an immune adjuvant, a radiotherapy delivery means, a radioactive substance, a combination thereof, or the like.

[0057] The immune checkpoint inhibitors or direct dendritic cell activators or means of the present disclosure may be provided in the form of a pharmaceutical composition. In certain embodiments, the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds may be converted in a subject to at least one compound of, for example, a Mycobacterium tuberculosis extract (i.e., may be provided as a prodrug).

[0058] In one embodiment, the immunoadjuvant that can be used in the present disclosure can include a hot water extract of Mycobacterium tuberculosis or a portion thereof.

[0059] In one embodiment, the radiation therapy delivery means can be any means (device, etc.) for providing X-rays, gamma rays, electron beams, proton beams, heavy particle beams, etc., and the radiation may be one type of radiation or two or more types of radiation. In one aspect, the radiation therapy delivery means of the present disclosure may include a radiosensitizer, may be provided together with a radiation irradiation device, may be provided together with a radioactive material, or may include any combination thereof. In the present disclosure, the radiation therapy delivery means is preferably configured to provide palliative radiation. More preferably, the radiation therapy delivery means is configured to irradiate to have an abscopal effect. In yet another embodiment, the radiation therapy delivery means is configured to irradiate measurable lesions present other than the target lesion.

[0060] In the present disclosure, whether dendritic cells are directly activated can be determined by confirming an increase in the expression level of CD80 / 86 on the surface of dendritic cells in the presence of an immune adjuvant compared to the absence of the immune adjuvant, in an experiment that includes measuring the increase in the expression level in the presence of a substance or factor of interest compared to the absence of the immune adjuvant.

[0061] In one preferred embodiment, the immune checkpoint inhibitor may be an inhibitor of factors such as PD-1, PD-L1, or CTLA-4. A combination of these inhibitors may also be used. For example, the immune checkpoint inhibitor may be a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. A single agent may be an inhibitor of multiple factors, PD-1, PD-L1, and CTLA-4. Specific examples include, but are not limited to, nivolumab, pembrolizumab, and atezolizumab.

[0062] In one embodiment, the cancer preferably expresses PD-L1, but is not limited to this. In another embodiment, the cancer may include, but is not limited to, lung cancer. In a preferred embodiment, the cancer or tumor may have an EGFR gene mutation, but is not limited to this. Thus, in one example, the treatment, prevention, or recurrence prevention may be administered to a subject who has been treated with a tyrosine kinase inhibitor (e.g., EGFR-TKI). In a specific embodiment, the treatment, prevention, or recurrence prevention may be administered to a subject who has not been treated with an immune checkpoint inhibitor. In another embodiment, the treatment, prevention, or recurrence prevention may be administered to a subject who has been determined to be refractory to treatment with an immune checkpoint inhibitor. In a specific embodiment, the treatment, prevention, or recurrence prevention of the present disclosure may be administered to, but is not limited to, a subject who has been treated with an immune checkpoint inhibitor and has subsequently progressed to disease progression (PD).

[0063] In one embodiment, the subject is a subject whose tumor is CXCL10-positive, which facilitates the invasion of CXCR3-positive cells. In another embodiment, the technology of the present disclosure is used to enhance CXCL10 production. In another embodiment, the subject is + T cells low Therefore, the disclosed technology can be used to deliver CD8 + In a specific embodiment, the present disclosure is directed to the treatment of patients with tumor mutational burden who have no other treatment options. high and CD8+ T cells low The present invention can be used for the treatment, prevention, or prevention of recurrence of inoperable or metastatic solid cancers.

[0064] In an embodiment of the present disclosure, the present disclosure may be used together with a regulatory T cell inhibitor. The regulatory T cell inhibitor may be a COX-2 inhibitor, and preferably, the regulatory T cell inhibitor may be a COX-2 inhibitor. The COX-2 inhibitor may be, but is not limited to, celecoxib or other COX-2 inhibitors (e.g., etodolac, meloxicam, nabumetone, zaltoprofen, lornoxicam).

[0065] (Medicine, treatment, and other medical technologies) The pharmaceuticals used in the techniques for treating, preventing, or preventing the recurrence of cancer of the present disclosure can be used by any method known in the art as pharmaceuticals.

[0066] In certain embodiments, pharmaceutical compositions may include one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds can be converted to at least one Mycobacterium tuberculosis extract in a subject (i.e., a prodrug). When multiple agents are included, they may be included in a single composition (combined drug) or in separate compositions. When formulated as a single composition, the formulation may be formulated using any form known in the art, including those exemplified herein. Multiple agents may be provided in addition to the immune checkpoint inhibitor and / or direct dendritic cell activator or means disclosed herein, along with one or more other medicaments (e.g., surgery, anti-cancer agents such as chemotherapy) or to achieve a therapy (e.g., administration of an anti-cancer agent, radiation therapy, etc.). The immune checkpoint inhibitor and / or direct dendritic cell activator or means disclosed herein may be provided or administered in combination with one or more other medicaments or therapies (e.g., surgery, chemotherapy, radiation therapy, anti-cancer agents). In one embodiment, one or more other pharmaceutical agents or therapies (e.g., surgery, chemotherapy, radiation therapy, anti-cancer agents) may be administered at an appropriate time after the administration of the immune checkpoint inhibitor and / or dendritic cell direct activator or method of the present disclosure. When administered separately, two or more pharmaceutical agents may be provided as a kit. Examples of anti-cancer agents include, but are not limited to, chemotherapeutic agents such as antimetabolites and alkylating agents, antiproliferative agents, cytotoxic agents, agents used in radiation therapy, anti-angiogenic agents, apoptotic agents, anti-tubulin agents, anti-cancer antibiotics, microtubule-active agents, tyrosine kinase inhibitors, proteasome inhibitors, anaplastic lymphoma kinase inhibitors, Janus kinase inhibitors, CDK inhibitors, MEK inhibitors, Raf kinase inhibitors, molecularly targeted therapies such as PARP inhibitors and antibody drugs, platinum-based agents, immunotherapy such as dendritic cell therapy, gene therapy, other small molecule drugs, and other drugs for treating cancer.

[0067] Compositions disclosed herein suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (usually with a flavored base, which is sucrose and acacia or tragacanth), powder, granules, solutions in aqueous or non-aqueous liquids, suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups, lozenges (with an inert base, such as gelatin, glycerin, sucrose, and / or acacia), and / or mouthwashes, each containing a predetermined amount of at least one compound of the present disclosure.

[0068] The compositions disclosed herein may be administered as a bolus, electuary, or paste.

[0069] The immune checkpoint inhibitor and / or direct dendritic cell activator or means of the present disclosure can be administered in any dosage form, and any dosage form can be used as long as it can produce its effect, whether oral or parenteral, with parenteral administration being preferred.

[0070] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) may comprise one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; agar, calcium carbonate, potato or tapioca starch, alginic acid, certain The pharmaceutical composition may be mixed with any of disintegrating agents such as silicates, sodium carbonate, and sodium starch glycolate, solution retarders such as paraffin, absorption accelerators such as quaternary ammonium compounds, wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polypropylene oxide copolymers, absorbents such as kaolin and bentonite clay, lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0071] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins such as hydroxypropyl-β-cyclodextrin may be used to dissolve the compound.

[0072] Components of the present disclosure can include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, coloring agents, perfumes, and preservatives. Suspensions can contain suspending agents in addition to one or more compounds according to the present disclosure, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0073] The combinations disclosed herein can be made into suppositories for rectal or vaginal administration, which can be prepared by mixing one or more compounds according to the present disclosure with one or more suitable non-irritating excipients or carriers, including cocoa butter, polyethylene glycol, suppository waxes, or salicylates, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the compound of the present disclosure. Pharmaceutical compositions suitable for vaginal administration can also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art to be appropriate.

[0074] Dosage forms for topical or transdermal administration of the combinations of this disclosure may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Pharmaceutical compositions or tablets may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0075] The ointments, pastes, creams, and gels can contain, in addition to the combinations of the present disclosure, additives such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0076] Powders and sprays can contain, in addition to the pharmaceutical composition or tablets of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Additionally, sprays can contain common propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0077] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also intended to be within the scope of this disclosure.

[0078] Combinations suitable for parenteral administration may comprise at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, or sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0079] As used herein, the term "salt" includes acid and / or base salts formed with inorganic and / or organic acids and bases. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, and / or the like, balanced by a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19, describes pharmaceutically acceptable salts in detail.

[0080] Pharmaceutically acceptable salts can be formed with inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanoate, and the like. Examples of suitable salts include benzoyl benzoates, ... In some embodiments, organic acids that can yield salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0081] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the compounds with a suitable base or acid, respectively. Non-limiting examples of pharmaceutically acceptable salts derived from bases include alkali metal, alkaline earth metal, ammonium, and N(C1-4 alkyl)4 salts. Non-limiting examples of suitable alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Additionally, non-limiting examples of suitable pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, as appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Non-limiting examples of suitable organic bases from which salts can be formed include primary amines, secondary amines, tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In certain embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0082] In embodiments of the present disclosure, the subject may be a patient before the onset of cancer, after cancer treatment, in the early stage of cancer, or in a precancerous state. Alternatively, the subject may be a healthy individual. When the subject is a healthy individual, the method is performed as a preventive method.

[0083] Cancers of interest in the present disclosure include, but are not limited to, esophageal cancer, gastroesophageal junction cancer, renal cell carcinoma, lung cancer, gastrointestinal cancer, leukemia, lymphoma, myeloma, brain cancer, pancreatic cancer, endometrial cancer, prostate cancer, liver cancer, bladder cancer, gastroesophageal adenocarcinoma, chondrosarcoma, colorectal adenocarcinoma, colorectal cancer, breast cancer, renal cell carcinoma, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, sarcoma, genitourinary cancer, gynecological cancer, and adrenocortical carcinoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is colorectal adenocarcinoma. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is renal cell carcinoma. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the cancer may be unresectable. In certain embodiments, the cancer may be progressive. In certain embodiments, the cancer may be refractory. In certain embodiments, the cancer may be recurrent. In certain embodiments, the cancer may be metastatic. In various embodiments of the present disclosure, the target cancer may include common carcinomas, relatively indolent carcinomas (e.g., those that are less sensitive to the immune system), oral squamous cell carcinoma, cervical cancer, MHC class I-negative carcinomas that are less susceptible to CD8-positive T cells, cancers resistant to immune checkpoint inhibitors, etc. A cancer patient refers to a patient suffering from the above-mentioned "cancer." In one embodiment, the disease, disorder, or symptom targeted by the present disclosure includes melanoma.

[0084] Without wishing to be bound by theory, human T cells have a portion that can bind to factors on the individual's own cells so that they do not attack cells other than the individual's own T cells, and a representative factor (molecule) in this portion is PD-1. On the other hand, factors (molecules) such as PD-L1 are present on general cells, and when PD-L1 binds to PD-1, the general cells are protected from attack by T cells (immune cells). This mechanism is the immune checkpoint system, which suppresses the activity of T cells. Since cancer cells themselves are also cells of the individual's own origin, this immune checkpoint system protects them from attack by T cells (immune cells).

[0085] Without wishing to be bound by theory, immune checkpoint inhibitors (ICIs) are drugs that inhibit the immune checkpoint system, for example, by inhibiting stimulation of immune checkpoint molecules (PD-1), which are inhibitory receptors for immune function present on T cells, which are immune cells. Because immune checkpoint inhibitors are drugs that inhibit the immune suppression system, the patient's immune function is activated by administering these drugs. Then, by inhibiting immune checkpoint molecules in cancer cells, T cells become able to attack the cancer cells.

[0086] Without wishing to be bound by theory, Extract Z is a suitable therapeutic agent used to increase sensitivity to immune checkpoint inhibitors. Extract Z was developed as a treatment for tuberculosis and is a clear, colorless subcutaneous injection, the main components of which are a polysaccharide called lipoarabinomannan extracted from Mycobacterium tuberculosis, nucleic acids, and lipids.

[0087] Without wishing to be bound by theory, administration of Extract Z has the effect of increasing sensitivity to immune checkpoint inhibitors (ICIs). In addition to the administration of these therapeutic agents, radiation exposure can also be expected to have the effect of increasing sensitivity to immune checkpoint inhibitors (ICIs).

[0088] In one embodiment, a patient's cancer is treated by combining such a treatment with an immune checkpoint inhibitor (first treatment) with a treatment to increase sensitivity to the immune checkpoint inhibitor (second treatment). In other words, the cancer treatment method of this embodiment includes a step of administering a treatment by administering an immune checkpoint inhibitor (first treatment) to a cancer patient, and a step of administering a treatment to increase sensitivity to the immune checkpoint inhibitor (second treatment) to the cancer patient.

[0089] In one embodiment, the immune checkpoint inhibitor in the first treatment is nivolumab, pembrolizumab, or atezolizumab, which is an antibody against PD-1 on T cells, and inhibits the immune checkpoint between PD-1 on T cells and PD-L1 on cancer cells. The therapy in the second treatment is radiation therapy, administration of Extract Z, or a combination thereof.

[0090] In one embodiment, when the first treatment and the second treatment are combined, the first treatment and the second treatment may be administered to the patient simultaneously for a predetermined period of time. Alternatively, either the first treatment or the second treatment may be administered to the patient for a predetermined period of time, and then the other treatment may be administered to the patient for a predetermined period of time. Alternatively, either the first treatment or the second treatment may be administered to the patient for a predetermined period of time, and then both treatments may be administered to the patient for a predetermined period of time. Alternatively, both the first treatment and the second treatment may be administered to the patient for a predetermined period of time, and then only one of the treatments may be administered to the patient for a predetermined period of time. Furthermore, the above-mentioned treatments may be combined appropriately and periodically repeated.

[0091] In the various forms described above, the timing for changing therapy is determined based on predetermined changes in the patient's test results (such as medical images of the patient, measurement results (measurements) of the patient's tumor markers, and PET scan results of the patient), as described below.

[0092] In one embodiment, the first treatment and the second treatment are combined, making it possible to eliminate or reduce cancer tissue through the synergistic effect of the effects of the first treatment and the second treatment. Without wishing to be bound by theory, the second treatment (radiation, administration of Extract Z, or a combination of administration of Extract Z and radiation) increases sensitivity to immune checkpoint inhibitors, while the first treatment (administration of an immune checkpoint inhibitor) allows the attacking power of T cells to be exerted against cancer cells, thereby eliminating or reducing the patient's cancer tissue.

[0093] FIG. 1 is a block diagram showing the configuration of a system that uses a program according to this embodiment, and FIG. 2 is a flowchart showing a treatment procedure according to this embodiment.

[0094] 1 includes a control unit 11, a reading unit 12, a storage unit 13, a display unit 14, an input unit 15, and a bus 16. The control unit 11 is connected to the other hardware units constituting the system 1 via the bus 16.

[0095] The control unit 11 is configured using a CPU (Central Processing Unit), an MPU (Micro Processing Unit), etc., and executes the program of this embodiment. The reading unit 12 reads the program 3 of this embodiment recorded on a portable recording medium 2 such as a flexible disk. The storage unit 13 is configured using an SRAM (Static Random Access Memory), a DRAM (Dynamic Random Access Memory), etc., and stores information required during the processing performed by the control unit 11, and the program 3 read by the reading unit 12.

[0096] The display unit 14 is configured with a liquid crystal display panel or the like, and displays patient history information, processing results by the control unit 11 (type of therapy administered to the patient, implementation period of each therapy), etc. The input unit 15 is configured with a keyboard, mouse, etc., and accepts input information from the user.

[0097] An image acquisition device 4 that acquires medical images of the patient (CT images, X-ray images, PET images, etc.) is connected to the system 1, and the medical images of the patient are input to the system 1 (control unit 11) periodically or in response to a request from the system 1 (control unit 11). Also, a tumor marker measuring device 5 that measures the patient's tumor marker (specifically, CEA: Carcinoembryonic Antigen) is connected to the system 1, and the measured value of the patient's tumor marker (CEA) is input to the system 1 (control unit 11) periodically or in response to a request from the system 1 (control unit 11).

[0098] In the above example, the program 3 is read from the portable recording medium 2 using the reading unit 12, but it may be stored in advance in the storage unit 13. Also, the program 3 may be acquired from an external server via a network (not shown).

[0099] Next, the treatment procedure in this embodiment will be described with reference to the flowchart in FIG.

[0100] The control unit 11 specifies a first period during which either a treatment using an immune checkpoint inhibitor (first treatment) or a treatment for increasing sensitivity to the immune checkpoint inhibitor (second treatment) will be administered (step S1). Here, the control unit 11 also specifies which of radiation exposure, administration of Extract Z, or a combination of administration of Extract Z and radiation exposure will be administered as the second treatment. In this case, the first period and the type of second treatment are specified based on, for example, input from the user received via the input unit 15. The control unit 11 itself may specify the first period and the type of second treatment based on the patient's medical history, treatment history information from other cases, etc. The specified first period and type of second treatment are displayed on the display unit 14.

[0101] While continuing one of the treatments, the control unit 11 acquires medical images of the patient obtained by the image acquisition device 4 (step S2).

[0102] The control unit 11 determines whether the cancer tissue has shrunk based on the acquired medical image (step S3). If the cancer tissue has shrunk (step S3: YES), the process returns to step S2.

[0103] On the other hand, if the cancer tissue has not shrunk (step S3: NO), the control unit 11 acquires the measured value of the patient's tumor marker obtained by the tumor marker measuring device 5 (step S4).

[0104] The control unit 11 determines whether or not the measurement value of the acquired tumor marker has increased (step S5). If the measurement value has not increased (step S5: NO), the process returns to step S2.

[0105] On the other hand, if the measured value of the tumor marker is increasing (step S5: YES), the control unit 11 specifies a second period during which the other of the treatment with an immune checkpoint inhibitor (first treatment) or the treatment for increasing sensitivity to the immune checkpoint inhibitor (second treatment) is administered (step S6), and the process ends. In this case, the second period is specified, for example, in response to an input from the user received via the input unit 15. The control unit 11 itself may specify the second period based on the patient's medical history, treatment history information from other cases, etc. The specified second period is displayed on the display unit 14.

[0106] In the embodiment described above, the implementation period of the other of the first treatment or the second treatment is specified in step S6, but the implementation periods of both the first treatment and the second treatment may be specified.

[0107] In the above-described embodiment, in step S5, the implementation period of the other (or both) therapy is identified when the measured value of the tumor marker increases, but the implementation period of the other (or both) therapy may also be identified when the glucose uptake based on the PET examination results increases. Also, in step S5, it may be determined whether to proceed to the processing of step S6 (identification of the implementation period of the other (or both) therapy) depending on both the fluctuation in the measured value of the tumor marker and the fluctuation in the glucose uptake based on the PET examination results.

[0108] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be adopted. The same applies to "or." When it is stated in this specification that "within a range of two values," the range includes the two values ​​themselves.

[0109] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0110] The present disclosure has been described above by showing preferred embodiments for ease of understanding. Hereinafter, the present disclosure will be described based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims. [Example]

[0111] Examples are described below. Where necessary, the handling of animals used in the following examples complied with relevant ethical standards and guidelines and was conducted in accordance with the Declaration of Helsinki. While the specific reagents used were those listed in the examples, equivalent products from other manufacturers (Sigma-Aldrich, Wako Pure Chemical Industries, Nakarai, R&D Systems, USCN Life Science Inc., etc.) can also be used.

[0112] (Manufacturing example: Extract Z) Extract Z used in this example was prepared as follows. Mycobacterium tuberculosis strain Aoyama B, which had been freeze-dried and stored at -20°C, was cultured in a soy-based potato medium. (1) This seed culture is then cultured at 37±1°C. (2)The resulting cells were transferred to a 0.45 μm membrane filter and cultured at 37±1°C for 5–7 weeks (main culture). The resulting cells were washed with water for injection, then 20 times the wet cell weight of water for injection was added and heated at 100°C for 120 minutes to obtain an extract. This extract was then filtered through a 0.45 μm membrane filter and concentrated under reduced pressure to a sugar content (D-arabinose equivalent by the phenol-sulfuric acid method) of 4.0–6.0 mg / mL. Next, to remove proteins, 1% w / v sulfosalicylic acid was added to the concentrate, which was then left at 10°C or below for 15–20 minutes. The precipitate was then centrifuged (10°C or below, 1150 × G, 10 minutes), and the supernatant was collected. The protein concentration of the supernatant was 0.30 mg / mL (Lowry method, tyrosine equivalent). The sulfosalicylic acid was then removed from the supernatant until the supernatant was below the detection limit (10 ppm or below, ferric chloride solution method). This solution is concentrated under reduced pressure to a sugar content of 1.8-2.2 mg / mL. Sodium chloride (0.9% w / v) and an equal volume of cold ethanol to the concentrate are added, and the mixture is left at or below 10°C for at least 40 hours. The precipitate (high molecular weight polysaccharides) is then centrifuged (10°C or below, 2040 x G, 10 minutes). Four volumes of cold ethanol are then added to the supernatant, and the mixture is left at or below 10°C for at least 40 hours. The precipitate is then recovered by centrifugation (10°C or below, 2040 x G, 10 minutes). The precipitate is dissolved in water for injection, the sugar content is adjusted to 1.8-2.2 mg / mL, and the mixture is filtered through a 0.45 μm membrane filter and autoclaved (121°C, 20 minutes) to give Extract Z solution.

[0113] (1): Sauton potato medium Washed potato pieces are immersed in Sauton medium, sterilized at 115°C for 15 minutes, and then used as Sauton potato medium. Sauton's medium L-Asparagine (monohydrate) 4.0g Citric acid (monohydrate) 2.0g Magnesium sulfate (heptahydrate) 0.5g Potassium hydrogen phosphate (anhydrous) 0.5g Ferrous ammonium citrate 0.05g 60mL of glycerin Dissolve the above in water to make 1000 mL. Adjust the pH to 7.0-7.3 with sodium hydroxide solution.

[0114] (2): Production medium L-Asparagine (monohydrate) 4.0g Citric acid (monohydrate) 2.0g Magnesium sulfate (heptahydrate) 0.5g Potassium hydrogen phosphate (anhydrous) 0.5g Ferrous ammonium citrate 0.05g 60mL of glycerin Dissolve the above in water to make 1000 mL and sterilize by high-pressure steam (121°C, 20 minutes). Adjust the pH to 7.0-7.3 with sodium hydroxide solution.

[0115] The physicochemical properties of the obtained Extract Z solution were as follows: (1) Appearance Slight yellow clear liquid (2) pH 4.50~5.30 (3) Protein content 3.5% by weight (as amino acids) in the freeze-dried product (4) Nucleic acid content 0.1% by weight in freeze-dried product (5) The main monosaccharides constituting polysaccharides Mannose 43.4% by weight, arabinose 18.2% by weight, glucose 10.4% by weight. (After hydrolysis with 2N trifluoroacetic acid at 100°C for 2 hours, the product was analyzed by liquid chromatography using 2-cyanoacetamide fluorescent derivatives (S. Honda, et al., Anal. Chem., 52, 1079 (1980)).

[0116] The Extract Z solution prepared by the method described in the above manufacturing example can be diluted appropriately before use. In the following examples, it was diluted 1 to 50,000 times to adjust to an appropriate concentration before use.

[0117] The manufacturers and catalog numbers of the antibodies and staining reagents used in the following examples are as follows: CD80 (Miltenyi Biotec, catalog number 130-102-372) CD86 (Miltenyi Biotec, catalog number 130-102-506) CD11b (Miltenyi Biotec, Catalog No. 130-113-811) CD11c (Miltenyi Biotec, catalog number 130-122-016) CD45 (Miltenyi Biotec K.K., catalog number 130-119-130) CD4 (Miltenyi Biotec K.K., Catalog No. 130-123-899) CD8 (Life Technologies Corporation, catalog number 25-0081-82) TCRβ (BioLegend Incorporated, Catalog No. 109220) NK (anti-CD49b antibody; Miltenyi Biotec K.K., catalog number 130-102-258) MHC class II (Miltenyi Biotec, Catalog No. 130-123-785) PD-L1 (anti-CD274 antibody; Life Technologies Corporation, catalog number 12-5982-81) PI (Propidium Iodide Solution; dead cell marker; Miltenyi Biotec K.K., Cat. No. 130-093-233)

[0118] Specific examples of treatment for cancer patients are described below with reference to Figure 3 (Example 1: Example 1 of immune checkpoint inhibitor + radiation exposure alone), Figure 4 (Example 2: Example 2 of immune checkpoint inhibitor + radiation exposure alone), Figure 5 (Example 3: Example of immune checkpoint inhibitor after Extract Z administration), Figure 6 (Example 4: Example of combined immune checkpoint inhibitor + Extract Z administration + radiation exposure), and Figures 10 and 11 (example of combined immune checkpoint inhibitor + Extract Z administration + radiation exposure for a subject who had received effective treatment with a tyrosine kinase inhibitor and an immune checkpoint inhibitor but subsequently developed progressive disease (PD)).

[0119] Example 1 The patient was a 69-year-old man diagnosed with squamous cell lung cancer without driver gene mutations, clinical TNM classification: cTxN3M1b, stage: IVb.

[0120] Between September 2017 and November 2018, the patient received intravenous infusion of nivolumab, a type of anti-PD-1 antibody immune checkpoint inhibitor, at a dose of 240 mg every two weeks. However, as shown in the CT image in Figure 3, swelling of the metastatic cervical lymph nodes progressed. In December 2018, the cervical lymph nodes were irradiated with 30 Gy / 10 fr radiation. Nivolumab has been administered intravenously at a dose of 240 mg every two weeks since December 2018 (as of December 2019). As a result, swelling of the cervical lymph nodes has been suppressed (April and October 2019), resulting in partial remission, and the treatment is effective.

[0121] Example 2 The patient was a 60-year-old man diagnosed with recurrent lung adenocarcinoma without driver gene mutations, TNM classification: rTxN3M1b, stage: IVb.

[0122] Nivolumab was administered intravenously at a dose of 240 mg every two weeks from November 2017 to February 2019, but swelling of the metastatic cervical lymph nodes progressed, as shown in the CT image in Figure 4. In March 2019, the cervical lymph nodes were irradiated with 30 Gy / 10 fr radiation. Nivolumab has been administered intravenously at a dose of 240 mg every two weeks since March 2019 and continues to be administered intravenously at a dose of 240 mg every two weeks from this date (December 2019). As a result, swelling of the cervical lymph nodes has been suppressed (May 2019), resulting in partial remission, and the treatment is effective.

[0123] Example 3 The patient was a 67-year-old woman diagnosed with EGFR gene mutation-positive (deletion of ecton 19) lung adenocarcinoma, clinical TNM classification: cT1bN3M1b, stage: IVb.

[0124] Extract Z administration began on April 1, 2019. As the tumor marker (CEA) measurement value increased from 57.0 to 277.0, Extract Z administration was discontinued on June 3 of the same year, and nivolumab was started as an intravenous infusion at 240 mg every two weeks. After that, the tumor marker (CEA) measurement value dropped dramatically from 277.0 to 63.2.

[0125] As shown in the CT image in Figure 5, the cancer tissue that was present before treatment had almost completely disappeared after treatment, demonstrating the synergistic effect of Extract Z administration and nivolumab administration, resulting in an excellent therapeutic effect.

[0126] Example 4 The patient was a 55-year-old woman diagnosed with EGFR gene mutation-positive (deletion of ecton 19) lung adenocarcinoma, clinical TNM classification: cT3bN2M1c, stage: IVb.

[0127] On June 20, 2019, the patient began receiving intravenous infusion of pembrolizumab, a type of anti-PD-1 antibody and immune checkpoint inhibitor, at a dose of 200 mg every three weeks. As the tumor marker (CEA) measurement increased from 25.0 to 98.8, on August 15 of the same year, the patient began receiving Extract Z while continuing pembrolizumab. At this time, the patient received 30 Gy / 10 fr radiation therapy. Subsequently, the tumor marker (CEA) measurement decreased dramatically from 98.8 to 41.5.

[0128] As shown in the X-ray image in Figure 6, the area of ​​cancer tissue temporarily grew larger on August 15th during treatment (before administration of Extract Z), but after treatment (administration of Extract Z + radiation exposure), it had become significantly smaller than before treatment. The synergistic effect of the combination of pembrolizumab administration and Extract Z administration + radiation exposure resulted in an excellent therapeutic effect.

[0129] Example 5: Immunoadjuvant / Radiotherapy Use for Direct Activation of Dendritic Cells In this example, the use of immunoadjuvant / radiotherapy to directly activate dendritic cells was confirmed. (material and method) Immune adjuvant = Extract Z Radiation therapy

[0130] Example 6: Example of direct activation of dendritic cells by administration of immune adjuvant This example demonstrates direct activation of dendritic cells by administration of an immune adjuvant. C3H / HeN mice were subcutaneously administered 1 mg / kg of saline or Extract Z once daily in the right groin (20 mice per group). 29 days after the start of saline or Extract Z administration, 1 × 10 oral squamous cell carcinoma Sq-1979 cells were administered. 6 The animals are injected subcutaneously into the ventral cavity. On day 36 after the start of administration of saline or Extract Z, tumors and lymph nodes are collected from five mice, pooled, and analyzed using a flow cytometer. [Antibody used] Antibodies against CD80, CD86, CD11b, and CD11c

[0131] (result) Increased expression of CD80 / 86 on the surface of dendritic cells was observed in the Extract Z administration group. This result suggests that administration of Extract Z activates dendritic cells.

[0132] Example 7: Example of direct dendritic cell activation by administration of radiation therapy This example demonstrates direct activation of dendritic cells by administration of radiation therapy. Cancer cells are injected subcutaneously into mice to create subcutaneous tumor-bearing mice. After the cancer cells are subcutaneously implanted, half of the mice are irradiated with localized radiation. After irradiation, subcutaneous tumors and lymph nodes are collected from the irradiated and non-irradiated mice, and the expression levels of CD80 / 86 on the surface of dendritic cells are measured using a flow cytometer. On the 36th day after the start of irradiation (the same timing as for the non-irradiated group), tumors and lymph nodes are collected, pooled from 5 mice, and analyzed using a flow cytometer. [Antibody used] Antibodies against CD80, CD86, CD11b, and CD11c

[0133] Example 8: Combination of multiple direct dendritic cell activation techniques This example demonstrates the combined use of multiple direct dendritic cell activation techniques. Patients with cervical cancer at a stage where chemoradiotherapy is indicated will be administered normal saline or Extract Z. Platinum-based drugs (cisplatin or carboplatin) will be administered simultaneously or asynchronously with normal saline or Extract Z, and definitive radiation therapy will be performed. Subsequently, immune parameters (CD11c, CD14, CD16, CD19, CD24, CD27, CD38, CD80, CD86, CD123, CD138, CCR5, CCR7, CXCR3, HLA-DR, CD3, CD4, CD8, CD45RA, CD56, CD69, CD159a, CTLA-4, NKp46, PD-1, IFNγ, TNFα, perforin, granzyme B, IL4, FoxP3, IL17A, Ki67, CXCL9, CXCL10, IL10, IL12p70) will be measured in the patient group, as well as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

[0134] Example 9: Combination of immune checkpoint inhibitors and immune adjuvants This example demonstrates the use of an immune checkpoint inhibitor in combination with an immune adjuvant.

[0135] Patients with solid tumors, no existing treatment options, and tumor mutational burden high and CD8 + T Cell invasion low Normal saline or Extract Z will be administered to this group of patients. An immune checkpoint inhibitor (e.g., pembrolizumab) will be administered simultaneously or at different times with normal saline or Extract Z. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) will then be measured in this group of patients.

[0136] Example 10: Another example of combined use of immune checkpoint inhibitors and immune adjuvants This example demonstrates an example of combined use of an immune checkpoint inhibitor and an immune adjuvant. Extract Z will be administered to patients with non-small cell lung cancer who have not responded to immune checkpoint inhibitor monotherapy. Immune checkpoint inhibitors and palliative radiation therapy will be administered simultaneously or asynchronously with Extract Z. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) will then be measured in this patient group.

[0137] Example 11: Combination of immune checkpoint inhibitors, immune adjuvants, and radiation therapy This example demonstrates the combined use of an immune checkpoint inhibitor, an immune adjuvant, and radiation therapy.

[0138] Patients with non-small cell lung cancer who have no existing treatment options, are EGFR mutation-positive, and are intolerant or refractory to EGFR-TKIs will be administered saline or Extract Z. Immune checkpoint inhibitors and palliative radiation therapy will be administered simultaneously or asynchronously with saline or Extract Z. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) will then be measured in this patient group.

[0139] Example 12: Combination of immune checkpoint inhibitors, immune adjuvants, radiation therapy, and COX-2 inhibitors Extract Z will be administered to patients with non-small cell lung cancer who have not responded to immune checkpoint inhibitor monotherapy. Extract Z will be administered simultaneously or asynchronously with immune checkpoint inhibitors, palliative radiation therapy, and regulatory T cell suppressors. Afterwards, PFS (Progression-Free Survival), OS (Overall Survival), and ORR (Objective Response Rate) will be measured in this patient group.

[0140] Example 13: Examples of immune adjuvants that enhance CXCL10 production This example demonstrates that agents of the present disclosure enhance CXCL10 production.

[0141] Bone marrow-derived cells were collected from C3H / HeJ mice (male), and the collected bone marrow-derived cells were cultured at 4 × 10 6 The cells were cultured for 6 days in the presence of 20 ng / mL GM-CSF and 20 ng / mL IL-4 on a 1000 x 1000 plate. After the culture, the bone marrow-derived cells were collected and diluted to 2 x 10 5 The cells were seeded at 1 / well and stimulated with 0.4 μg / mL, 0.8 μg / mL, 1.6 μg / mL, or 3.2 μg / mL of Extract Z. Six hours after stimulation, the culture supernatant was collected and the CXCL10 concentration was measured by ELISA.

[0142] The results are shown in Figure 7. As the concentration of Extract Z used for stimulation increased, the CXCL10 concentration in the culture supernatant increased. Therefore, Extract Z was found to have the effect of enhancing CXCL10 production.

[0143] Example 14: Treatment of CXCL10-positive cancer or tumor with immune adjuvant [CXCL10 positive] We will administer immune adjuvants to subcutaneously transplanted cancer cell models to confirm their antitumor or life-prolonging effects. For subcutaneously transplanted models in which antitumor or life-prolonging effects have been confirmed, we will harvest the tumors and examine the CXCL10 gene expression levels in the tumors to confirm that they are high. [CXCR3 positive] The immune adjuvant is administered to a subcutaneously transplanted cancer cell model to confirm its antitumor or life-prolonging effect. For subcutaneously transplanted models in which an antitumor or life-prolonging effect has been confirmed, the tumor is harvested and CXCR3-positive cells in the tumor are examined using a flow cytometer or immunostaining to confirm a high rate of positive cells.

[0144] Example 15: Example of the effect of promoting CD8+ T cell infiltration into tumors In this example, the agent of the present disclosure induces intratumoral CD8 + It has the effect of promoting T cell infiltration.

[0145] C3H / HeN mice were subcutaneously administered saline or Extract Z at 1 mg / kg once daily in the right groin (40 mice per group). 29 days after the start of saline or Extract Z administration, 1 × 10 oral squamous cell carcinoma Sq-1979 cells were injected. 6 Seven days after Sq-1979 cell transfer, tumors were harvested from five mice and pooled for analysis by flow cytometry. [Antibodies and reagents used] Antibodies against CD45 Antibodies to CD8 Antibody against TCRβ chain PI (dead cell marker)

[0146] (result) The results are shown in Figure 8. Administration of Extract Z increased intratumoral CD8 + On the other hand, the effect of Extract Z is nonspecific immunostimulation, so the CD8 + T cells include both cells with anti-tumor effects and cells that express CTLA-4 and inhibit the anti-tumor effects.

[0147] Example 16: Tumor Mutational Burden in Patients with No Other Treatment Options, Including Immune Adjuvants high and CD8 + T cells low (Examples of treatment or prevention of inoperable or metastatic solid cancer) In this example, we investigated the efficacy and safety of immunotherapy for patients with tumor mutational burden who have no other treatment options, including immunoadjuvants. high and CD8 + T cells low The present invention provides a demonstration of the treatment or prevention of inoperable or metastatic solid cancers.

[0148] Patients with solid tumors, no existing treatment options, and tumor mutational burden high and CD8 + T Cell invasion low Normal saline or Extract Z will be administered to this group of patients. An immune checkpoint inhibitor (e.g., pembrolizumab) will be administered simultaneously or at different times with normal saline or Extract Z. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) will then be measured in this group of patients.

[0149] Example 17: Regimen Treatment Example This example demonstrates an example of a combination regimen of an immune checkpoint inhibitor, radiation therapy, and Extract Z.

[0150] (1) Immune checkpoint inhibitors: Use one of the following single agents. (a) Nivolumab is administered by intravenous infusion at a rate of 240 mg every two weeks. (b) Pembrolizumab is administered by intravenous infusion over 30 minutes at a dose of 200 mg every 3 weeks, or by intravenous infusion over 30 minutes at a dose of 400 mg every 6 weeks. (c) Atezolizumab is administered intravenously over 30 minutes at a dose of 1200 mg every 3 weeks. (2) Radiation therapy Palliative irradiation for non-brain metastases is 2Gy x 20-25 fractions, or a dose equivalent to this: for example, 3Gy x 10 fractions. The method of palliative irradiation is determined by the radiation oncologist at each institution. (3) Extract Z (a) The drug solution is drawn into a 1 mL syringe, and a portion of it (preferably about 0.05 mL) is injected subcutaneously into the upper arm. (b) Twice a week (c) From the start of radiation therapy to the end of radiation therapy (maximum 8 weeks) (4) Repeated radiation therapy and Extract Z Nine months after the start of treatment, radiation therapy and Extract Z may be repeated at a different site.

[0151] Example 18: Example showing the ratio of tumor-infiltrating cells after administration of Extract Z In this example, an analysis of the ratio of tumor-infiltrating cells following administration of the agent of the present disclosure is shown.

[0152] C3H / HeN mice were subcutaneously administered 1 mg / kg of saline or Extract Z once daily in the right groin for 35 days (20 mice per group). As shown in Table 1, 1 × 10 oral squamous cell carcinoma Sq-1979 cells were administered 29 days after the start of saline or Extract Z administration. 6 1 × 10 oral squamous cell carcinoma Sq-1979 cells were injected subcutaneously into the ventral cavity, and 200 μg / body of anti-PD-1 antibody was injected intraperitoneally on days 28, 31, and 34 after the start of saline or Extract Z administration. 6 The mice were subcutaneously injected with saline or Extract Z into the ventral cavity, and on days 28, 31, and 34 after the start of saline or Extract Z administration, 200 μg / body of anti-PD-1 antibody or control antibody was injected intraperitoneally. On day 36 after the start of saline or Extract Z administration, tumors and lymph nodes were collected from five mice, pooled, and analyzed using a flow cytometer. [Antibodies and reagents used] Antibodies against CD45, CD4, CD8, and TCR (T cell receptor) Antibodies against NK, MHC class II, and PD-L1 PI (dead cell marker)

[0153] (result) The results are shown in Tables 1 and 2. Among the tumor-infiltrating cells, CD8 +The percentage of T cells was 4.34% in the saline-treated group, but 10.43% in the Extract Z-treated group (Table 1). Furthermore, the percentage was 3.91% in the anti-PD-1 antibody-only treated group, but 11.58% in the Extract Z and anti-PD-1 antibody-coated group (Table 2). These results suggest that administration of Extract Z increases the CD8 + It was shown that T cell infiltration into tumors was induced. [Table 1] [Table 2]

[0154] Example 19: Example showing the ratio of antigen-presenting cell markers in lymph nodes after administration of Extract Z This example shows an analysis of the ratio of antigen-presenting cell markers in lymph nodes following administration of the agent of the present disclosure.

[0155] C3H / HeN mice were subcutaneously administered 1 mg / kg of saline or Extract Z once daily in the right groin for 35 days (20 mice per group). As shown in Table 3, 1 × 10 oral squamous cell carcinoma Sq-1979 cells were administered 29 days after the start of saline or Extract Z administration. 6 1 × 10 oral squamous cell carcinoma Sq-1979 cells were injected subcutaneously into the ventral cavity, and 200 μg / body of anti-PD-1 antibody was injected intraperitoneally on days 28, 31, and 34 after the start of saline or Extract Z administration. 6 The mice were subcutaneously injected with saline or Extract Z into the ventral cavity, and on days 28, 31, and 34 after the start of saline or Extract Z administration, 200 μg / body of anti-PD-1 antibody or control antibody was injected intraperitoneally. On day 36 after the start of saline or Extract Z administration, tumors and lymph nodes were collected from five mice, pooled, and analyzed using a flow cytometer. [Antibodies and reagents used] Antibodies against CD45, CD80, CD86, CD11b, CD11c, MHC class II, and PD-L1 PI (dead cell marker)

[0156] (result) The results are shown in Tables 3 and 4. Among the antigen-presenting cell markers in lymph nodes, CD80 + The percentage of CD80 / MHC class II cells was 6.09% in the saline-treated group, but 8.38% in the Extract Z-treated group. Furthermore, the percentage was 6.08% in the anti-PD-1 antibody-only treated group, but 6.89% in the Extract Z and anti-PD-1 antibody-treated group (Table 4). These results suggest that administration of Extract Z significantly increased the number of CD80 / MHC class II cells. + It was shown that the expression of [Table 3] [Table 4]

[0157] Example 20: Example demonstrating PD-L1 expression in cultured Sq-1979 cells This example shows the analysis of PD-L1 expression in cultured Sq-1979 cells with agents of the present disclosure.

[0158] Cultured oral squamous cell carcinoma Sq-1979 cells were harvested, stained with anti-PD-L1 antibody and control antibody, and measured using a flow cytometer.

[0159] (result) The results are shown in Figure 9. Sq-1979 cells were shown to be PD-L1 positive, as 88.78% of the cells were positive when stained with the anti-PD-L1 antibody and 1.57% of the cells were positive with the control antibody.

[0160] Example 21: Effect of combined use of Extract Z and immune checkpoint inhibitors In this example, Extract Z and an anti-CTLA-4 antibody are administered to a mouse tumor model, and it is confirmed that the anti-tumor effect or life-prolonging effect is synergistically increased. Spleen cells or lymph nodes are collected from mice, immune cells are isolated, and Extract Z and CTLA-4 antibody are added. Extract Z exhibits IFN-γ production (T cell activation) when added in vitro, so we will confirm whether the addition of CTLA-4 antibody synergistically increases this IFN-γ production.

[0161] Example 22: Administration of Extract Z induces tumor infiltration of CD8 + T cells are CTLA-4 + (Example showing that In this example, tumor-infiltrating CD8 + Confirm increased CTLA-4 expression on T cells.

[0162] Extract Z administration increased overall CD8 + CTLA-4 not only promotes T cell infiltration but also inhibits antitumor effects + CD8 + We confirm that it also promotes T cell infiltration.

[0163] Example 23: Example of treatment with Extract Z, immune checkpoint inhibitors and radiation In this example, the therapeutic effect of combined use of Extract Z, an immune checkpoint inhibitor, and radiation was confirmed.

[0164] The patient was a 57-year-old man diagnosed with EGFR gene mutation-positive (exon 19 deletion) lung adenocarcinoma, clinical TNM classification: cT2aN2M1c, stage: IVb.

[0165] After starting afatinib in October 2015, the patient was diagnosed with a recurrence of the T790M mutation in 2016, and osimertinib was initiated in December 2016. Progression was confirmed in June 2017, and chemotherapy with cisplatin and pemetrexed was performed. Treatment with erlotinib and bevacizumab was then initiated, but progression was confirmed again. Therefore, in September 2017, intravenous infusion of nivolumab was initiated at 240 mg every two weeks. As a result, the primary tumor almost completely disappeared, and lymph node metastasis disappeared. However, on November 6, 2020, progression of the primary tumor, multiple pulmonary metastases, and metastasis to the right adrenal gland were observed.

[0166] While continuing administration of nivolumab, the patient underwent 30Gy / 10fr radiation therapy and four administrations of Extract Z to the right adrenal metastasis between November 17 and November 28, 2020.

[0167] As a result, the measured value of the tumor marker (CEA) decreased from 35.3 to 22.7. Furthermore, as shown in the CT image in Figure 10, after treatment (administration of Extract Z + radiation), the primary tumor had slightly shrunk, and some of the intrapulmonary metastatic lesions had clearly shrunk.

[0168] We believe that the abscopal effect was achieved through the synergistic effect of nivolumab and the combination of Extract Z and radiation. Furthermore, it was demonstrated that excellent therapeutic effects can be achieved even in patients in later lines of treatment who have undergone all standard treatments but have experienced disease progression.

[0169] (Note) As described above, the present disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the present disclosure should be interpreted solely by the claims. It is understood that the patents, patent applications, and other documents cited herein are incorporated by reference into this specification as if the contents themselves were specifically set forth herein. This application claims priority to Japanese Patent Application No. 2019-238657 filed with the Japan Patent Office on December 27, 2019, and Japanese Patent Application No. 2020-171493 filed with the Japan Patent Office on October 9, 2020, the entire contents of which are incorporated by reference into this specification. [Industrial Applicability]

[0170] The present disclosure provides novel mechanism-based methods for the prevention and treatment of diseases such as cancer.

Claims

1. a) immune checkpoint inhibitors and b) a direct dendritic cell activator; a) and b) are administered at different times or simultaneously, wherein the immune checkpoint inhibitor is an antibody, and the dendritic cell direct activator comprises a hot water extract of Mycobacterium tuberculosis. the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. Combination.

2. A composition or medical device for treating, preventing, or preventing the recurrence of cancer in a subject, comprising a direct activator of dendritic cells, the composition or medical device being administered or used in combination with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody and the direct activator of dendritic cells comprises a hot water extract of Mycobacterium tuberculosis, the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. Composition or medical device.

3. A composition for treating, preventing, or preventing recurrence of cancer in a subject, comprising an immune checkpoint inhibitor, wherein the composition is administered in combination with a direct activator of dendritic cells, wherein the immune checkpoint inhibitor is an antibody and the direct activator of dendritic cells comprises a hot water extract of Mycobacterium tuberculosis. the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. composition.

4. The combination, composition or medical device according to any one of claims 1 to 3, wherein said direct dendritic cell activator further comprises a means for delivering radiotherapy.

5. The combination, composition or medical device according to any one of claims 1 to 4, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor and a CTLA-4 inhibitor, and the immune checkpoint inhibitor is an antibody.

6. The combination, composition or medical device according to any one of claims 1 to 5, wherein the cancer expresses an immune checkpoint factor.

7. The combination, composition or medical device according to any one of claims 1 to 6, wherein the cancer expresses PD-L1.

8. The combination, composition or medical device according to any one of claims 1 to 7, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab and atezolizumab.

9. The combination, composition or medical device according to any one of claims 1 to 8, wherein the cancer has an EGFR gene mutation.

10. The combination, composition or medical device according to any one of claims 1 to 9, wherein the treatment, prevention or recurrence prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor.

11. The combination, composition or medical device according to any one of claims 1 to 10, wherein the treatment, prevention or recurrence prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor.

12. The combination, composition, or medical device according to any one of claims 1 to 11, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been determined to be ineffective in treatment with an immune checkpoint inhibitor.

13. The combination, composition or medical device according to any one of claims 1 to 12, wherein the treatment, prevention or recurrence prevention is administered to a subject who has been treated with an immune checkpoint inhibitor and has been efficacious thereafter, but has subsequently developed progressive disease (PD).

14. The combination, composition, or medical device according to any one of claims 1 to 12, wherein the treatment, prevention, or recurrence prevention is administered to a subject who has been effectively treated with a tyrosine kinase inhibitor and a treatment with an immune checkpoint inhibitor, but has subsequently developed progressive disease (PD).

15. The combination, composition or medical device according to any one of claims 1 to 14, wherein the subject exhibits CXCL10 positivity in the cancer.

16. The subject is a CD8 ＋ T cell ｌｏｗ The combination, composition or medical device according to any one of claims 1 to 15, wherein the subject is a

17. a) immune checkpoint inhibitors and b) an immune adjuvant; a) and b) are administered at different times or simultaneously, wherein the immune checkpoint inhibitor is an antibody, and the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis. the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. Combination.

18. A composition for treating, preventing, or preventing recurrence of cancer in a subject, comprising an immune adjuvant, wherein the composition is administered in combination with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an antibody and the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis, the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. composition.

19. A composition for treating, preventing, or preventing recurrence of cancer in a subject, comprising an immune checkpoint inhibitor, wherein the composition is administered in combination with an immune adjuvant, wherein the immune checkpoint inhibitor is an antibody and the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis, the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. composition.

20. 20. The combination or composition of any one of claims 17 to 19, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor, and the immune checkpoint inhibitor is an antibody.

21. A combination, composition or medical device for activating dendritic cells, comprising the combination or composition according to any one of claims 17 to 20 and a means for providing radiotherapy.

22. 22. The combination, composition or medical device of claim 21, wherein said radiation therapy delivery means comprises at least one selected from the group consisting of a radiosensitizer, a radiation delivery device and a radioactive material.

23. 23. The combination, composition or medical device of claim 21 or 22, wherein said radiation therapy delivery means is configured to provide palliative radiation.

24. 24. The combination, composition or medical device according to any one of claims 21 to 23, wherein said radiotherapy delivery means is configured to irradiate in an abscopal manner.

25. 25. The combination, composition or medical device of any one of claims 21 to 24, wherein the radiotherapy delivery means is configured to irradiate measurable lesions other than the lesion of interest.

26. A combination, composition or medical device described in any one of claims 17 to 25, further comprising a regulatory T cell inhibitor.

27. 27. The combination, composition or medical device of claim 26, wherein said regulatory T cell inhibitor comprises a COX-2 inhibitor.

28. 28. The combination, composition or medical device of claim 27, wherein said COX-2 inhibitor is selected from the group consisting of celecoxib, etodolac, meloxicam, nabumetone, zaltoprofen and lornoxicam.

29. A pharmaceutical or device for treating, preventing, or preventing recurrence of cancer in a subject with a specific regimen, comprising: The medicament or device comprises a combination of an immune checkpoint inhibitor and a direct dendritic cell activator, and the regimen comprises: a) administering an immune checkpoint inhibitor, and b) A pharmaceutical or device comprising a step of administering a dendritic cell direct activator, wherein the immune checkpoint inhibitor is an antibody, and the dendritic cell direct activator comprises a hot water extract of Mycobacterium tuberculosis, the cancer is non-small cell lung cancer; The immune checkpoint inhibitor comprises an antibody against at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. Medicines or devices.

30. The medicament or device of claim 29, wherein the subject has not received treatment with an immune checkpoint inhibitor or is a subject for whom treatment with a single immune checkpoint inhibitor is ineffective.

31. In said particular regimen, said immune checkpoint inhibitor is i) nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks or 400 mg every 6 weeks; or iii) atezolizumab, 1200 mg administered every 3 weeks; 31. A medicament or device according to any one of claims 29 or 30.

32. The particular regimen comprises: c) administering radiation therapy The medicament or device according to any one of claims 29 to 31, further comprising:

33. The pharmaceutical or device according to claim 32, wherein the radiotherapy is palliative irradiation for treatment other than brain metastasis, and is administered at 3 Gy in 10 fractions or at 2 Gy in 20 to 25 fractions.

34. The medicament or device according to any one of claims 29 to 33, wherein the dendritic cell direct activator comprises Extract Z, and Extract Z is administered by drawing up the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the solution twice a week.

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