Cancer treatment methods and medicines

Abstract

This invention provides a composition, composition, and medical device for treating, preventing, or preventing recurrence of cancer or tumors. The invention provides a composition, composition, and medical device for treating, preventing, or preventing recurrence of cancer or tumors, and includes an immune checkpoint inhibitor and a dendritic cell direct activator or means. In another embodiment, this invention provides a novel cancer treatment method as immunotherapy, and the medicine used therein, which utilizes the combined administration of an immune checkpoint inhibitor and treatment to enhance sensitivity to the immune checkpoint inhibitor to treat cancer, thereby expecting excellent therapeutic effects.

Description

[Technical Field]

[0001] This invention relates to a method for treating cancer, compositions and components used in cancer treatment, and procedures for cancer treatment, particularly to an immunotherapy-based cancer treatment method, compositions, components, and procedures. Furthermore, this invention relates to a novel technique for activating dendritic cells. [Previous Technology]

[0002] Currently, the commonly practiced cancer treatments include surgical therapy (removing cancerous tissue through surgery), chemotherapy (administering anticancer agents containing molecularly targeted drugs), radiation therapy (irradiating cancerous tissue with radiation), immunotherapy (treating patients with hyperactive immune function), and combinations thereof.

[0003] Among these, immunotherapy is a treatment method that utilizes the innate "immune" ability to enhance the body's immunity in order to eliminate foreign substances that have invaded the body, thereby seeking to treat cancer. Surgical therapy, chemotherapy, and radiation therapy use external factors (surgery, anticancer agents, radiation) to treat cancer. In contrast, immunotherapy mainly utilizes the individual's original immunity (immune cells) to treat cancer. [Summary of the Invention]

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

[0005] For example, the present invention provides the following embodiments as representative embodiments. [Item 1] A composition for treating, preventing, or preventing recurrence of cancer or tumor, characterized in that it comprises: a) an immune checkpoint inhibitor, and b) a dendritic cell direct activator or mechanism; and a) and b) are administered simultaneously or concurrently. [Item 2] A composition or medical device characterized in that it comprises a dendritic cell direct activator or mechanism for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition or medical device is administered or used in combination with an immune checkpoint inhibitor. [Item 3] A composition characterized in that it comprises an immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition is administered in combination with a dendritic cell direct activator or mechanism. [Item 4] A composition, composition, or medical device as described in any of the preceding items, wherein the dendritic cell direct activator or mechanism comprises at least one selected from the group consisting of a radiation therapy providing mechanism and an immune adjuvant. [Item 5] The composition, formulation, 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 (Programmed Death-1), PD-L1 (Programmed Death Ligand-1), and CTLA-4 (Cytotoxic T Lymphocyte-associated Antigen 4). [Item 6] The composition, formulation, 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 PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item 7] The composition, formulation, or medical device described in any of the preceding items, wherein the cancer or tumor expresses immune checkpoint factors. [Item 8] The composition, formulation, or medical device described in any of the preceding items, wherein the cancer expresses PD-L1. [Item 9] The composition, formulation, or medical device described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item 10] The composition, formulation, or medical device described in any of the above items, wherein the cancer is lung cancer. [Item 11] The composition, formulation, or medical device described in any of the above items, wherein the cancer or tumor has an EGFR (Epidermal Growth Factor Receptor) gene mutation.[Item 12] The composition, formulation, or medical device described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item 13] The composition, formulation, or medical device described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item 14] The composition, formulation, or medical device described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who was deemed ineffective in treatment with an immune checkpoint inhibitor. [Item 15] The composition, formulation, or medical device described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently developed progressive disease (PD). [Item 16] A composition, formulation, or medical device as described in any of the preceding items, wherein the subject shows CXCL10 positivity in its tumor. [Item 17] A composition, formulation, or medical device as described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item 18] A formulation for directly activating dendritic cells, comprising an immune adjuvant. [Item 19] A formulation as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item 20] A formulation as 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 the absence of the immune adjuvant. [Item 21] A composition for treating, preventing, or preventing recurrence of cancer or tumors, characterized by comprising: a) an immune checkpoint inhibitor and b) an immune adjuvant; and a) and b) are administered concurrently or simultaneously. [Item 22] A composition characterized in that it comprises an immune adjuvant for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition is administered in combination with an immune checkpoint inhibitor. [Item 23] A composition characterized in that it comprises an immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition is administered in combination with an immune adjuvant. [Item 24] A composition or composition as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item 25] A composition as 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] A composition or component as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item 27] ​​A composition, component, or medical device for activating dendritic cells, comprising a composition as described in any of the preceding items and a radiation therapy providing facility. [Item 28] A composition, component, or medical device as described in any of the preceding items, wherein the radiation therapy providing facility comprises at least one agent selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item 29] A composition, component, or medical device as described in any of the preceding items, characterized in that the radiation therapy providing facility is configured to provide palliative irradiation. [Item 30] A composition, component, or medical device as described in any of the preceding items, characterized in that the radiation therapy providing facility is configured to provide irradiation in a manner having an accompanying abscopal effect. [Item 31] A composition, component, or medical device as described in any of the preceding items, characterized in that: the radiation therapy provider is configured to irradiate lesions that can be measured but are not included in the target lesion range. [Item 32] A composition, component, or medical device as described in any of the preceding items, further comprising a controlled T-cell inhibitor. [Item 33] A composition, component, or medical device as described in any of the preceding items, wherein the controlled T-cell inhibitor comprises a COX-2 (Cyclooxygenase-2) inhibitor. [Item 34] A composition, component, or medical device as described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam. [Item 35] A composition or medical device for activating dendritic cells, comprising a radiation therapy provider. [Item 36] The composition or medical device described in any of the preceding items, wherein the radiation therapy provider comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [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 the absence of the immune adjuvant. [Item 38] The composition or medical device described in any of the preceding items, characterized in that the radiation therapy provider is configured to provide palliative irradiation.[Item 39] The component or medical device described in any of the preceding items is characterized in that: the radiation therapy providing mechanism is configured to irradiate in a manner having an accompanying telescopic effect. [Item 40] The component or medical device described in any of the preceding items is characterized in that: the radiation therapy providing mechanism is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item 41] A program is characterized in that: it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering a first treatment to the patient using an immune checkpoint inhibitor, and / or any one or both of a dendritic cell activator or mechanism; and determining an optimal treatment program based on the patient's response. [Item 42] The program described in any of the preceding items is characterized in that: the patient's response is a specific change in the patient's medical image and the measured values ​​of the patient's tumor markers. [Item 43] A medicine, characterized in that it is used for the prevention or treatment of cancer in a patient, and the medicine comprises a combination of an immune checkpoint inhibitor and a dendritic cell activator or mechanism, and based on information on optimized specific markers of the combination obtained from the patient, specifies the usage and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or mechanism that has a therapeutic or preventive effect, and administers it based on the specified usage and dosage. [Item 44] A medicine or device, characterized in that it is used for the treatment, prevention or recurrence prevention of cancer, cancer or tumor in a subject in a specific manner, and the medicine comprises a combination of an immune checkpoint inhibitor and a dendritic cell activator or mechanism; the manner includes the steps of: a) administering an immune checkpoint inhibitor, and b) administering a dendritic cell activator. [Item 45] A medicine or device as described in any of the preceding items, wherein the subject system has not received treatment with an immune checkpoint inhibitor, or has not responded to treatment with a single dose of an immune checkpoint inhibitor. [Item 46] The medicine or device described in any of the above items, wherein in the above specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item 47] The medicine or device described in any of the above items, wherein the above specific regimen further includes: c) the step of performing radiation therapy. [Item 48] The medicine or device described in any of the above items, characterized in that: the radiation therapy is palliative irradiation other than brain metastasis, and is administered at 3 Gy for 10 sessions or at 2 Gy for 20-25 sessions.[Item 49] A medicine or device as described in any of the above items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week. [Item A1] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering to the subject a) an effective amount of an immune checkpoint inhibitor and b) an effective amount of a dendritic cell direct activator or mechanism simultaneously or concurrently. [Item A2] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering or using an effective amount of a dendritic cell direct activator or mechanism to the subject, wherein the administration of the dendritic cell direct activator or mechanism is combined with an effective amount of an immune checkpoint inhibitor. [Item A3] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering an effective amount of an immune checkpoint inhibitor to the subject, wherein the administration of the immune checkpoint inhibitor is in combination with an effective amount of a dendritic cell direct activator or apparatus. [Item A4] The method described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises at least one selected from the group consisting of a radiation therapy provider and an immune adjuvant. [Item A5] The method described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item A6] The method described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item A7] The method described in any of the above items, wherein the cancer or tumor exhibits immune checkpoint factors. [Item A8] The method described in any of the above items, wherein the cancer exhibits PD-L1. [Item A9] The method described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item A10] The method described in any of the above items, wherein the cancer is lung cancer. [Item A11] The method described in any of the above items, wherein the cancer or tumor has an EGFR gene mutation. [Item A12] The method described in any of the above items, performed on a subject who has received treatment with a tyrosine kinase inhibitor. [Item A13] The method described in any of the above items, performed on a subject who has not received treatment with an immune checkpoint inhibitor.[Item A14] The method described in any of the preceding items is performed on a subject deemed ineffective in treatment with an immune checkpoint inhibitor. [Item A15] The method described in any of the preceding items is performed on a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently develops progressive disease (PD). [Item A16] The method described in any of the preceding items, wherein the subject shows CXCL10 positivity in its tumor. [Item A17] The method described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item A18] A method for directly activating dendritic cells in a subject, comprising the step of administering an effective amount of an immune adjuvant to the subject. [Item A19] The method described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item A20] The method described in any of the above items, wherein the activation is determined by measuring the increased expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to the absence of the immune adjuvant. [Item A21] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering to the subject a) an effective amount of an immune checkpoint inhibitor and b) an effective amount of an immune adjuvant simultaneously or concurrently. [Item A22] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering to the subject an effective amount of an immune adjuvant, wherein the administration of the immune adjuvant is in combination with an effective amount of an immune checkpoint inhibitor. [Item A23] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering an immune checkpoint inhibitor to the subject, wherein the immune checkpoint inhibitor is administered in combination with an immune adjuvant. [Item A24] The method as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item A25] The method as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item A26] The method as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item A27] A method for activating dendritic cells, which further utilizes a radiation therapy facility. [Item A28] The method described in any of the above items, wherein the radiation therapy provider comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices and radioactive substances.[Item A29] The method described in any of the above items, wherein the radiation therapy provider is configured to provide palliative irradiation. [Item A30] The method described in any of the above items, wherein the radiation therapy provider is configured to irradiate in a manner with accompanying distance effects. [Item A31] The method described in any of the above items, wherein the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item A32] The method described in any of the above items, wherein a controlled T-cell inhibitor is further administered. [Item A33] The method described in any of the above items, wherein the controlled T-cell inhibitor comprises a COX-2 inhibitor. [Item A34] The method described in any of the above items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam. [Item A35] A method for activating dendritic cells, comprising the step of applying a radiation therapy providing device to a subject. [Item A36] The method as described in any of the preceding items, wherein the radiation therapy providing device comprises at least one selected from the group consisting of a radiation sensitizer, a radiation irradiation device, and a radioactive substance. [Item A37] The method as 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 the absence of the adjuvant. [Item A38] The method as described in any of the preceding items, wherein the radiation therapy providing device is configured to provide palliative irradiation. [Item A39] The method as described in any of the preceding items, wherein the radiation therapy providing device is configured to irradiate in a manner with accompanying distance effects. [Item A40] The method as described in any of the preceding items, wherein the radiation therapy providing device is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item A41] A method for treating or preventing cancer in a patient, comprising: causing a computer to perform the following steps: administering to the patient a first treatment using an effective amount of an immune checkpoint inhibitor, and / or an effective amount of either or both of a dendritic cell activator or a mechanism; and determining an optimal treatment program based on the patient's response. [Item A42] The method described in any of the preceding items is characterized in that: the patient's response is a specific change in the patient's medical images and the measured values ​​of the patient's tumor markers.[Item A43] A method for preventing or treating cancer in a patient, comprising the steps of: administering an effective amount of a combination of an immune checkpoint inhibitor and an effective amount of a dendritic cell activator or mechanism; and, based on information obtained from the patient regarding the optimized specific marker of the combination, specifying the usage and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or mechanism that has therapeutic or preventive effects, and administering it based on the specified usage and dosage. [Item A44] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject according to a specific regimen, comprising the steps of: administering an effective amount of a combination of an immune checkpoint inhibitor and an effective amount of a dendritic cell activator or mechanism; and the regimen comprising the steps of: a) administering an effective amount of an immune checkpoint inhibitor, and b) administering an effective amount of a dendritic cell activator. [Item A45] The method described in any of the above items, wherein the tested system has not received treatment with an immune checkpoint inhibitor, or has failed treatment with a single dose of an immune checkpoint inhibitor. [Item A46] The method described in any of the above items, wherein in the above specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item A47] The method described in any of the above items, wherein the above specific regimen further includes: c) the step of performing radiation therapy. [Item A48] The method described in any of the above items, wherein the radiation therapy is palliative irradiation other than brain metastasis, administered at 3 Gy for 10 fractions or at 2 Gy for 20–25 fractions. [Item A49] The method described in any of the above items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week. [Item B1] Use of a) an immune checkpoint inhibitor and b) a dendritic cell direct activator or mechanism in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors. [Item B2] Use of a dendritic cell direct activator or mechanism in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, and in combination with an immune checkpoint inhibitor. [Item B3] Use of an immune checkpoint inhibitor in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, and in combination with a dendritic cell direct activator or mechanism.[Item B4] As described in any of the above items, the dendritic cell direct activator or apparatus comprises at least one selected from the group consisting of radiation therapy providers and immune adjuvants. [Item B5] As described in any of the above items, the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item B6] As described in any of the above items, the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item B7] As described in any of the above items, the cancer or tumor expresses immune checkpoint factors. [Item B8] As described in any of the above items, the cancer expresses PD-L1. [Item B9] As described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item B10] As described in any of the above items, wherein the cancer is lung cancer. [Item B11] As described in any of the above items, wherein the cancer or tumor has an EGFR gene mutation. [Item B12] As described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item B13] As described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item B14] As described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has been deemed ineffective in treatment with an immune checkpoint inhibitor. [Item B15] The use as described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently develops progressive disease (PD). [Item B16] The use as described in any of the preceding items, wherein the subject shows CXCL10 positivity in their tumor. [Item B17] The use as described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item B18] Use of an immune adjuvant in the manufacture of a pharmaceutical for the direct activation of dendritic cells. [Item B19] The use as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof.[Item B20] The use as described in any of the preceding items, wherein the activation is determined by measuring the increased expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to the absence of the adjuvant. [Item B21] The use of a) an immune checkpoint inhibitor and b) an immune adjuvant in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors. [Item B22] The use of an immune adjuvant in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors, and in combination with an immune checkpoint inhibitor. [Item B23] The use of an immune checkpoint inhibitor in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors, and in combination with an immune adjuvant. [Item B24] The use as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item B25] As described in any of the preceding items, the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item B26] As described in any of the preceding items, the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item B27] As described in any of the preceding items, characterized in that: a radiation therapy provision institution is provided for the subject. [Item B28] As described in any of the preceding items, the radiation therapy provision institution comprises at least one agent selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive materials. [Item B29] As described in any of the preceding items, characterized in that: the radiation therapy provision institution is configured to provide palliative irradiation. [Item B30] The use described in any of the preceding items is characterized in that: the radiation therapy provider is configured to irradiate in a manner that has an accompanying telescopic effect. [Item B31] The use described in any of the preceding items is characterized in that: the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item B32] The use described in any of the preceding items is characterized in that: a controlled T-cell inhibitor is further administered to the subject. [Item B33] The use described in any of the preceding items, wherein the controlled T-cell inhibitor comprises a COX-2 inhibitor. [Item B34] The use described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam.[Item B35] Use of a radiation therapy provider in the manufacture of medicine for activating dendritic cells. [Item B36] The use as described in any of the preceding items, wherein the radiation therapy provider comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item B37] The use as 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 the absence of the adjuvant. [Item B38] The use as described in any of the preceding items, characterized in that the radiation therapy provider is configured to provide palliative irradiation. [Item B39] The use as described in any of the preceding items, characterized in that the radiation therapy provider is configured to perform irradiation in a manner with accompanying distance effects. [Item B40] The use as described in any of the preceding items, characterized in that the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item B41] A program characterized in that it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering a first treatment to the patient using an immune checkpoint inhibitor and / or any one or both of a dendritic cell activator or mechanism; and determining an optimal treatment program based on the patient's response. [Item B42] The program described in any of the preceding items is characterized in that the patient's response is a specific change in the patient's medical image and the measured values ​​of the patient's tumor markers. [Item B43] Use of a combination of an immune checkpoint inhibitor and a dendritic cell activator or mechanism in the manufacture of a medicine, characterized in that it is used to prevent or treat cancer in a patient, and the medicine is based on information obtained from the patient regarding the optimized specific markers of the combination, determining the usage and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or mechanism having a therapeutic or preventive effect, and administering it based on the determined usage and dosage. [Item B44] Use of an immune checkpoint inhibitor and dendritic cell activator in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject in a specific regimen. [Item B45] The use described in any of the preceding items, wherein the subject system has not received treatment with an immune checkpoint inhibitor, or has failed treatment with a single dose of an immune checkpoint inhibitor.[Item B46] As described in any of the preceding items, wherein in the specific regimen described above, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item B47] As described in any of the preceding items, wherein the specific regimen described above further includes: c) the step of performing radiation therapy. [Item B48] As described in any of the preceding items, characterized in that: the radiation therapy is palliative irradiation other than brain metastasis, and is administered at 3 Gy for 10 sessions or at 2 Gy for 20-25 sessions. [Item B49] As described in any of the preceding items, wherein the dendritic cell activator or apparatus comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week. [Item C1] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors, characterized in that it is used in combination with a dendritic cell direct activator or apparatus. [Item C2] A dendritic cell direct activator or apparatus for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item C3] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that it is administered in combination with a dendritic cell direct activator or apparatus. [Item C4] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises at least one selected from the group consisting of radiation therapy providers and immune adjuvants. [Item C5] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item C6] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item C7] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the cancer or tumor expresses immune checkpoint factors. [Item C8] An immune checkpoint inhibitor, or dendritic cell direct activator or mechanism described in any of the above items, wherein the cancer manifests PD-L1.[Item C9] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as 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 C10] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the cancer is lung cancer. [Item C11] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the cancer or tumor has an EGFR gene mutation. [Item C12] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has received treatment using a tyrosine kinase inhibitor. [Item C13] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item C14] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who was deemed ineffective in treatment with an immune checkpoint inhibitor. [Item C15] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently developed progressive disease (PD). [Item C16] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the preceding items, wherein the subject shows CXCL10 positivity in their tumor. [Item C17] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item C18] An immune adjuvant for directly activating dendritic cells. [Item C19] An immune adjuvant as described in any of the preceding items, comprising a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item C20] An immune adjuvant as described in 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 the absence of the immune adjuvant. [Item C21] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors, characterized in that it is administered in combination with an immune adjuvant.[Item C22] An immune adjuvant for treating, preventing, or preventing 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 recurrence of cancer or tumor in a subject, characterized in that it is administered in combination with an immune adjuvant. [Item C24] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item C25] An immune adjuvant or immune checkpoint inhibitor as 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 C26] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item C27] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that: it is then administered to a radiation therapy provider. [Item C28] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the radiation therapy provider comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item C29] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that: the radiation therapy provider is configured to provide palliative irradiation. [Item C30] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that: the radiation therapy provider is configured to irradiate in a manner with accompanying distance effects. [Item C31] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that: the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item C32] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, further comprising a control T-cell inhibitor. [Item C33] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the control T-cell inhibitor comprises a COX-2 inhibitor. [Item C34] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam. [Item C35] A radiation therapy provider for activating dendritic cells.[Item C36] A radiation therapy provider as described in any of the preceding items comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item C37] A radiation therapy provider as 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 the absence of the adjuvant. [Item C38] A radiation therapy provider as described in any of the preceding items, characterized in that it is configured to provide palliative irradiation. [Item C39] A radiation therapy provider as described in any of the preceding items, characterized in that it is configured to perform irradiation in a manner with accompanying distance effects. [Item C40] A radiation therapy provider as described in any of the preceding items, characterized in that it is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item C41] A program characterized in that it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering a first treatment to the patient using an immune checkpoint inhibitor and / or any one or both of a dendritic cell activator or apparatus; and determining an optimal treatment program based on the patient's response. [Item C42] The program described in any of the preceding items is characterized in that the patient's response is a specific change in the patient's medical image and the measured values ​​of the patient's tumor markers. [Item C43] An immune checkpoint inhibitor characterized in that it is used to prevent or treat cancer in a patient, and is administered in combination with a dendritic cell activator or apparatus; and based on information obtained from the patient regarding the optimized specific markers of the combination, determining the usage and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or apparatus that has a therapeutic or preventive effect, and administering it based on the determined usage and dosage. [Item C43A] A dendritic cell activator or apparatus, characterized in that: it is used for the prevention or treatment of cancer in a patient, and is administered in combination with an immune checkpoint inhibitor; and based on information on the optimized specific markers of the combination obtained from the patient, the combination of the immune checkpoint inhibitor and the dendritic cell activator or apparatus having therapeutic or preventive effects is specified in terms of usage and dosage, and is administered based on the specified usage and dosage. [Item C44] An immune checkpoint inhibitor used for the treatment, prevention, or recurrence prevention of cancer, cancer, or tumor in a subject according to a specific regimen, the regimen comprising the step of administering the immune checkpoint inhibitor in combination with a dendritic cell activator. [Item C44A] A dendritic cell activator used for the treatment, prevention, or recurrence prevention of cancer, cancer, or tumor in a subject according to a specific regimen, the regimen comprising the step of administering the dendritic cell activator in combination with an immune checkpoint inhibitor.[Item C45] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein the tested system has not received treatment with an immune checkpoint inhibitor, or has failed treatment with a single dose of an immune checkpoint inhibitor. [Item C46] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein in the above specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item C47] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein the above specific regimen further includes: c) a step of performing radiation therapy. [Item C48] An immune checkpoint inhibitor or dendritic cell activator as described in any of the preceding items, characterized in that: the radiation therapy is palliative irradiation other than brain metastasis, and is administered at 3 Gy for 10 sessions or at 2 Gy for 20-25 sessions. [Item C49] An immune checkpoint inhibitor or dendritic cell activator as described in any of the preceding items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week.

[0006] Furthermore, the present invention provides the following items. [Item X1] A composition for treating, preventing, or preventing recurrence of cancer or tumor, characterized in that it comprises: a) an immune checkpoint inhibitor, and b) a dendritic cell direct activator or mechanism; and a) and b) are administered simultaneously or concurrently. [Item X2] A composition or medical device characterized in that it comprises a dendritic cell direct activator or mechanism for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition or medical device is administered or used in combination with an immune checkpoint inhibitor. [Item X3] A composition characterized in that it comprises an immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition is administered in combination with a dendritic cell direct activator or mechanism. [Item X4] A composition, composition, or medical device as described in any of the preceding items, wherein the dendritic cell direct activator or mechanism comprises at least one selected from the group consisting of a radiation therapy provider and an immune adjuvant. [Item X5] A composition, component, or medical device as described in any of the above items, wherein the dendritic cell direct activator or mechanism comprises a radiation therapy delivery mechanism and an immune adjuvant. [Item X6] A composition, component, or medical device as described in any of the above items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item X7] A composition, component, or medical device as described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item X8] A composition, component, or medical device as described in any of the above items, wherein the cancer or tumor expresses immune checkpoint factors. [Item X9] A composition, component, or medical device as described in any of the above items, wherein the cancer expresses PD-L1. [Item X10] The composition, formulation, or medical device described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item X11] The composition, formulation, or medical device described in any of the above items, wherein the cancer is lung cancer. [Item X12] The composition, formulation, or medical device described in any of the above items, wherein the cancer or tumor has an EGFR gene mutation. [Item X13] The composition, formulation, or medical device described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject after treatment with a tyrosine kinase inhibitor.[Item X14] The composition, formulation, or medical device described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item X15] The composition, formulation, or medical device described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who was deemed ineffective in treatment with an immune checkpoint inhibitor. [Item X16] The composition, formulation, or medical device described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently developed progressive disease (PD). [Item X17] The composition, formulation, or medical device described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with both a tyrosine kinase inhibitor and an immune checkpoint inhibitor, subsequently developed progressive disease (PD). [Item X18] A composition, formulation, or medical device as described in any of the preceding items, wherein the subject shows CXCL10 positivity in its tumor. [Item X19] A composition, formulation, or medical device as described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item X20] A formulation for directly activating dendritic cells, comprising an immune adjuvant. [Item X21] A formulation as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item X22] A formulation as described in 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 the absence of the immune adjuvant. [Item X23] A composition for treating, preventing, or preventing recurrence of cancer or tumor, characterized in that it comprises: a) an immune checkpoint inhibitor and b) an immune adjuvant; and a) and b) are administered concurrently or alternately. [Item X24] A composition characterized in that it comprises an immune adjuvant for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition is administered in combination with an immune checkpoint inhibitor. [Item X25] A composition characterized in that it comprises an immune checkpoint inhibitor for treating, preventing, or preventing recurrence of cancer or tumor in a subject, and the composition is administered in combination with an immune adjuvant. [Item X26] A composition or composition as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof.[Item X27] A composition as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item X28] A composition or composition as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item X29] A composition, composition, or medical device for activating dendritic cells, comprising a composition as described in any of the preceding items and a radiation therapy providing facility. [Item X30] A composition, composition, or medical device as described in any of the preceding items, wherein the radiation therapy providing facility comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item X31] A composition, composition, or medical device as described in any of the preceding items, characterized in that the radiation therapy providing facility is configured to provide palliative irradiation. [Item X32] The composition, formulation, or medical device described in any of the preceding items is characterized in that: the radiation therapy provider is configured to irradiate in a manner having an accompanying telescopic effect. [Item X33] The composition, formulation, or medical device described in any of the preceding items is characterized in that: the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item X34] The composition, formulation, or medical device described in any of the preceding items further comprises a controlled T-cell inhibitor. [Item X35] The composition, formulation, or medical device described in any of the preceding items, wherein the controlled T-cell inhibitor comprises a COX-2 inhibitor. [Item X36] The composition, formulation, or medical device described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam. [Item X37] A composition or medical device for activating dendritic cells, comprising a radiation therapy providing mechanism. [Item X38] The composition or medical device described in any of the preceding items, wherein the radiation therapy providing mechanism comprises at least one selected from the group consisting of a radiation sensitizer, 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 the absence of the adjuvant. [Item X40] The composition or medical device described in any of the preceding items, characterized in that the radiation therapy providing mechanism is configured to provide palliative irradiation.[Item X41] The component or medical device described in any of the preceding items is characterized in that: the radiation therapy providing mechanism is configured to irradiate in a manner having an accompanying telescopic effect. [Item X42] The component or medical device described in any of the preceding items is characterized in that: the radiation therapy providing mechanism is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item X43] A program is characterized in that: it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering a first treatment to the patient using an immune checkpoint inhibitor, and / or any one or both of a dendritic cell activator or mechanism; and determining an optimal treatment program based on the patient's response. [Item X44] The program described in any of the preceding items is characterized in that: the patient's response is a specific change in the patient's medical image and the measured values ​​of the patient's tumor markers. [Item X45] A medicine, characterized in that it is used for the prevention or treatment of cancer in a patient, and the medicine comprises a combination of an immune checkpoint inhibitor and a dendritic cell activator or mechanism, and based on information on optimized specific markers of the combination obtained from the patient, specifies the usage and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or mechanism that has a therapeutic or preventive effect, and administers it based on the specified usage and dosage. [Item X46] A medicine or device, characterized in that it is used for the treatment, prevention, or recurrence prevention of cancer, cancer, or tumor in a subject according to a specific regimen, and the medicine comprises a combination of an immune checkpoint inhibitor and a dendritic cell activator or mechanism; the regimen includes the steps of: a) administering an immune checkpoint inhibitor, and b) administering a dendritic cell activator. [Item X47] A medicine or device as described in any of the preceding items, wherein the subject system has not received treatment with an immune checkpoint inhibitor, or has not responded to treatment with a single dose of an immune checkpoint inhibitor. [Item X48] The medicine or device described in any of the above items, wherein in the above-described specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item X49] The medicine or device described in any of the above items, wherein the above-described specific regimen further includes: c) the step of performing radiation therapy. [Item X50] The medicine or device described in any of the above items, characterized in that: the radiation therapy is palliative irradiation other than brain metastasis, and is administered at 3 Gy for 10 sessions or at 2 Gy for 20-25 sessions.[Item X51] A medicine or device as described in any of the above items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week. [Item XA1] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering to the subject simultaneously or concurrently a) an effective amount of an immune checkpoint inhibitor and b) an effective amount of a dendritic cell direct activator or mechanism. [Item XA2] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering or using an effective amount of a dendritic cell direct activator or mechanism to the subject, wherein the administration of the dendritic cell direct activator or mechanism is combined with an effective amount of an immune checkpoint inhibitor. [Item XA3] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering an effective amount of an immune checkpoint inhibitor to the subject, wherein the administration of the immune checkpoint inhibitor is in combination with an effective amount of a dendritic cell direct activator or apparatus. [Item XA4] The method described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises at least one selected from the group consisting of a radiation therapy provider and an immune adjuvant. [Item XA5] The method described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises a radiation therapy provider and an immune adjuvant. [Item XA6] The method described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XA7] The method described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item XA8] The method described in any of the above items, wherein the cancer or tumor exhibits immune checkpoint factors. [Item XA9] The method described in any of the above items, wherein the cancer exhibits PD-L1. [Item XA10] The method described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item XA11] The method described in any of the above items, wherein the cancer is lung cancer. [Item XA12] The method described in any of the above items, wherein the cancer or tumor has an EGFR gene mutation. [Item XA13] The method described in any of the above items, performed on a subject after treatment with a tyrosine kinase inhibitor.[Item XA14] The method described in any of the above items is performed on a subject who has not received treatment with an immune checkpoint inhibitor. [Item XA15] The method described in any of the above items is performed on a subject who was deemed ineffective in treatment with an immune checkpoint inhibitor. [Item XA16] The method described in any of the above items is performed on a subject who responded to treatment with an immune checkpoint inhibitor but subsequently developed progressive disease (PD). [Item XA17] The method described in any of the above items is performed on a subject who responded to treatment with both a tyrosine kinase inhibitor and an immune checkpoint inhibitor but subsequently developed progressive disease (PD). [Item XA18] The method described in any of the above items, wherein the subject shows CXCL10 positivity in their tumor. [Item XA19] A method as described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item XA20] A method for directly activating dendritic cells in a subject, comprising the step of administering an effective amount of an immune adjuvant to the subject. [Item XA21] A method as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XA22] A method as 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 the absence of the immune adjuvant. [Item XA23] A method for treating, preventing, or preventing recurrence of cancer or tumors in a subject, comprising the steps of administering a) an effective amount of an immune checkpoint inhibitor and b) an effective amount of an immune adjuvant to the subject simultaneously or concurrently. [Item XA24] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering an effective amount of an immune adjuvant to the subject, wherein the administration of the immune adjuvant is in combination with an effective amount of an immune checkpoint inhibitor. [Item XA25] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject, comprising the steps of administering an immune checkpoint inhibitor to the subject, wherein the immune checkpoint inhibitor is in combination with an immune adjuvant. [Item XA26] The method described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XA27] The method described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4.[Item XA28] A method as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item XA29] A method for activating dendritic cells, which further utilizes a radiation therapy providing facility. [Item XA30] A method as described in any of the preceding items, wherein the radiation therapy providing facility comprises at least one agent selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive materials. [Item XA31] A method as described in any of the preceding items, wherein the radiation therapy providing facility is configured to provide palliative irradiation. [Item XA32] A method as described in any of the preceding items, wherein the radiation therapy providing facility is configured to irradiate in a manner having an accompanying distance effect. [Item XA33] A method as described in any of the preceding items, wherein the radiation therapy providing facility is configured to irradiate measurable lesions not included in the target lesion range. [Item XA34] The method described in any of the preceding items further administers a controlled T-cell inhibitor. [Item XA35] The method described in any of the preceding items, wherein the controlled T-cell inhibitor comprises a COX-2 inhibitor. [Item XA36] The method described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam. [Item XA37] A method for activating dendritic cells, comprising the step of applying a radiation therapy providing apparatus to a subject. [Item XA38] The method described in any of the preceding items, wherein the radiation therapy providing apparatus comprises at least one selected from the group consisting of a radiation sensitizer, a radiation irradiation device, and a radioactive substance. [Item XA39] The method described in any of the above items, wherein the activation is determined by measuring the increased expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to the absence of the adjuvant. [Item XA40] The method described in any of the above items, wherein the radiation therapy provider is configured to provide palliative irradiation. [Item XA41] The method described in any of the above items, wherein the radiation therapy provider is configured to perform irradiation in a manner that has accompanying distance effects. [Item XA42] The method described in any of the above items, wherein the radiation therapy provider is configured to irradiate measurable lesions not included in the target lesion range.[Item XA43] A method for treating or preventing cancer in a patient, comprising: having a computer perform the following steps: administering to the patient a first treatment using an effective amount of an immune checkpoint inhibitor and / or an effective amount of either or both of a dendritic cell activator or apparatus; and determining an optimal treatment program based on the patient's response. [Item XA44] The method described in any of the preceding items, characterized in that: the patient's response is a specific change in the patient's medical image and the measured values ​​of the patient's tumor markers. [Item XA45] A method for preventing or treating cancer in a patient, comprising the following steps: administering an effective amount of a combination of an immune checkpoint inhibitor and an effective amount of a dendritic cell activator or apparatus; and determining the usage and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or apparatus having a therapeutic or preventive effect based on information obtained from the patient regarding the optimized specific markers obtained from the patient, and administering the treatment based on the determined usage and dosage. [Item XA46] A method for treating, preventing, or preventing recurrence of cancer or tumor in a subject using a specific regimen, comprising the steps of: administering an effective amount of an immune checkpoint inhibitor and an effective amount of a dendritic cell activator or mechanism; and the regimen comprising the steps of: a) administering an effective amount of an immune checkpoint inhibitor, and b) administering an effective amount of a dendritic cell activator. [Item XA47] A method as described in any of the preceding items, wherein the subject system has not received treatment with an immune checkpoint inhibitor, or has failed treatment with a single dose of an immune checkpoint inhibitor. [Item XA48] A method as described in any of the preceding items, wherein in the specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item XA49] The method described in any of the preceding items, wherein the specific procedure further includes: c) the step of performing radiation therapy. [Item XA50] The method described in any of the preceding items, wherein the radiation therapy is palliative irradiation other than brain metastasis, and is administered at 3 Gy for 10 sessions or at 2 Gy for 20-25 sessions. [Item XA51] The method described in any of the preceding items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week. [Item XB1] The use of a) an immune checkpoint inhibitor and b) a dendritic cell direct activator or mechanism in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors.[Item XB2] Use of a dendritic cell direct activator or apparatus in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, and in combination with an immune checkpoint inhibitor. [Item XB3] Use of an immune checkpoint inhibitor in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, and in combination with a dendritic cell direct activator or apparatus. [Item XB4] The use as described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises at least one selected from the group consisting of a radiation therapy provider and an immune adjuvant. [Item XB5] The use as described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises a radiation therapy provider and an immune adjuvant. [Item XB6] The use as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XB7] As described in any of the above items, the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item XB8] As described in any of the above items, the cancer or tumor exhibits immune checkpoint factors. [Item XB9] As described in any of the above items, the cancer exhibits PD-L1. [Item XB10] As described in any of the above items, the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item XB11] As described in any of the above items, the cancer is lung cancer. [Item XB12] As described in any of the above items, the cancer or tumor has an EGFR gene mutation. [Item XB13] As described in any of the above items, the treatment, prevention, or relapse prevention is administered to a subject who has received treatment with a tyrosine kinase inhibitor. [Item XB14] As described in any of the above items, the treatment, prevention, or relapse prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item XB15] As described in any of the above items, the treatment, prevention, or relapse prevention is administered to a subject who was deemed ineffective in treatment with an immune checkpoint inhibitor. [Item XB16] As described in any of the above items, the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently developed progressive disease (PD).[Item XB17] The use as described in any of the above items, wherein the treatment, prevention, or relapse prevention is performed on a subject who, although responding to treatment with a tyrosine kinase inhibitor and an immune checkpoint inhibitor, subsequently develops progressive disease (PD). [Item XB18] The use as described in any of the above items, wherein the subject shows CXCL10 positivity in their tumor. [Item XB19] The use as described in any of the above items, wherein the subject is a subject with low CD8+ T cell count. [Item XB20] Use of an immune adjuvant in the manufacture of a pharmaceutical for the direct activation of dendritic cells. [Item XB21] The use as described in any of the above items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XB22] The use as described in any of the preceding items, wherein the activation is determined by measuring the increased expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to the absence of the immune adjuvant. [Item XB23] The use of a) an immune checkpoint inhibitor and b) an immune adjuvant in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors. [Item XB24] The use of an immune adjuvant in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors, and in combination with an immune checkpoint inhibitor. [Item XB25] The use of an immune checkpoint inhibitor in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors, and in combination with an immune adjuvant. [Item XB26] The use as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XB27] As described in any of the preceding items, the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XB28] As described in any of the preceding items, the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item XB29] As described in any of the preceding items, characterized in that: a radiation therapy provision institution is provided for the subject. [Item XB30] As described in any of the preceding items, the radiation therapy provision institution comprises at least one agent selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive materials. [Item XB31] As described in any of the preceding items, characterized in that: the radiation therapy provision institution is configured to provide palliative irradiation.[Item XB32] The use as described in any of the preceding items, characterized in that: the radiation therapy provider is configured to irradiate in a manner having an accompanying telescopic effect. [Item XB33] The use as described in any of the preceding items, characterized in that: the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item XB34] The use as described in any of the preceding items, characterized in that: a controlled T-cell inhibitor is further administered to the subject. [Item XB35] The use as described in any of the preceding items, wherein the controlled T-cell inhibitor comprises a COX-2 inhibitor. [Item XB36] The use as described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopiprofen, and lornoxicam. [Item XB37] The use of a radiation therapy provider in the manufacture of a pharmaceutical, for activating dendritic cells. [Item XB38] As described in any of the preceding items, the radiation therapy provider comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item XB39] As described in any of the preceding items, 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 the absence of the adjuvant. [Item XB40] As described in any of the preceding items, the radiation therapy provider is configured to provide palliative irradiation. [Item XB41] As described in any of the preceding items, the radiation therapy provider is configured to perform irradiation in a manner with accompanying distance effects. [Item XB42] As described in any of the preceding items, the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item XB43] A program characterized in that it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering a first treatment to the patient using an immune checkpoint inhibitor, and / or any one or both of a dendritic cell activator or mechanism; and determining an optimal treatment program based on the patient's response. [Item XB44] The program described in any of the preceding items is characterized in that the patient's response is a specific change in the patient's medical images and the measured values ​​of the patient's tumor markers.[Item XB45] Use of a combination of an immune checkpoint inhibitor and a dendritic cell activator or mechanism in the manufacture of a medicine, characterized in that: it is used to prevent or treat cancer in a patient, and the medicine is administered based on information obtained from the patient regarding the optimized specific markers of the combination, specifying the method of use and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell activator or mechanism having therapeutic or preventive effects, and is administered based on the specified method of use and dosage. [Item XB46] Use of an immune checkpoint inhibitor and a dendritic cell activator in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject according to a specific regimen. [Item XB47] The use described in any of the preceding items, wherein the subject system has not received treatment with an immune checkpoint inhibitor, or has failed treatment with a single dose of an immune checkpoint inhibitor. [Item XB48] As described in any of the above items, wherein in the above-described specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item XB49] As described in any of the above items, wherein the above-described specific regimen further includes: c) the step of performing radiation therapy. [Item XB50] As described in any of the above items, characterized in that: the radiation therapy is palliative irradiation other than brain metastasis, and is administered at 3 Gy for 10 sessions or at 2 Gy for 20-25 sessions. [Item XB51] As described in any of the above items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week. [Item XC1] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors, characterized in that it is used in combination with a dendritic cell direct activator or mechanism. [Item XC2] A dendritic cell direct activator or mechanism for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item XC3] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that it is administered in combination with a dendritic cell direct activator or mechanism. [Item XC4] An immune checkpoint inhibitor, or dendritic cell direct activator or apparatus as described in any of the above items, wherein the dendritic cell direct activator or apparatus comprises at least one selected from the group consisting of radiation therapy providers and immune adjuvants.[Item XC5] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the dendritic cell direct activator or apparatus comprises a radiation therapy provider and an immune adjuvant. [Item XC6] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XC7] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item XC8] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the cancer or tumor expresses immune checkpoint factors. [Item XC9] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the above items, wherein the cancer exhibits PD-L1. [Item XC10] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the above items, wherein the immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab. [Item XC11] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the above items, wherein the cancer is lung cancer. [Item XC12] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the above items, wherein the cancer or tumor has an EGFR gene mutation. [Item XC13] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has received treatment using a tyrosine kinase inhibitor. [Item XC14] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who has not received treatment with an immune checkpoint inhibitor. [Item XC15] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who was deemed ineffective in treatment with an immune checkpoint inhibitor. [Item XC16] An immune checkpoint inhibitor, dendritic cell direct activator, or apparatus described in any of the above items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently developed progressive disease (PD).[Item XC17] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the treatment, prevention, or relapse prevention is administered to a subject who, although responding to treatment with a tyrosine kinase inhibitor and an immune checkpoint inhibitor, subsequently develops progressive disease (PD). [Item XC18] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the subject shows CXCL10 positivity in their tumor. [Item XC19] An immune checkpoint inhibitor, or dendritic cell direct activator, or apparatus as described in any of the preceding items, wherein the subject is a subject with low CD8+ T cell count. [Item XC20] An immune adjuvant for direct activation of dendritic cells. [Item XC21] An immune adjuvant as described in any of the preceding items, comprising a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XC22] An immune adjuvant as described in any of the preceding items, wherein the activation is determined by measuring the increased expression of CD80 / 86 on the surface of dendritic cells in the presence of the immune adjuvant compared to the absence of the immune adjuvant. [Item XC23] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors, characterized in that it is administered in combination with an immune adjuvant. [Item XC24] An immune adjuvant for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that it is administered in combination with an immune checkpoint inhibitor. [Item XC25] An immune checkpoint inhibitor for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that it is administered in combination with an immune adjuvant. [Item XC26] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the immune adjuvant comprises a hot water extract of Mycobacterium tuberculosis or a portion thereof. [Item XC27] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4. [Item XC28] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. [Item XC29] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that it is subsequently administered to a radiation therapy provider.[Item XC30] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the radiation therapy provider comprises at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item XC31] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that the radiation therapy provider is configured to provide palliative irradiation. [Item XC32] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that the radiation therapy provider is configured to irradiate in a manner having an accompanying distance effect. [Item XC33] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, characterized in that the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item XC34] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, further comprising a controlled T-cell inhibitor. [Item XC35] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the controlled T-cell inhibitor comprises a COX-2 inhibitor. [Item XC36] An immune adjuvant or immune checkpoint inhibitor as described in any of the preceding items, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib, etodoxacin, meloxicam, nabumetone, zaltopibuprofen, and lornoxicam. [Item XC37] A radiation therapy providing apparatus for activating dendritic cells. [Item XC38] A radiation therapy providing apparatus as described in any of the preceding items, comprising at least one selected from the group consisting of radiation sensitizers, radiation irradiation devices, and radioactive substances. [Item XC39] A radiation therapy providing apparatus as 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 the absence of the immune adjuvant. [Item XC40] A radiation therapy provider as described in any of the preceding items, characterized in that it is configured to provide palliative irradiation. [Item XC41] A radiation therapy provider as described in any of the preceding items, characterized in that it is configured to irradiate in a manner with accompanying telescopic effects. [Item XC42] A radiation therapy provider as described in any of the preceding items, characterized in that it is configured to irradiate lesions that can be measured but are not within the scope of the target lesion. [Item XC43] A program, characterized in that it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering a first treatment to the patient using an immune checkpoint inhibitor, and / or any one or both of a dendritic cell activator or mechanism; and determining the optimal treatment program based on the patient's response.[Item XC44] The procedure described in any of the above items is characterized in that: the patient's response is a specific change in the patient's medical image and the measured values ​​of the patient's tumor markers. [Item XC45] An immune checkpoint inhibitor, characterized in that: it is used to prevent or treat cancer in a patient, and is administered in combination with a dendritic cell activator or mechanism; and based on information on the optimized specific markers of the combination obtained from the patient, the combination of the immune checkpoint and the dendritic cell activator or mechanism that has a therapeutic or preventive effect is specified in the dosage and administration based on the specified dosage and administration. [Item XC45A] A dendritic cell activator or apparatus, characterized in that: it is used for the prevention or treatment of cancer in a patient, and is administered in combination with an immune checkpoint inhibitor; and based on information on the optimized specific markers of the combination obtained from the patient, the combination of the immune checkpoint inhibitor and the dendritic cell activator or apparatus having therapeutic or preventive effects is specified in terms of usage and dosage, and is administered based on the specified usage and dosage. [Item XC46] An immune checkpoint inhibitor used for the treatment, prevention, or recurrence prevention of cancer, cancer, or tumor in a subject according to a specific regimen, the regimen comprising the step of administering the immune checkpoint inhibitor in combination with a dendritic cell activator. [Item XC46A] A dendritic cell activator used for the treatment, prevention, or recurrence prevention of cancer, cancer, or tumor in a subject according to a specific regimen, the regimen comprising the step of administering the dendritic cell activator in combination with an immune checkpoint inhibitor. [Item XC47] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein the tested system has not received treatment with an immune checkpoint inhibitor or has failed treatment with a single dose of an immune checkpoint inhibitor. [Item XC48] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein in the above specific regimen, the immune checkpoint inhibitor i) is nivolumab, administered at 240 mg every 2 weeks; ii) is pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) is atezolizumab, administered at 1200 mg every 3 weeks. [Item XC49] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein the above specific regimen further includes: c) a step of performing radiation therapy. [Item XC50] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, characterized in that: the above radiation therapy is palliative irradiation other than brain metastasis, and is irradiated 10 times with 3 Gy or 20 to 25 times with 2 Gy.[Item XC51] An immune checkpoint inhibitor or dendritic cell activator as described in any of the above items, wherein the dendritic cell activator or mechanism comprises Extract Z, and Extract Z is administered by aspirating the drug solution into a 1 mL syringe and subcutaneously injecting 0.05 mL of the drug solution twice a week.

[0007] In one embodiment, the cancer treatment method of the present invention is characterized in that it is a method for treating cancer and combines treatment using immune checkpoint inhibitors with treatment to improve sensitivity to immune checkpoint inhibitors.

[0008] In one embodiment, the cancer treatment method of the present invention is characterized in that it is a method for treating a patient’s cancer and includes the following steps: 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 the sensitivity to the immune checkpoint inhibitor.

[0009] In one embodiment, the cancer treatment method of the present invention is characterized in that the second step is performed simultaneously or at different times from the first step described above.

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

[0011] In one embodiment, the medicine of the present invention is characterized in that it is a cancer treatment comprising an immune checkpoint inhibitor and administered in combination with radiation therapy, wherein the above-mentioned treatment increases the sensitivity to the immune checkpoint inhibitor by irradiation with the radiation.

[0012] In one embodiment, the medicine of the present invention is characterized in that: it is a cancer treatment comprising an immune checkpoint inhibitor and Extract Z, wherein the immune checkpoint inhibitor and Extract Z are administered at different times or simultaneously, and the above-mentioned treatment improves the sensitivity to the immune checkpoint inhibitor by administering Extract Z.

[0013] In one embodiment, the program of the present invention is characterized in that it is used to treat a patient with cancer, and causes a computer to perform the following steps: specifying a first period, wherein the first period is either a first treatment using an immune checkpoint inhibitor or a second treatment to improve the sensitivity to the immune checkpoint inhibitor; and specifying a second period, wherein the second period is when the examination results related to the patient show a specific change, and then administering another treatment or both of the first and second treatments to the patient.

[0014] In one embodiment, the program of the present invention is characterized in that: the specific change is a specific change in the medical image of the patient and the measured value of the tumor marker of the patient.

[0015] In one embodiment, the program of the present invention is characterized in that: the second treatment described above includes at least one of radiation irradiation, the administration of Extract Z, and the combined use of radiation irradiation.

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

[0017] In one embodiment, in the present invention, cancer treatment is performed by combining treatment with immune checkpoint inhibitors (first treatment) and treatment to increase sensitivity to immune checkpoint inhibitors (second treatment), and the synergistic effect of the two treatments is used to eliminate or shrink cancer tissue.

[0018] In one embodiment of the present invention, before or during treatment using immune checkpoint inhibitors (first treatment), a second treatment is performed to increase sensitivity to immune checkpoint inhibitors. The aim is to increase the effectiveness of sensitivity to immune checkpoint inhibitors.

[0019] In one embodiment, the present invention specifies a first period in which either a first treatment utilizing an immune checkpoint inhibitor or a second treatment to improve sensitivity to the immune checkpoint inhibitor is performed; and a second period in which another treatment or both of the first and second treatments are performed when patient-related examination results show a specific change (e.g., when cancerous tissue does not shrink in imaging diagnostics and tumor marker measurements increase). The aim is to achieve a synergistic effect in the effectiveness of the first and second treatments.

[0020] In one embodiment of the present invention, as a treatment to improve sensitivity to immune checkpoint inhibitors, one or a combination of radiation irradiation, Extract Z administration, and radiation irradiation is performed to improve sensitivity to immune checkpoint inhibitors.

[0021] In one embodiment, in the present invention, nivolumab, pembrolizumab or atezolizumab, which are antibodies against PD-1 of T cells, are used as immune checkpoint inhibitors to inhibit immune checkpoints of T cells and cancer cells.

[0022] In this invention, one or more of the above-mentioned features may appear in other combinations besides those explicitly stated. Further embodiments and advantages of this invention can be learned by reading and understanding the following detailed description if necessary. [Effects of the Invention]

[0023] In this invention, dendritic cells can be activated unexpectedly. Furthermore, this invention can provide a method for effectively treating or preventing cancer or tumors using immune adjuvants, etc.

Implementation Method

[0024] Hereinafter, the present invention will be described with reference to one preferred form. Throughout this specification, unless otherwise specified, singular expressions are to be understood to also include their plural meaning. Therefore, singular articles (e.g., "a," "an," "the," etc. in the case of English) are to be understood to also include their plural meaning unless otherwise specified. Furthermore, unless otherwise specified, the terms used in this specification are to be understood to be used in the meaning commonly used in the field. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention pertains. In cases of conflict, this specification (including definitions) takes precedence.

[0025] (Definitions) The following explains the terms used in this specification.

[0026] In this specification, "immune checkpoint inhibitor" is a substance that can block the transmission of immunosuppressive messages by binding to immune checkpoint molecules or their ligands, thereby relieving the inhibition of T cell activation caused by immune checkpoint molecules. Specifically, examples include those targeting PD-1, PD-L1, PD-L2, CTLA-4, LAG-3 (Lymphocyte Activation Gene-3), TIM-1 (T cell immunoglobulin mucin domain containing molecules 1), TIM-3, TIM-4, VISTA (V-domain immunoglobulin suppressor of T cell activation), BTLA (B and T lymphocyte attenuator), TIGIT (T cell immunoreceptor with Ig and ITIM domains), A2AR, 4-1BB, 4-1BBL, 2B4 (CD244), KIR family receptors, B7.1, and B7.2. B7-H2, B7-H3, B7-H4, B7-H6, BATE, CD39, CD40, CD47, CD48, CD73, CD94 / NKG2A, CD96, CD160, CD200, CD200R, CD274, butyrophilins, CEACAM1 (Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1), CSF-1R (Colony stimulating factor 1 receptor), DcR3 (Decoy Receptor 3), EDO, Foxpl, GARP (Glutamie Acid Rich Protein), GITR (glucocorticoid-induced tumor necrosis factor receptor), gp49B, HHLA2 (Human endogenous... Human endogenous retrovirus H long terminal repeat associating protein 2, HVEM (herpesvirus entry mediator), ICOS (inducible co-stimulator), IDO (indoleamine 2,3-dioxygenase), ILT (Immunoglobulin-like transcript)-2, ILT-4, LAIR-1 (Leukocyte-associated immunoglobulin-like receptor 1), MAFB (Musculoaponeurotic fibrosarcoma oncogene homolog B), and MICA.Inhibitors of the following proteins are preferred: β-blockers (Major histocompatibility cemplex class I chain-related protein A / B), NKG2A / HLA-E, NR4A2, OCT-2 (Octamer-binding transcription factor-2), OX-40, PIR-B (Paired immunoglobin-like receptor B), Rara (retinoic acid receptor alpha), SIRP (Signal Regulatory Protein), TDO (Tryptophan 2,3-dioxygenase), TLR3 (Toll-like receptor 3), and TNFR (Tumor Necrosis Factor Receptor). Inhibitors targeting PD-1, PD-L1, and CTLA-4 are also preferred. Anti-PD-1 antibodies, as one type of PD-1 inhibitor, inhibit the binding of PD-1 to PD-L1 on T cells, thereby blocking the transmission of inhibitory signals and maintaining T cell activation. Anti-PD-L1 antibodies, as one type of PD-L1 inhibitor, inhibit the interaction between PD-1 and PD-1 on T cells by binding to PD-L1 expressed by cancer cells or antigen-presenting cells, thus preventing the transmission of inhibitory signals to T cells and maintaining T cell activation. Anti-CTLA-4 antibodies, as one type of CTLA-4 inhibitor, maintain T cell activation by competing with CD28 ligands on dendritic cells, blocking inhibitory signals from immune cells via CD28. Examples of anti-PD-1 antibodies include nivolumab, pembrolizumab, spartazolizumab, and cimiprimab; examples of anti-PD-L1 antibodies include atezolizumab, durvalumab, and avelumab; and examples of anti-CTLA-4 antibodies include ipilimumab and trimelimumab.

[0027] In this specification, "immune checkpoint factors" are factors that suppress the immune response against oneself to maintain immune homeostasis and inhibit excessive immune responses. The original purpose of "immune checkpoint factors" is to inhibit excessive activation of T cells and prevent them from attacking themselves. However, in the process of carcinogenesis, they are used to prevent cancer cells from being attacked by the immune system, thus allowing cancer cells to proliferate. Therefore, by inhibiting immune checkpoint factors in cancer cells, T cells can 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, and 2B4. (CD244), 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, lactolipoprotein, CEACAM1, 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 α), SIRP, TDO, TLR3, and TNFR.

[0028] In this specification, the term "dendritic cell direct activator or device" refers to an agent or device that can directly (i.e., without the presence of other molecules) activate dendritic cells in vivo or in vitro in a subject. Examples of "dendritic cell direct activators or devices" include radiation therapy devices and immune adjuvants. In this invention, regarding whether "dendritic cells" are "directly activated," as illustrated in the examples, if the expression of CD80 / 86, a cell membrane surface marker, is higher in the presence of a candidate substance or factor than in the absence of the substance or factor (e.g., saline) + control antibody group, then the candidate substance or factor can be considered directly activated, and the device can be deemed to meet the criteria of a "dendritic cell direct activator or device."

[0029] In this specification, "radiation therapy provider" refers to methods, devices, equipment, drugs, and instruments used to provide radiation therapy to subjects.

[0030] In this specification, the term "medical device" refers to an object that is inserted into or implanted into an object or applied to the surface of an object for the purpose of treatment, prevention, or recurrence prevention. Common examples of medical devices, in addition to any device used in radiation therapy, include vascular stents, fasteners, ports, tubing, frames, and grafts.

[0031] In this specification, "EGFR gene mutation" refers to a mutation in the EGFR gene. "EGFR" refers to the epidermal growth factor receptor, which functions in cell proliferation and growth. If a mutation occurs in the EGFR gene, cell proliferation and growth are constantly activated, leading to carcinogenesis. It is known that "EGFR gene mutation" can cause non-squamous cell carcinoma, a type of lung cancer.

[0032] In this specification, "tyrosine kinase inhibitor (TKI)" refers to an agent that inhibits tyrosine kinase. Tyrosine kinase inhibitors inhibit cancer growth by blocking the signaling pathways related to daily diet in cancer cells. Representative examples of "tyrosine kinase inhibitors" include: afatinib, erlotinib, osimertinib (AZD9291), AZD3759, gemifloxacin, canertinib, lapatinib, cetuximab, mateuzumab, zalurumab, and panitumumab.

[0033] In this specification, the term "immune adjuvant" refers to any drug or factor that assists the immune response, such as hot water extract of human tuberculosis or a portion thereof.

[0034] In this specification, "CXCL10" is short for CXC motif chemokine ligand 10, also known as IP-10, interferon-γ inducible protein 10, or small inducible cytokine B10. In humans, it is an 8.7 kDa protein encoded by the CXCL10 gene, containing 77 amino acids in a non-glycosylated protein. It is a chemokine formed in response to treatment of monocytes, endothelial cells, and fibroblasts with IFNγ (interferon-γ). IP-10 functions as a chemotactic inducer of CXCR3, which is expressed as a G protein-binding receptor and is mainly found in activated T cells and NK (Natural Killer) cells. In addition, it is also known as CXCL10, C7, IFI10, INP10, IP-10, SCYB10, crg-2, gIP-10, mob-1, CXC motif chemokine ligand 10, CXC motif chemokine 10, etc. As an ID (identity code), it is also known as NM_001565 (nucleic acid) and NP_001556 (protein).

[0035] In this specification, the term "CXCL10 production enhancement" means an increase in the production (or quantity) of CXCL10.

[0036] In this specification, the term "cancer or tumor showing CXCL10 positivity" means that CXCL10 is positive in cancer or tumor.

[0037] In this specification, "CXCR3" has the same meaning as commonly used in the art, referring to one of the CXC chemokine receptor family, which are G protein conjugate receptors. Besides G protein conjugate receptor 9 (GPR9) or CD183, it is sometimes also referred to as CD182; CKR-L2; CMKAR3; IP10-R; Mig-R; MigR, etc. Two mutants of CXCR3 are known. CXCR3-A binds to CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC), which are CXC chemokines, while CXCR3-B can also bind to CXCL4. Examples of nucleic acid IDs include NM_001142797 and NM_001504, and examples of protein IDs include NP_001136269 and NP_001495.

[0038] In this specification, "low CD8+ T cell count" refers to T cells that are positive for CD8. In this specification, the infiltration of CD8-positive T cells is evaluated based on the confirmed cell count using a slide with at least three different high-power fields of view (maximum, objective 40x and eyepiece 10x). The number of CD8-positive cells is recorded; low infiltration is defined as fewer than five cells in three fields of view, and high infiltration is defined as more than five cells.

[0039] In this specification, the term "human-type Mycobacterium tuberculosis hot water extract" typically refers to a substance produced by human-type Mycobacterium tuberculosis, which is a mixture of polysaccharides mainly composed of arabinose, mannose, and glucose. The anticancer effects of human-type Mycobacterium tuberculosis hot water extract have been studied in the industry for some time, but the detailed mechanism of action is not always clear, and it has not been used as a preventative drug. Furthermore, it may appropriately contain trace components such as proteins, peptides, amino acids, nucleic acids, and lipids (glycolipids). As an example of human-type Mycobacterium tuberculosis hot water extract, Extract Z, as described in this specification, can be used. Therefore, in the technology of this invention, Extract Z, as described in detail in this specification, or any formulation manufactured using it as a technical grade drug, can be used as a human-type Mycobacterium tuberculosis hot water extract.

[0040] A representative method for manufacturing hot water extracts of human tuberculosis bacteria is described below.

[0041] Human tuberculosis bacilli are cultured in a constant temperature bath at 37°C for 3-7 weeks. The membrane-like bacterial cells formed on the culture medium are then filtered out, and the wet bacterial cells obtained by washing with water to remove the culture medium components are used as the extraction raw material. The bacterial cells are suspended in 15-40 times their wet weight of distilled water, heated at 90-120°C for 80-180 minutes, and extracted. Bacterial residues are removed using a sterile filter. The extract is concentrated to below 60%, and acetone, trichloroacetic acid, ammonium sulfate, or sulfosalicylic acid are added to it at 0.5-3% (w / v). The mixture is stirred and allowed to stand. The precipitate is then removed by centrifugation, and the supernatant is dialyzed with running water. The dialysate is concentrated under reduced pressure to 1 / 20 to 1 / 4 of its original volume. Sodium chloride is added to the concentrate at a concentration of 0.5% to 1% (w / v), followed by 2 to 4 times its volume of ethanol. After standing, the solution is centrifuged to remove the precipitate. Then, 2 to 6 times its volume of ethanol is added to the supernatant, and after standing, the solution is centrifuged again, collecting the precipitated polysaccharides, etc., thus obtaining a hot water extract of Mycobacterium tuberculosis. Those skilled in the art will understand that the same product can be obtained by appropriately changing the above conditions.

[0042] The term "prevention" in this invention refers to the act of administering the effective components of this invention to a person suffering from a disease, for example, with the aim of preventing the onset of the disease.

[0043] In this invention, "treatment" refers to the act of administering the effective components of this invention to a person (subject, patient) diagnosed with a disease by a physician or equivalent practitioner, for example, with the aim of reducing the disease or symptoms, preventing the cancer from growing, or restoring it to the state before the onset of the disease. Furthermore, even if the purpose of administration is to prevent the disease or symptoms from worsening or to prevent the cancer from growing, it is still considered a treatment act as long as the recipient is a patient.

[0044] In this specification, "radiation therapy" refers to a treatment method that utilizes radiation irradiation. Examples of radiation include X-rays, gamma rays, electron beams, proton beams, heavy particle beams, etc. One type of radiation can be used, or two or more types of radiation can be used. In one embodiment, the "radiation therapy providing mechanism" of the present invention can include radiation sensitizers, radiation irradiation devices, radioactive materials, etc. In the present invention, the "radiation therapy providing mechanism" is preferably configured to provide palliative irradiation. More preferably, the "radiation therapy providing mechanism" is configured to perform irradiation in a manner that has an accompanying distance effect. In yet another embodiment, the "radiation therapy providing mechanism" is configured to irradiate lesions that can be measured but are not within the scope of the target lesion.

[0045] In this specification, the term "controlling T cell inhibitor" refers to any drug or device that inhibits controlling T cells. Whether controlling T cells are inhibited can be determined, for example, by the following methods: (1) Collecting CD4+CD25+ cells from the spleen or tumor of a mouse, co-culturing them with effector T cells collected from and differentiated from the spleen of a mouse, and confirming the proliferation of effector T cells. The drug is administered in vivo or added during the in vitro culture of CD4+CD25+ cells. (2) Transplanting cancer cells into a mouse and administering the drug. Collecting the tumor and calculating the ratio of FoxP3+ cells among the CD4+CD25+ cells infiltrating the tumor. (3) Transplanting cancer cells into a mouse and administering the drug. Collecting the tumor and confirming the expression of the FoxP3 gene. Furthermore, the target animal is not limited to mice and may be other animals (including humans). Examples of controlling T cell inhibitors include COX-2 inhibitors, but are not limited to these.

[0046] In this specification, the term "COX-2 inhibitor" refers to an inhibitor of prostaglandin-endoperoxidase 2. Examples include celecoxib, etodoxacin, meloxicam, nabumetone, zaltopibuprofen, lornoxicam, etc.

[0047] The term "carrier" as used in this specification refers, for example, to a pharmaceutically permissible substance, composition, or excipient, such as a liquid or solid extender, diluent, additive, solvent, or encapsulating agent, that is associated with or capable of transporting or delivering the target pharmaceutical compound from one organ or part of the body to another organ or part of the body. "Pharmaceutically permissible" means compatible with other ingredients in the formulation and harmless to the patient. Non-limiting examples of pharmaceutically permissible carriers, carriers, and / or diluents include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; excipients such as astragalus gum, malt, gelatin, talc, cocoa butter, and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; glycerol, sorbitol, mannitol, and polyols such as polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; alginic acid; water without pyrogenic substances; isotonic physiological saline; Ringel's solution; ethanol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical preparations. The composition may include wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers. It may also include colorants, releasing agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and antioxidants.

[0048] In this specification, "non-oral (parenteral) administration" refers to any form of administration that is not administered orally. It refers to any form and level of administration that is effective in treating or preventing diseases such as cancer. Examples of non-oral administration methods include administration via dermal or mucosal absorption, including injection or infusion, or combinations thereof. For example, as an administration via dermal or mucosal absorption, the effect is achieved by contacting the skin or mucosa with a coating, patch, or spray, allowing the drug in the preparation to be transferred into the body through the skin or mucosa. Examples of administration via injection or infusion include intravenous, intradermal, subcutaneous, intramuscular, and enteric (enema) administration, as well as bolus injection and / or continuous infusion. These can also be suspensions, liquids, emulsions, or embedding agents in oily or aqueous media containing other formulation substances such as suspending agents, stabilizers, and / or dispersants. As an enteral (enema) administration, it can be continuously delivered into the proximal small intestine using a tube and a portable infusion pump via percutaneous endoscopic gastrostomy. Subcutaneous or intradermal administration is also preferred. Non-oral administration (e.g., percutaneous administration) can also be performed using plasters / patches or powders, sprays, ointments, creams, lotions, gels, and solutions. Compositions suitable for non-oral administration may contain at least one sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, embedding agent, or sterile powder that can be reformulated into a sterile injectable solution or dispersion just before use, as per pharmaceutical permissible.

[0049] (Description of Preferred Embodiments) Preferred embodiments of the present invention will be described below. The embodiments provided below are provided to better understand the present invention, and it should be understood that the scope of the present invention is not limited to the following description. Therefore, those skilled in the art will understand that appropriate modifications can be made within the scope of the present invention with reference to the description in this specification. Furthermore, it should be understood that the following embodiments of the present invention can be used alone or in combination.

[0050] <Direct Activation of Dendritic Cells> In one embodiment, the present invention provides various agents or mechanisms for directly activating dendritic cells. In one embodiment, the present invention provides a composition comprising an immune adjuvant for directly activating dendritic cells, its use, and a method of using the adjuvant. In an exemplary embodiment, the immune adjuvant comprises a Mycobacterium tuberculosis extract, such as a hot water extract of human tuberculosis or a portion thereof. In another embodiment, the present invention provides a composition or medical device comprising a radiation therapy providing mechanism for activating dendritic cells, its use, and a method of using the adjuvant. Here, the radiation therapy providing mechanism comprises at least one selected from the group consisting of a radiation sensitizer, a radiation irradiation device, and a radioactive substance. For example, the radiation therapy providing mechanism is configured to provide palliative irradiation. In a preferred embodiment, the radiation therapy providing mechanism is configured to irradiate in a manner that has an accompanying telescopic effect. In a specific example, the radiation therapy providing mechanism is configured to irradiate a measurable lesion that is not within the scope of the target lesion.

[0051] In this invention, whether dendritic cells are directly activated can be determined by an experiment including the following steps, which confirm whether the expression level of CD80 / 86 on the surface of dendritic cells increases when the target substance or factor is present, compared to the absence of the target substance or factor; the above steps are to determine whether the expression level of CD80 / 86 on the surface of dendritic cells increases when the immune adjuvant is present, compared to the absence of the immune adjuvant.

[0052] <Combined use of immune checkpoint inhibitors and dendritic cell direct activators> The present invention is based on the discovery that the combined use of immune checkpoint inhibitors and dendritic cell direct activators or mechanisms can exert specific and effective therapeutic and preventive effects on malignant growths such as cancer.

[0053] In summary, the present invention provides a composition for treating, preventing, or preventing recurrence of cancer or tumors in a subject by using a combination of an immune checkpoint inhibitor and a dendritic cell direct activator or mechanism; a method for treating, preventing, or preventing recurrence; and a combination of an immune checkpoint inhibitor and a dendritic cell direct activator or mechanism for treating, preventing, or preventing recurrence. The administration or provision of the immune checkpoint inhibitor and the dendritic cell direct activator or mechanism may be simultaneous or asynchronous, and either one may be administered first.

[0054] In another embodiment, the present invention provides a composition, use, or medical device, application, treatment method, prevention method, or recurrence prevention method for treating, preventing, or preventing recurrence of cancer or tumors in a subject using a dendritic cell direct activator or mechanism. The dendritic cell direct activator or mechanism is administered or used in combination with an immune checkpoint inhibitor. In yet another embodiment, the present invention provides a composition, use, or medical device, application, treatment method, prevention method, or recurrence prevention method for treating, preventing, or preventing recurrence of cancer or tumors in a subject using an immune checkpoint inhibitor. The immune checkpoint inhibitor is administered or used in combination with a dendritic cell direct activator or mechanism.

[0055] In a representative morphological sample, examples of dendritic cell direct activators or mechanisms include: immune adjuvants, radiation therapy providers, radioactive substances, combinations thereof, etc.

[0056] The immune checkpoint inhibitor or dendritic cell direct activator or mechanism of the present invention can be provided in the form of a pharmaceutical composition. In a particular embodiment, the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically permissible carrier, wherein, in the test subject, one or more compounds may be converted, for example, into at least one compound of Mycobacterium tuberculosis extract (i.e., can be provided in the form of a prodrug).

[0057] In one embodiment, the immune adjuvant that can be used in the present invention may include, for example, hot water extract of Mycobacterium tuberculosis or a portion thereof.

[0058] In one embodiment, the radiation therapy provider may use any device (or apparatus) that provides X-rays, gamma rays, electron beams, proton beams, heavy particle beams, etc., as radiation. One type of radiation may be used, or two or more types of radiation may be used. In one embodiment, the radiation therapy provider of the present invention may include a radiation sensitizer, which may be provided together with a radiation irradiation device, or together with a radioactive material, or may include any combination thereof. In the present invention, the radiation therapy provider is preferably configured to provide palliative irradiation. More preferably, the radiation therapy provider is configured to irradiate in a manner that has an accompanying telescopic effect. In a further embodiment, the radiation therapy provider is configured to irradiate lesions that can be measured but are not within the scope of the target lesion.

[0059] In this invention, whether dendritic cells are directly activated can be determined by an experiment including the following steps: whether the expression level of CD80 / 86 on the surface of dendritic cells increases when the target substance or factor is present, compared to the absence of the target substance or factor; the above steps are to determine whether the expression level of CD80 / 86 on the surface of dendritic cells increases when the immune adjuvant is present, compared to the absence of the immune adjuvant.

[0060] In a preferred embodiment, the immune checkpoint inhibitor may be an inhibitor of factors such as PD-1, PD-L1, and CTLA-4. It may also be a combination of these inhibitors. In one example, the immune checkpoint inhibitor may be a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, etc. One dose may be an inhibitor of multiple factors such as PD-1, PD-L1, and CTLA-4. As a specific embodiment, examples include nivolumab, pembrolizumab, or atezolizumab, but it is not limited to these.

[0061] In one embodiment, PD-L1 is preferably a cancer manifestation, but is not limited thereto. In another embodiment, cancer may include lung cancer, but is not limited thereto. In a preferred embodiment, cancer or tumor may be one with an EGFR gene mutation, but is not limited thereto. Therefore, in one instance, treatment, prevention, or relapse prevention may be performed on a subject receiving treatment with a tyrosine kinase inhibitor (e.g., EGFR-TKI). In one specific embodiment, treatment, prevention, or relapse prevention may be performed on a subject who has not received treatment with an immune checkpoint inhibitor. In another embodiment, treatment, prevention, or relapse prevention may be performed on a subject who is deemed ineffective in treatment with an immune checkpoint inhibitor. In one specific embodiment, the treatment, prevention, or relapse prevention of the present invention may be performed on a subject who, although responding to treatment with an immune checkpoint inhibitor, subsequently develops progressive disease (PD), but is not limited thereto.

[0062] In one embodiment, the tested system is a subject whose tumor shows CXCL10 positivity. This is because CXCR3-positive cells are more likely to invade. In another embodiment, the technique of the present invention is used for CXCL10 hyperactivity. In another embodiment, the tested subject is a subject with low CD8+ T cell count. Therefore, the technique of the present invention can be used to promote the infiltration of CD8+ T cells into the tumor. In specific embodiments, the present invention can be used for the treatment, prevention, or recurrence prevention of unresectable or metastatic solid tumors with high tumor mutational burden and low CD8+ T cell count when there are no other treatment options.

[0063] In embodiments of the present invention, the present invention may also be used in conjunction with a controlled T-cell inhibitor. The controlled T-cell inhibitor may be a COX-2 inhibitor, preferably a COX-2 inhibitor. As a COX-2 inhibitor, celecoxib, other COX-2 inhibitors (e.g., etodoxacin, meloxicam, nabumetone, zaltopibuprofen, lornoxicam), etc., may be used, but are not limited thereto.

[0064] (Medical technology such as medicine and treatment) The medicine used in the present invention for the treatment, prevention or recurrence prevention of cancer may be used by any method known in the field as a pharmaceutical product.

[0065] In a specific embodiment, the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically permissible carrier, wherein the one or more compounds may be converted in the test subject into at least one Mycobacterium tuberculosis extract (i.e., a prodrug). In the case of comprising a plurality of pharmaceutical agents, they may be contained in a single composition (compound) or in different compositions. In the case of formulation in the form of a single composition, as a formulation, it may be formulated using known forms in the art, including those exemplified in this specification. In addition to the immune checkpoint inhibitors and / or dendritic cell direct activators or mechanisms of the present invention, the plurality of pharmaceutical agents may also be provided together with one or more other pharmaceuticals (e.g., anticancer agents such as surgical agents, chemotherapy agents, etc.) or provided in a manner that implements a therapeutic method (e.g., anticancer agent administration, radiation therapy, etc.). The immune checkpoint inhibitor and / or dendritic cell direct activator or mechanism of the present invention can be provided or administered in combination with one or more other medicines or treatments (e.g., surgery, chemotherapy, radiation therapy, anticancer agents). In one embodiment, one or more other medicines or treatments (e.g., surgery, chemotherapy, radiation therapy, anticancer agents) can be administered after a suitable time following the administration of the immune checkpoint inhibitor and / or dendritic cell direct activator or mechanism of the present invention. In the case of separate administration, two or more medicines can be provided in a kit form. Examples of anticancer agents include: antimetabolites, alkylating agents and other chemotherapeutic agents, proliferation inhibitors, cytotoxic agents, agents used in radiation therapy, anti-angiogenic agents, apoptosis agents, anti-microtubule agents, anticancer antibiotics, microtubule antagonists, tyrosine kinase inhibitors, proteasome inhibitors, undifferentiated lymphoma kinase inhibitors, JAK kinase inhibitors, CDK (Cyclin-dependent kinase) inhibitors, MEK (Methyl Ethyl Ketone) inhibitors, Raf kinase inhibitors, PARP (poly-ADP-ribose polymerase) inhibitors or antibody drugs and other molecularly targeted therapies, platinum preparations, immunotherapy such as dendritic cell therapy, gene therapy, other low-molecular-weight drugs, and other agents used to treat cancer, but this is not intended to be limited.

[0066] The compositions disclosed in this specification suitable for oral administration may be in the form of capsules, flat capsules, pills, tablets, rhomboid tablets (typically using sucrose and gum arabic or astragalus gum as a flavor base), powders, granules, solutions of aqueous or non-aqueous liquids, suspensions of aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil emulsions, elixirs, slurries, lozenges (using inert bases such as gelatin, glycerin, sucrose, and / or gum arabic), and / or oral cleansers, each containing a specific amount of at least one compound of the present invention.

[0067] The compositions disclosed in this specification can be administered in the form of pellets, licks, or ointments.

[0068] The immune checkpoint inhibitor and / or dendritic cell direct activator or mechanism of the present invention can be administered in any form, whether orally or non-orally, as long as it can exert its effect. Non-oral administration is preferred.

[0069] Orally administered solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) may be combined with one or more pharmaceutically permissible carriers such as sodium citrate or dicalcium phosphate, and / or fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silica, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic, humectants such as glycerin, agar, calcium carbonate, etc. The pharmaceutical composition may contain any one of the following: potato or cassava starch, alginate, certain silicates, sodium carbonate, and sodium glycolate disintegrants; paraffin wax and other dissolution delayers; quaternary ammonium compounds and other absorption enhancers; cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polypropylene oxide copolymers and other wetting agents; kaolin and bentonite clay and other absorbents; talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof and other lubricants; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffers. Furthermore, the same type of solid composition may also be used as a filler in soft and hard filled gelatin capsules by using lactose or lactose and high molecular weight polyethylene glycol as additives.

[0070] Liquid dosage forms for oral administration may include pharmaceutically permissible emulsions, microemulsions, solutions, suspensions, slurries, and elixirs. In addition to the active ingredient, liquid dosage forms may also include inert diluents used in the prior art, such as water or other solvents, cosolvents, and emulsifiers, examples of which include: ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. Furthermore, cyclodextrins such as hydroxypropyl-β-cyclodextrin may be used to dissolve the compound.

[0071] The components of the present invention may include humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, and preservatives. In addition to one or more compounds of the present invention, the suspension may also contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, finely crystalline cellulose, aluminum hydroxide, bentonite, agar, and astragalus gum, and mixtures thereof.

[0072] The compositions disclosed in this specification can be formulated as suppositories for rectal or vaginal administration. They can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating additives or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate. The suppositories are solid at room temperature but liquid at body temperature, and thus melt and release the compounds of the present invention within the rectal or vaginal cavity. Pharmaceutical compositions suitable for vaginal administration may also include pessaries, tampons, creams, gels, ointments, foams, or sprays containing carriers known in the prior art.

[0073] Dosage forms for topical or transdermal administration of the compositions used in the present invention may include powders, sprays, ointments, creams, lotions, gels, solutions, patches, and inhalants. Pharmaceutical compositions or tablets may be mixed under sterile conditions with pharmaceutically permissible carriers and preservatives, buffers, or pressurized gases as deemed necessary.

[0074] Ointments, creams, creams, and gels, in addition to the compositions of the present invention, may also contain additives such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0075] In addition to the pharmaceutical composition or pharmaceutical tablets of the present invention, the powder and spray may also contain additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of such substances. Furthermore, the spray may contain conventional high-pressure gases such as chlorofluorocarbons, and volatile non-substituted hydrocarbons such as butane and propane.

[0076] This can be interpreted as ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., also being within the scope of this invention.

[0077] A composition suitable for non-oral administration may contain at least one sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, or sterile powder that can be reformulated into a sterile injectable solution or dispersion just before use, as a pharmaceutical product.

[0078] The term "salt" as used in this specification includes acid and / or base salts formed from inorganic and / or organic acids and bases. When used in this specification, the term "pharmaceutically permissible salt" means a salt that, to the extent of reliable medical judgment, is suitable for use in contact with the tissues of a test subject without causing excessive toxicity, irritation, allergic reactions, and / or similar complications, and for which the effect / risk ratio is commensurate. Pharmaceutically permissible salts are well known in the art. For example, pharmaceutically permissible salts are described in detail in Berge et al., J. Pharmaceutical Sciences (1977) 66: 1-19.

[0079] Pharmaceutically permissible salts can be generated from 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 permissible salts include: adipate, alginate, ascorbate, aspartate, and benzenesulfonate. Sulfonate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, gluconate, glycerol phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. In several embodiments, the organic acids that can generate the salt 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.

[0080] Salts can be prepared by reacting the compound with a suitable base or acid separately, either on-site or separately, during the separation and purification of the disclosed compound. Non-limiting examples of pharmaceutically permissible salts obtained from bases include alkali metals, alkaline earth metals, ammonium, and N+ (C1-4 alkyl)4 salts. Non-limiting examples of suitable base or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Furthermore, non-limiting examples of pharmaceutically permissible salts may, as needed, include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide ions, carboxyl ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions. Non-limiting examples of suitable organic bases that can produce salts include primary amines, secondary amines, tertiary amines, substituted amines including naturally derived substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In certain embodiments, the alkali addition salt permissible as a pharmaceutical product may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0081] In embodiments of the present invention, the subject of the test may be a patient before the onset of cancer, after cancer treatment, in the early stages of cancer, or in a state with a high probability of developing cancer. Alternatively, the subject of the test may be a healthy person. When a healthy person is the subject of the test, it is implemented as a preventive method.

[0082] The cancers targeted in this invention are not limited, but can include: esophageal cancer, esophagogastric junction cancer, renal cell carcinoma, lung cancer, digestive system cancer, leukemia, lymphoma, myeloma, brain cancer, pancreatic cancer, endometrial cancer, prostate cancer, liver cancer, bladder cancer, esophageal and gastric 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 cancer, etc. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is colorectal adenocarcinoma. In a specific embodiment, the cancer is melanoma. In a specific embodiment, the cancer is breast cancer. In a specific embodiment, the cancer is bladder cancer. In a specific embodiment, the cancer is renal cell carcinoma. In a specific embodiment, the cancer is pancreatic cancer. In a particular embodiment, the cancer is endometrial cancer. In a particular embodiment, the cancer may be unresectable. In a particular embodiment, the cancer may be progressive. In a particular embodiment, the cancer may be refractory. In a particular embodiment, the cancer may be recurrent. In a particular embodiment, the cancer may be metastatic. In various embodiments of the present invention, the cancer targeted may include common cancer, cancer with relatively slow progression (e.g., cancer with low sensitivity to the immune system), oral squamous cell carcinoma, cervical cancer, MHC (Major Histocompatibility Complex) type I negative cancer where CD8-positive T cells are ineffective, cancer resistant to immune checkpoint inhibitors, etc. The term "cancer patient" refers to a patient suffering from the aforementioned "cancer". In one embodiment, the disease, disorder, or symptom targeted by the present invention includes melanoma.

[0083] In human T cells, there exists a component that can bind to factors of the individual's own cells to prevent attacks from cells other than the individual's own T cells. PD-1 is a representative factor (molecule) of this component. On the other hand, factors (molecules) such as PD-L1 exist in normal cells. For example, by binding PD-L1 to PD-1, normal cells can avoid attacks from T cells (immune cells); however, we do not wish to limit ourselves to this theory. This mechanism is an immune checkpoint system that inhibits T cell activity. Since cancer cells themselves originate from the individual's own cells, this immune checkpoint system is utilized to prevent attacks from T cells (immune cells).

[0084] Immune checkpoint inhibitors (ICIs) are, for example, drugs that inhibit the immune checkpoint system by inhibiting the stimulation of immune checkpoint molecules (PD-1), immunosuppressive receptors present on T cells, which are immune cells. Since immune checkpoint inhibitors are drugs that suppress the immune system, administration of these drugs activates the patient's immune function. Furthermore, by inhibiting immune checkpoint molecules in cancer cells, T cells can attack cancer cells; however, this is not intended to be the sole focus.

[0085] Extract Z is suitable as a therapeutic agent to enhance sensitivity to immune checkpoint inhibitors. Extract Z is a drug developed as a treatment for tuberculosis. It is a colorless and transparent subcutaneous injection solution, and its main components are polysaccharides of lipoarabinomannan extracted from human tuberculosis, nucleic acids, and lipids; however, it is not desired to be limited to this theory.

[0086] The administration of these Extract Zs can enhance sensitivity to immune checkpoint inhibitors (ICIs). In addition to administering these therapeutic agents, it is also hoped that radiation irradiation can enhance sensitivity to immune checkpoint inhibitors (ICIs); however, it is not desired to be limited to this theory.

[0087] In one embodiment, this treatment using immune checkpoint inhibitors (first treatment) and a treatment to increase sensitivity to immune checkpoint inhibitors (second treatment) are combined to treat a patient's cancer. In other words, the cancer treatment method of this embodiment includes the following steps: administering treatment using immune checkpoint inhibitors to a cancer patient (first treatment); and administering treatment to a cancer patient to increase sensitivity to immune checkpoint inhibitors (second treatment).

[0088] In one embodiment, as an immune checkpoint inhibitor in the first treatment, nivolumab, pembrolizumab, or atezolizumab, which are antibodies targeting PD-1 on T cells, are used to inhibit the immune checkpoints of PD-1 on T cells and PD-L1 on cancer cells. Furthermore, as a therapy in the second treatment, radiation irradiation, administration of Extract Z, or a combination thereof are performed.

[0089] In one embodiment, when combining the first treatment and the second treatment, the first treatment and the second treatment may be administered to the patient simultaneously over a specific period of time. Alternatively, either the first treatment or the second treatment may be administered to the patient over a specific period of time, followed by the other treatment over a specific period of time. Alternatively, either the first treatment or the second treatment may be administered to the patient over a specific period of time, followed by both treatments over a specific period of time. Alternatively, both the first treatment and the second treatment may be administered to the patient over a specific period of time, followed by only one treatment over a specific period of time. Furthermore, the above-described forms may be appropriately combined and repeated periodically.

[0090] In the various forms described above, the timing of the change of therapy is specified based on specific changes in the patient's relevant examination results (patient's medical images, patient's tumor marker measurement results (measured values), patient's PET (Positron Emission Tomography) examination results, etc.).

[0091] In one embodiment, the first treatment and the second treatment are combined, so the synergistic effect of the effects of the first treatment and the second treatment can eliminate or shrink cancerous tissue. The second treatment (radiation, Extract Z administration, or a combination of Extract Z administration and radiation) can increase sensitivity to immune checkpoint inhibitors, and the first treatment (administration of immune checkpoint inhibitors) can exert T-cell attack power on cancer cells, thus eliminating or shrinking the patient's cancerous tissue; however, it is not intended to be limited to this theory.

[0092] Figure 1 is a block diagram showing the structure of the system using the program in this embodiment, and Figure 2 is a flowchart showing the treatment sequence in this embodiment.

[0093] The system 1 shown in FIG1 includes a control unit 11, a reading unit 12, a memory unit 13, a display unit 14, an input unit 15, and a bus 16. The control unit 11 is connected to other hardware components constituting the system 1 via the bus 16.

[0094] The control unit 11 is constructed using a CPU (Central Processing Unit), MPU (Micro Processing Unit), etc., and executes the program in this embodiment. The read unit 12 reads the program 3 of this embodiment recorded on a portable recording medium 2, such as a flexible optical disc. The memory unit 13 includes SRAM (Static Random Access Memory), DRAM (Dynamic Random Access Memory), etc., and stores information required for the processing performed by the control unit 11 and the program 3 read by the read unit 12.

[0095] The display unit 14 includes a liquid crystal display panel, etc., which displays the patient's resume information, processing results obtained from the control unit 11 (the type of treatment implemented on the patient, the duration of each treatment), etc. The input unit 15 includes a keyboard, mouse, etc., which accepts input information from the user.

[0096] An image acquisition device 4 is connected to the system 1 to acquire medical images (CT (Computed Tomography) images, X-ray images, PET images, etc.) of the patient. The patient's medical images are periodically or as requested by the system 1 (control unit 11). Furthermore, a tumor marker analyzer 5 is connected to the system 1 to measure the patient's tumor markers (specifically, CEA (Carcinoembryonic Antigen)). The measured values ​​of the patient's tumor markers (CEA) are periodically or as requested by the system 1 (control unit 11).

[0097] Furthermore, in the above example, program 3 is read from portable recording medium 2 using reading unit 12, but it can also be pre-memorized in memory unit 13. Also, program 3 can be obtained from an external server via a network not shown.

[0098] Next, referring to the flowchart in Figure 1, the treatment sequence in this embodiment will be explained.

[0099] The control unit 11 specifies a first period (step S1) for implementing either treatment using an immune checkpoint inhibitor (first treatment) or treatment to increase sensitivity to immune checkpoint inhibitors (second treatment). Here, it also specifies which treatment is used as the second treatment: radiation irradiation, Extract Z administration, or a combination of Extract Z administration and radiation irradiation. In this case, for example, the first period and the type of the second treatment are specified based on input from the user received via the input unit 15. Furthermore, the control unit 11 itself can specify the first period and the type of the second treatment based on the patient's medical history, treatment history information from other cases, etc. The specified first period and the type of the second treatment are displayed on the display unit 14.

[0100] While continuing any treatment, the control unit 11 acquires a medical image of the patient obtained by the image acquisition device 4 (step S2).

[0101] 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.

[0102] On the other hand, when the cancerous tissue does not shrink (step S3: no), the control unit 11 acquires the measured values ​​of the patient's tumor markers obtained by the tumor marker measuring device 5 (step S4).

[0103] The control unit 11 determines whether the measured value of the acquired tumor marker has increased (step S5). If the measured value has not increased (step S5: no), the process returns to step S2.

[0104] On the other hand, when the measured value of tumor markers increases (step S5: Yes), the control unit 11 identifies a second period (step S6) and terminates the process; this second period is the timing of implementing one of two treatments: treatment using immune checkpoint inhibitors (first treatment) and treatment to improve sensitivity to immune checkpoint inhibitors (second treatment). In this case, the second period is identified, for example, based on input information from the user received via the input unit 15. Furthermore, the control unit 11 may also identify the second period itself based on the patient's medical history, treatment history information in other cases, etc. The identified second period is displayed on the display unit 14.

[0105] Furthermore, in the above-described form, in step S6, the implementation period of the first treatment and the second treatment is specified, and the implementation period of the first treatment and the second treatment can also be specified individually.

[0106] In the above embodiments, in step S5, when the measured value of tumor markers increases, the implementation period of another (or two) therapies is specified. However, based on the PET scan results, when glucose intake increases, the implementation period of another (or two) therapies can also be specified. Furthermore, it can be determined whether to proceed to step S6 (specification of the implementation period of another (or two) therapies) based on both the change in the measured value of tumor markers in step S5 and the change in glucose intake based on the PET scan results.

[0107] In this specification, the term "or" is used when "at least one or more" of the items exemplified in the text can be used. The same applies to "or". In this specification, when it is explicitly stated as "within a range of two values", the range also includes the two values ​​themselves.

[0108] The scientific literature, patents, patent applications and other references cited in this specification are used as a whole and are equally cited in this specification as the individual references.

[0109] The preferred embodiments have been described above to facilitate understanding of the present invention. The present invention will now be described based on embodiments; however, the above description and the following embodiments are provided for illustrative purposes only and are not intended to limit the scope of the present invention. Therefore, the scope of the present invention is not limited to the embodiments and examples specifically described in this specification, but only to the scope of the claims. Embodiments

[0110] Examples are described below. Where necessary, the handling of animals used in the following examples complied with relevant ethical guidelines or guidelines and was based on the Declaration of Helsinki. Specifically, the reagents used are the products described in the examples, but equivalent products from other manufacturers (Sigma-Aldrich, Wako Pure Chemicals, Nacalai, R&D Systems, USCN Life Science INC, etc.) may be substituted.

[0111] (Manufacturing Example: Extract Z) The Extract Z used in this example was manufactured as follows. Mycobacterium tuberculosis strain Aoyama B, which was freeze-dried and stored (-20°C), was cultured in Soton potato medium (1) at 37±1°C. The cultured bacteria were transferred to manufacturing medium (2) and cultured at 37±1°C for 5 to 7 weeks (formal culture). The obtained bacterial cells were washed with water for injection, and 20 times the weight of the wet bacterial cells was added with water for injection. The mixture was heated at 100°C for 120 minutes to obtain an extract. The extract was filtered using a 0.45 μm membrane filter and concentrated under reduced pressure to a sugar content (determined by the phenol-sulfuric acid method and converted to D-arabinose) of 4.0 to 6.0 mg / mL to obtain a concentrate. Subsequently, to remove protein, 1 w / v% sulfosalicylic acid was added to the concentrate, and after incubation at below 10°C for 15–20 minutes, the precipitate was centrifuged (below 10°C, 1150×G, 10 minutes), and the supernatant was recovered. The protein concentration of the supernatant was below 0.30 mg / mL (Lowry method, tyrosine conversion). Then, sulfosalicylic acid was removed until the supernatant concentration was below the detection limit (below 10 ppm, ferric chloride solution method). The solution was concentrated under reduced pressure to a sugar content of 1.8–2.2 mg / mL, with the addition of sodium chloride (0.9 w / v%) and an equal volume of cold ethanol, and incubated at below 10°C for at least 40 hours. The precipitate (polysaccharides in the high molecular weight region) was then centrifuged (below 10°C, 2040×G, 10 minutes). Subsequently, four times the volume of cold ethanol was added to the supernatant, and the mixture was left to stand at or below 10°C for at least 40 hours. The precipitate was then recovered by centrifugation (below 10°C, 2040×G, 10 minutes). The precipitate was dissolved in water for injection, and the sugar content was adjusted to 1.8–2.2 mg / mL. The solution was then filtered through a 0.45 μm membrane filter and autoclaved (121°C, 20 minutes) to prepare Extract Z solution.

[0112] (1): Sutong potato medium: Washed potato slices are immersed in Sutong medium and sterilized at 115°C for 15 minutes. This medium is then used as Sutong potato medium. Sutong medium: L-aspartic acid (monohydrate) 4.0 g, citric acid (monohydrate) 2.0 g, magnesium sulfate (heptahydrate) 0.5 g, dipotassium hydrogen phosphate (anhydrous) 0.5 g, ferric ammonium citrate 0.05 g, glycerol 60 mL. The above substances are dissolved in water to prepare 1000 mL. The pH value is adjusted to 7.0-7.3 using sodium hydroxide solution.

[0113] (2): Culture medium for manufacturing L-aspartic acid (monohydrate) 4.0 g, citric acid (monohydrate) 2.0 g, magnesium sulfate (heptahydrate) 0.5 g, dipotassium hydrogen phosphate (anhydrous) 0.5 g, ferric ammonium citrate 0.05 g, glycerol 60 mL. Dissolve the above substances in water to make 1000 mL, and autoclave (121℃, 20 minutes). The pH value is adjusted to 7.0-7.3 using sodium hydroxide solution.

[0114] The physicochemical properties of the obtained Extract Z liquid are as follows: (1) Appearance: slightly yellow transparent liquid (2) pH value: 4.50-5.30 (3) Protein content in the freeze-dried product: 3.5% by weight (based on amino acids) (4) Nucleic acid content in the freeze-dried product: 0.1% by weight (5) The main components of the polysaccharide are monosaccharides: mannose 43.4% by weight, arabinose 18.2% by weight, and glucose 10.4% by weight. (After hydrolysis in 2N trifluoroacetic acid at 100°C for 2 hours, the analyte was analyzed by liquid chromatography using a 2-cyanoacetamide fluorescent derivative (S. Honda, et al, Anal. Chem., 52, 1079 (1980)).

[0115] The Extract Z liquid prepared by the method described in the above manufacturing example can be used after appropriate dilution. In the following examples, it is diluted by 1 to 50,000 times and adjusted to an appropriate concentration before use.

[0116] The manufacturers and catalog numbers of the antibodies and staining reagents used in the following examples are as follows. CD80 (Miltenyi Biotec Co., Ltd., Catalog No. 130-102-372) CD86 (Miltenyi Biotec Co., Ltd., Catalog No. 130-102-506) CD11b (Miltenyi Biotec Co., Ltd., Catalog No. 130-113-811) CD11c (Miltenyi Biotec Co., Ltd., Catalog No. 130-122-016) CD45 (Miltenyi Biotec Co., Ltd., Catalog No. 130-119-130) CD4 (Miltenyi Biotec Co., Ltd., Catalog No. 130-123-899) CD8 (Life Technologies Corporation, Catalog No. 25-0081-82) TCRβ (BioLegend Incorporated, Catalog No. 109220) NK (Anti-CD49b antibody; Miltenyi Biotec Co., Ltd., Catalog No. 130-102-258) MHC Class II (Miltenyi Biotec Corporation, Catalog No. 130-123-785) PD-L1 (anti-CD274 antibody; Life Technologies Corporation, Catalog No. 12-5982-81) PI (Propidium Iodide Solution; dead cell marker; Miltenyi Biotec Corporation, Catalog No. 130-093-233)

[0117] The following are specific treatment examples for cancer patients, with reference to the following figures: Figure 3 (Example 1: Immune checkpoint inhibitor + radiation irradiation only), Figure 4 (Example 2: Immune checkpoint inhibitor + radiation irradiation only), Figure 5 (Example 3: Immune checkpoint inhibitor after Extract Z administration), Figure 6 (Example 4: Immune checkpoint inhibitor + Extract Z administration + radiation irradiation combined), and Figures 10 and 11 (Examples of subjects who responded to treatment with tyrosine kinase inhibitors and immune checkpoint inhibitors but subsequently developed progressive disease (PD), and who received immune checkpoint inhibitors + Extract Z administration + radiation irradiation).

[0118] (Example 1) The case was a 69-year-old male diagnosed with squamous cell carcinoma of the lung without driver gene mutation and clinical TNM (Tumor Node Metastasis) classification of cTxN3M1b and stage IVb.

[0119] From September 2017 to November 2018, nivolumab, an anti-PD-1 antibody and an immune checkpoint inhibitor, was administered intravenously at 240 mg doses every two weeks. However, as shown in the CT image in Figure 3, the metastatic cervical lymph nodes continued to swell. In December 2018, the cervical lymph nodes were irradiated with 30 Gy / 10 fr. Then, from December 2018 to the present (December 2019), nivolumab was continued intravenously at 240 mg doses every two weeks. The results showed that the swelling of the cervical lymph nodes was suppressed (April and October 2019), with partial remission, indicating a positive treatment outcome.

[0120] (Example 2) The case was a 60-year-old male diagnosed with lung adenocarcinoma without driver gene mutation, and recurrent TNM classification of rTxN3M1b and stage IVb.

[0121] From November 2017 to February 2019, nivolumab was administered intravenously at a dose of 240 mg every two weeks. However, as shown in the CT image in Figure 4, the metastatic cervical lymph nodes continued to swell. In March 2019, the cervical lymph nodes were irradiated with 30 Gy / 10 fr. Then, from March 2019 to the present (December 2019), nivolumab was continued to be administered intravenously at a dose of 240 mg every two weeks. The results showed that the swelling of the cervical lymph nodes was suppressed (May 2019), partially relieved, and the treatment was effective.

[0122] (Example 3) The case was a 67-year-old woman diagnosed with lung adenocarcinoma with EGFR gene mutation positive (exon 19 deletion), and clinical TNM classification of cT1bN3M1b and stage IVb.

[0123] Extract Z was started on April 1, 2019. The tumor marker (CEA) level increased from 57.0 to 277.0, therefore Extract Z was discontinued on June 3, 2019, and nivolumab was started via intravenous infusion at 240 mg doses every two weeks. Subsequently, the tumor marker (CEA) level decreased sharply from 277.0 to 63.2.

[0124] As shown in the CT image in Figure 5, the cancerous tissue present before treatment basically disappeared after treatment. Excellent therapeutic effect can be obtained by the synergistic effect of administering Extract Z and administering nivolumab.

[0125] (Example 4) The case was a 55-year-old woman diagnosed with lung adenocarcinoma with EGFR gene mutation positive (exon 19 deletion), and clinical TNM classification of cT3bN2M1c and stage IVb.

[0126] Starting June 20, 2019, pembrolizumab, one of the anti-PD-1 antibodies used as an immune checkpoint inhibitor, was administered intravenously at 200 mg doses every 3 weeks. The tumor marker (CEA) level increased from 25.0 to 98.8, therefore, on August 15, 2019, pembrolizumab was continued, and Extract Z was started simultaneously. At this time, 30 Gy / 10 fr radiation was administered concurrently with Extract Z. Subsequently, the tumor marker (CEA) level sharply decreased from 98.8 to 41.5.

[0127] As shown in the X-ray image in Figure 6, the area of ​​cancerous tissue temporarily increased in size on August 15 during the treatment process (before the administration of Extract Z), but after treatment (the administration of Extract Z + radiation irradiation), it shrank significantly compared to before treatment. The synergistic effect obtained by the combined administration of pembrolizumab and the administration of Extract Z + radiation irradiation can achieve excellent therapeutic effects.

[0128] (Example 5: Direct Activation of Dendritic Cells by Immune Adjuvant / Radiation Therapy) In this example, the direct activation of dendritic cells by immune adjuvant / radiation therapy was confirmed. (Materials and Methods) Immune Adjuvant = Extract Z Radiation Therapy

[0129] (Example 6: Example of direct activation of dendritic cells using immunoadjuvant) In this example, direct activation of dendritic cells using immunoadjuvant is demonstrated. C3H / HeN mice were subcutaneously injected once daily into the right groin with either saline or Extract Z 1 mg / kg (n=20 per group). On day 29, after initiating saline or Extract Z administration, 1×10⁶ oral squamous cell carcinoma Sq-1979 cells were subcutaneously injected into the ventral side. On day 36, after initiating saline or Extract Z administration, tumors and lymph nodes were collected, with 5 mice grouped together, and analyzed using flow cytometry. [Antibodies Used] Antibodies against CD80, CD86, CD11b, and CD11c were used.

[0130] (Results) Increased expression of CD80 / 86 on the surface of dendritic cells was observed in the Extract Z-treated population. This result suggests that dendritic cells are activated by Extract Z treatment.

[0131] (Example 7: Example of direct activation of dendritic cells using radiation therapy) In this example, direct activation of dendritic cells using radiation therapy is demonstrated. Cancer cells were subcutaneously injected into mice to create subcutaneous tumor mice. After subcutaneous transplantation of cancer cells, half of the mice were subjected to local subcutaneous irradiation. After irradiation, subcutaneous tumors and lymph nodes were collected from mice in both the irradiated and non-irradiated groups, and the expression levels of CD80 / 86 on the surface of dendritic cells were measured using flow cytometry. After the start of irradiation (at the same time point for the non-irradiated group), tumors and lymph nodes were collected on day 36, with 5 mice grouped together, and the results were measured using flow cytometry. [Antibodies used] Antibodies against CD80, CD86, CD11b, and CD11c were used.

[0132] (Example 8: Combination of Multiple Dendritic Cell Direct Activation Techniques) In this example, the combination of multiple dendritic cell direct activation techniques is demonstrated. A patient population with cervical cancer who is suitable for chemoradiotherapy is administered saline or Extract Z. Simultaneously or concurrently with the administration of saline or Extract Z, a platinum preparation (cisplatin or carboplatin) and radical radiation irradiation are 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), PFS (Progression-Free Survival), OS (Overall Survival), and ORR (Objective Response Rate) were measured in the patient population.

[0133] (Example 9: Combined use of immune checkpoint inhibitors and immune adjuvants) In this example, the combined use of immune checkpoint inhibitors and immune adjuvants is demonstrated.

[0134] Patients with solid tumors, no existing treatment options, high tumor mutational burden, and low CD8+ T cell invasion were given saline or Extract Z. An immune checkpoint inhibitor (e.g., pembrolizumab) was administered concurrently or concurrently with or different from the administration of saline or Extract Z. Subsequently, PFS (progression-free survival), OS (overall survival), and ORR (objective response rate) were measured in the patient population.

[0135] (Example 10: Another example of the combined use of immune checkpoint inhibitors and immune adjuvants) In this example, an example of the combined use of immune checkpoint inhibitors and immune adjuvants is shown. Extract Z was administered to patients with non-small cell lung cancer who had not responded to single-agent therapy with immune checkpoint inhibitors. Immune checkpoint inhibitors and palliative radiation therapy were administered concurrently or concurrently with the administration of Extract Z. Subsequently, PFS (progression-free survival), OS (overall survival), and ORR (objective response rate) were measured in the patient population.

[0136] (Example 11: Combined use of immune checkpoint inhibitors with immune adjuvants and radiation therapy) In this example, a combined use of immune checkpoint inhibitors with immune adjuvants and radiation therapy is shown.

[0137] Patients with non-small cell lung cancer who have no existing treatment options, are EGFR mutation-positive, and are EGFR-TKI intolerant or refractory were given saline or Extract Z. Immune checkpoint inhibitors and palliative radiation therapy were administered concurrently or concurrently with the administration of saline or Extract Z. Subsequently, PFS (progression-free survival), OS (overall survival), and ORR (objective response rate) were measured in the patient population.

[0138] (Example 12: Combined use of immune checkpoint inhibitors, immune adjuvants, radiation therapy, and COX-2 inhibitors) Extract Z was administered to patients with non-small cell lung cancer who had not responded to single-agent immune checkpoint inhibitor therapy. Simultaneously or concurrently with Extract Z administration, immune checkpoint inhibitors, palliative radiation therapy, and control T-cell inhibitors were administered. Subsequently, PFS (progression-free survival), OS (overall survival), and ORR (objective response rate) were measured in the patient population.

[0139] (Example 13: Example of increased production of CXCL10 by immune adjuvant) In this example, it is demonstrated that the CXCL10 produced by the agent of the present invention is increased.

[0140] Cells derived from the bone marrow were collected from male C3H / HeJ mice and cultured for 6 days at 4×10⁶ cells / culture dish (containing 20 ng / mL GM-CSF and 20 ng / mL IL-4). After culture, the bone marrow cells were seeded at 2×10⁵ cells / well and stimulated with Extract Z at concentrations of 0.4 μg / mL, 0.8 μg / mL, 1.6 μg / mL, and 3.2 μg / mL. The culture supernatant was collected after 6 hours of stimulation, and the CXCL10 concentration was determined by ELISA (Enzyme Linked Immunosorbent Assay).

[0141] The results are shown in Figure 7. It was confirmed that the concentration of CXCL10 in the culture supernatant increased with increasing concentration of Extract Z used as stimulation. Therefore, it was confirmed that Extract Z has the effect of continuously increasing the production of CXCL10.

[0142] (Example 14: Treatment of CXCL10-positive cancers or tumors using immune adjuvants) [CXCL10 positive] An immune adjuvant was administered to a subcutaneous transplantation model of cancer cells to confirm anti-tumor or life-prolonging effects. Tumors from subcutaneous transplantation models showing confirmed anti-tumor or life-prolonging effects were collected, and the expression level of the CXCL10 gene in the tumors was investigated, confirming a high expression level. [CXCR3 positive] An immune adjuvant was administered to a subcutaneous transplantation model of cancer cells to confirm anti-tumor or life-prolonging effects. Tumors from subcutaneous transplantation models showing confirmed anti-tumor or life-prolonging effects were collected, and the CXCR3-positive cells in the tumors were investigated using flow cytometry or immunostaining, confirming a high positive cell rate.

[0143] (Example 15: Example of promoting CD8+ T cell infiltration into tumor) In this example, the effect of the agent of the present invention in promoting CD8+ T cell infiltration into tumor is demonstrated.

[0144] C3H / HeN mice were subcutaneously injected once daily into the right groin with either saline or Extract Z 1 mg / kg (n=40 per group). On day 29, after initiating saline or Extract Z administration, 1×10⁶ Sq-1979 oral squamous cell carcinoma cells were subcutaneously injected into the ventral side. Tumors were collected 7 days after Sq-1979 cell inoculation, with each group consisting of 5 mice, and analyzed using flow cytometry. [Antibodies and Reagents Used] Antibody against CD45, antibody against CD8, antibody against the TCRβ (T cell receptor β) chain, and PI (dead cell marker).

[0145] (Results) The results are shown in Figure 8. Administration of Extract Z increased the number of CD8+ T cells within the tumor. Furthermore, since Extract Z acts as a non-specific immune activation agent, the CD8+ T cells infiltrating the tumor included both cells with anti-tumor effects and cells expressing CTLA-4 and inhibiting anti-tumor effects.

[0146] (Example 16: Treatment or prevention of unresectable or metastatic solid cancer with high tumor mutation burden and low CD8+ T cell count, with no other treatment options, including immune adjuvant) In this example, we demonstrate the treatment or prevention of unresectable or metastatic solid cancer with high tumor mutation burden and low CD8+ T cell count, with no other treatment options, including immune adjuvant.

[0147] Patients with solid tumors, no existing treatment options, high tumor mutation burden, and low CD8+ T cell invasion were given saline or Extract Z. An immune checkpoint inhibitor (e.g., pembrolizumab) was administered concurrently or concurrently with or separate from the administration of saline or Extract Z. Subsequently, PFS (progression-free survival), OS (overall survival), and ORR (objective response rate) were measured in the patient population.

[0148] (Example 17: Treatment regimen example) In this example, an example of a combination regimen of immune checkpoint inhibitor, radiation therapy, and Extract Z is shown.

[0149] (1) Immune checkpoint inhibitors: Use any of the following single-dose regimens. (a) In principle, administer 240 mg of nivolumab intravenously every 2 weeks; (b) In principle, administer 200 mg of pembrolizumab intravenously every 3 weeks for 30 minutes, or administer 400 mg of pembrolizumab intravenously every 6 weeks for 30 minutes; (c) In principle, administer 1200 mg of atezolizumab intravenously every 3 weeks for 30 minutes. (2) Radiation therapy: Palliative irradiation other than brain metastases is used, with 2 Gy for 20-25 fractions, or an equivalent dose, such as 3 Gy for 10 fractions. The method of palliative irradiation should be determined by the radiation oncologist at each facility. (3) Extract Z (a) Draw the drug solution into a 1 mL syringe and inject a portion of it (about 0.05 mL is appropriate) 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) Repeat radiation therapy and Extract Z administration. Nine months after the start of treatment, radiation therapy and Extract Z administration can be repeated on other sites.

[0150] (Example 18: Example showing the ratio of tumor-infiltrating cells when Extract Z is administered) In this example, an analysis of the ratio of tumor-infiltrating cells when the agent of the present invention is administered is shown.

[0151] In C3H / HeN mice, saline or Extract Z 1 mg / kg was repeatedly administered subcutaneously once daily for 35 days to the right groin (n=20 per group). In Table 1, after the start of saline or Extract Z administration, 1×10⁶ oral squamous cell carcinoma Sq-1979 cells were subcutaneously injected into the ventral side on day 29. After the start of saline or Extract Z administration, 200 μg / body of anti-PD-1 antibody was injected intraperitoneally on days 28, 31, and 34. In Table 2, after the start of saline or Extract Z administration, 1×10⁶ oral squamous cell carcinoma Sq-1979 cells were subcutaneously injected into the ventral side on day 29. After the start of saline or Extract Z administration, 200 μg / body of anti-PD-1 antibody or control antibody was injected intraperitoneally on days 28, 31, and 34. After initiating treatment with saline or Extract Z, tumors and lymph nodes were collected on day 36, with five tumors grouped together and analyzed using flow cytometry. [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).

[0152] (Results) The results are shown in Tables 1 and 2. Among tumor-infiltrating cells, CD8+ T cells accounted for 4.34% in the saline-treated population, compared to 10.43% in the Extract Z-treated population (Table 1). Furthermore, the percentage was 3.91% in the anti-PD-1 antibody-only population, compared to 11.58% in the population treated with both Extract Z and anti-PD-1 antibody (Table 2). These results indicate that Extract Z administration induces CD8+ T cell infiltration into the tumor. [Table 1] Table 1 Mean (cell ratio [%)) SE CD8+T physiological saline 4.34 0.07 Extract Z 10.43 0.50 CD4+T physiological saline 20.54 0.58 Extract Z 22.46 1.05 MHC Class II physiological saline 6.71 0.53 Extract Z 5.64 0.68 NK physiological saline 39.79 1.35 Extract Z 38.07 0.50 PD-L1+ / CD45+ physiological saline 68.62 1.36 Extract Z 65.04 1.71 PD-L1+ / CD8+T physiological saline 96.79 0.18 Extract Z 98.35 0.11 When 5 are combined into a group, let n=1 and n=4. **: p < 0.01 (Aspin-Welch t-test) [Table 2] Table 2 Cell types Sample Cell ratio (%) average value SE CD8+T / CD45+ saline solution + anti-PD-1 3.91 0.31 Extract Z+ Anti-PD-1 11.58 0.42 CD4+T / CD45+ saline solution + anti-PD-1 29.93 2.98 Extract Z+ Anti-PD-1 26.58 2.72 MHC Class II+ / CD45+ saline solution + anti-PD-1 4.81 1.08 Extract Z+ Anti-PD-1 4.36 0.19 NK / CD45+ saline solution + anti-PD-1 27.02 1.21 Extract Z+ Anti-PD-1 30.88 1.87 PD-L1+ / CD45+ saline solution + anti-PD-1 67.88 2.19 Extract Z+ Anti-PD-1 66.42 3.52 PD-L1+ / CD8+T saline solution + anti-PD-1 99.02 0.28 Extract Z+ Anti-PD-1 99.30 0.15 When 5 are combined into a group, let N=1 and N=4. ***p < 0.001 (Student t-test)

[0153] (Example 19: Example showing the ratio of antigen-presenting cell markers in lymph nodes when Extract Z is administered) In this example, the ratio analysis of antigen-presenting cell markers in lymph nodes when the agent of the present invention is administered is shown.

[0154] In C3H / HeN mice, saline or Extract Z 1 mg / kg was repeatedly administered subcutaneously once a day for 35 days to the right groin (n=20 per group). In Table 3, after the start of saline or Extract Z administration, 1×10⁶ oral squamous cell carcinoma Sq-1979 cells were subcutaneously injected into the ventral side on day 29. After the start of saline or Extract Z administration, 200 μg / body of anti-PD-1 antibody was injected intraperitoneally on days 28, 31, and 34. In Table 4, after the start of saline or Extract Z administration, 1×10⁶ oral squamous cell carcinoma Sq-1979 cells were subcutaneously injected into the ventral side on day 29. After the start of saline or Extract Z administration, 200 μg / body of anti-PD-1 antibody or control antibody was injected intraperitoneally on days 28, 31, and 34. After initiating treatment with saline or Extract Z, tumors and lymph nodes were collected on day 36, with five tumors grouped together and analyzed using flow cytometry. [Antibodies and Reagents Used] Antibodies PI (dead cell markers) targeting CD45, CD80, CD86, CD11b, CD11c, MHC class II, and PD-L1 were used.

[0155] (Results) The results are shown in Tables 3 and 4. Among the antigen-presenting cell markers in lymph nodes, CD80+ / MHC class II cells accounted for 6.09% in the saline-treated population, compared to 8.38% in the Extract Z-treated population. Furthermore, the percentage was 6.08% in the anti-PD-1 antibody-only population, compared to 6.89% in the population treated with both Extract Z and anti-PD-1 antibody (Table 4). These results indicate that Extract Z administration leads to increased CD80+ expression. [Table 3] Table 3 Mean (cell ratio [%)) SE CD80+ / MHC Class II physiological saline 6.09 0.12 Extract Z 8.38 0.60 CD86+ / MHC Class II physiological saline 28.44 1.01 Extract Z 26.37 1.11 CD11b+CD11c- / MHC Class II physiological saline 0.85 0.03 Extract Z 1.12 0.03 CD11b+CD11c+ / MHC Class II physiological saline 1.28 0.06 Extract Z 1.51 0.08 CD11b-CD11c+ / MHC Class II physiological saline 13.03 0.44 Extract Z 9.22 0.53 When 5 are combined into a group, let n=1 and n=4. *: p < 0.05 (Aspin-Welch t-test) [Table 4] Table 4 Cell types Sample Cell ratio (%) average value SE CD80+ / MHC Class II saline solution + anti-PD-1 6.08 0.27 Extract Z+ Anti-PD-1 6.89 0.22 CD86+ / MHC Class II saline solution + anti-PD-1 25.90 0.82 Extract Z+ Anti-PD-1 24.65 1.78 CD11b+CD11c- / MHC Class II saline solution + anti-PD-1 1.18 0.11 Extract Z+ Anti-PD-1 1.41 0.06 CD11b+CD11c+ / MHC Class II saline solution + anti-PD-1 0.84 0.06 Extract Z+ Anti-PD-1 0.86 0.04 CD11b-CD11c+ / MHC Class II saline solution + anti-PD-1 10.51 0.50 Extract Z+ Anti-PD-1 9.76 0.61 When 5 are combined into a group, let N=1 and N=4.

[0156] (Example 20: Example of the performance of PD-L1 in cultured Sq-1979 cells) In this example, the performance analysis of PD-L1 using the agent of the present invention in cultured Sq-1979 cells is shown.

[0157] Cultured oral squamous cell carcinoma Sq-1979 cells were recovered, stained with anti-PD-L1 antibody and control antibody, and analyzed by flow cytometry.

[0158] (Results) The results are shown in Figure 9. In the staining with anti-PD-L1 antibody, 88.78% of the cells were positive, while in the control antibody, 1.57% of the cells were positive, thus indicating that Sq-1979 cells are PD-L1 positive cells.

[0159] (Example 21: Effect of Combination of Extract Z and Immune Checkpoint Inhibitors) In this example, Extract Z and anti-CTLA-4 antibody were administered to a mouse tumor model to confirm a synergistic increase in anti-tumor effect or lifespan extension effect. Spleen cells or lymph nodes were collected from mice, immune cells were isolated, and Extract Z and CTLA-4 antibody were added. Extract Z showed an IFN-γ production effect (T cell activation effect) by being added in vitro; therefore, it was confirmed whether the synergistic increase in IFN-γ production was achieved by the combined use of CTLA-4 antibody.

[0160] (Example 22: Example of CTLA-4+ expression in CD8+ T cells infiltrating the tumor by administering Extract Z) In this example, the increase in CTLA-4 expression of tumor-infiltrating CD8+ T cells by administering Extract Z was confirmed.

[0161] It was confirmed that by administering Extract Z, not only was the overall infiltration of CD8+ T cells promoted, but the infiltration of CTLA-4+CD8+ T cells that inhibited anti-tumor effects was also promoted.

[0162] (Example 23: Example of treatment using Extract Z, immune checkpoint inhibitors and radiation irradiation) In this example, the therapeutic effect obtained by using Extract Z, immune checkpoint inhibitors and radiation irradiation was confirmed.

[0163] The case was a 57-year-old male diagnosed with lung adenocarcinoma with EGFR gene mutation positive (exon 19 deletion), and clinical TNM classification of cT2aN2M1c and stage IVb.

[0164] After starting afatinib treatment in October 2015, cancer recurrence with the T790M mutation was confirmed in 2016, so osimertinib treatment was started in December 2016. Deterioration was confirmed in June 2017, so chemotherapy with cisplatin and pemetrexed was initiated, followed by treatment with erlotinib and bevacizumab, but deterioration was confirmed again. Therefore, in September 2017, nivolumab was started at 240 mg intravenously every two weeks. The results showed that although the primary lesion and lymph node metastasis had essentially disappeared, on November 6, 2020, deterioration of the primary tumor, multiple lung metastases, and metastasis to the right adrenal gland were confirmed.

[0165] Nivolumab continued to be administered, while the right adrenal metastasis was irradiated with 30 Gy / 10 fr and administered Extract Z four times from November 17 to November 28, 2020.

[0166] The result was that the tumor marker (CEA) value decreased from 35.3 to 22.7. Furthermore, as shown in the CT image in Figure 10, it was confirmed that after treatment (Extract Z injection + radiation irradiation), the primary lesion shrank slightly, and some intrapulmonary metastatic lesions shrank significantly.

[0167] It is believed that the synergistic effect obtained by administering nivolumab and Extract Z combined with radiation irradiation confirms the presence of a distant effect. Furthermore, it indicates that excellent treatment outcomes can be achieved even in patients who have undergone all standard treatments but still experience deterioration and require second-line treatment.

[0168] (Note) As described above, the present invention has been illustrated using preferred embodiments, but it should be understood that the scope of the invention should be interpreted solely by the claims. Regarding the patents, patent applications, and other documents referenced in this specification, it should be understood that their contents are specifically described in this specification and are therefore incorporated herein by reference. This application claims priority to Japanese Patent Application No. 2019-238657 filed on December 27, 2019, and Japanese Patent Application No. 2020-171493 filed on October 9, 2020, and it should be understood that their contents are incorporated herein by reference in their entirety. [Industrial Applicability]

[0169] The present invention provides a method for the prevention and treatment of diseases such as cancer based on an unprecedented mechanism. [Simplified Explanation of the Diagram]

[0171] Figure 1 is a block diagram showing the system configuration using the program in this embodiment. Figure 2 is a flowchart showing the treatment sequence in this embodiment. Figure 3 is a graph illustrating the time progression of the treatment method in Example 1. Figure 4 is a graph illustrating the time progression of the treatment method in Example 2. Figure 5 is a graph illustrating the time progression of tumor marker measurement values ​​and treatment method in Example 3. Figure 6 is a graph illustrating the time progression of tumor marker measurement values ​​and treatment method in Example 4. Figure 7 is a graph showing the increased production of the immune adjuvant CXCL10 in Example 13. Figure 8 is a graph showing the effect of promoting CD8+ T cell infiltration into the tumor in Example 15. Figure 9 is a graph showing the performance of PD-L1 in cultured Sq-1979 cells in Example 20. Figure 10 is a graph illustrating the time progression of the treatment method in Example 23. Figure 11 is a graph illustrating the time progression of tumor marker measurement values ​​and treatment method in Example 23.

Claims

1. The use of an immune checkpoint inhibitor in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors, characterized in that: the immune checkpoint inhibitor is used in combination with a dendritic cell direct activator or a dendritic cell direct activating method, wherein the dendritic cell direct activator or dendritic cell direct activating method comprises a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, and wherein the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B.

2. The use of a dendritic cell direct activator or a dendritic cell direct activating method in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer or tumors in a subject, characterized in that: the dendritic cell direct activator or dendritic cell direct activating method is administered in combination with an immune checkpoint inhibitor, the dendritic cell direct activator or dendritic cell direct activating method comprises a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, and the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B.

3. As claimed in claim 1, wherein the aforementioned dendritic cell direct activator or dendritic cell direct activation method comprises at least one selected from the group consisting of radiation therapy provision methods and immune adjuvants; the aforementioned dendritic cell direct activator or dendritic cell direct activation method comprises radiation therapy provision methods and immune adjuvants; the aforementioned immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4; or the aforementioned immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors; the aforementioned cancer or tumor exhibits immune checkpoint factors; the aforementioned immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab; the aforementioned cancer is lung cancer; and the aforementioned cancer or tumor has an EGFR gene mutation. The above treatment, prevention, or relapse prevention is administered to subjects who have received treatment with tyrosine kinase inhibitors; or to subjects who have not received treatment with immune checkpoint inhibitors; or to subjects who were deemed ineffective in treatment with immune checkpoint inhibitors; or to subjects who, although effective in treatment with immune checkpoint inhibitors, subsequently developed progressive disease (PD); or to subjects who, although effective in treatment with both tyrosine kinase inhibitors and immune checkpoint inhibitors, subsequently developed progressive disease (PD), and the subjects showed CXCL10 positivity in their tumors and had low CD8+ T cell counts.

4. As requested in claim 3, wherein the aforementioned cancer manifestation is PD-L1.

5. As claimed in claim 2, wherein the aforementioned dendritic cell direct activator or dendritic cell direct activation method comprises at least one selected from the group consisting of radiation therapy provision methods and immune adjuvants; the aforementioned dendritic cell direct activator or dendritic cell direct activation method comprises radiation therapy provision methods and immune adjuvants; the aforementioned immune checkpoint inhibitor comprises an inhibitor targeting at least one factor selected from the group consisting of PD-1, PD-L1, and CTLA-4; or the aforementioned immune checkpoint inhibitor comprises at least one agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors; the aforementioned cancer or tumor exhibits immune checkpoint factors; the aforementioned immune checkpoint inhibitor comprises at least one selected from the group consisting of nivolumab, pembrolizumab, and atezolizumab; the aforementioned cancer is lung cancer; and the aforementioned cancer or tumor has an EGFR gene mutation. The above treatment, prevention, or relapse prevention is administered to subjects who have received treatment with tyrosine kinase inhibitors; or to subjects who have not received treatment with immune checkpoint inhibitors; or to subjects who were deemed ineffective in treatment with immune checkpoint inhibitors; or to subjects who, although effective in treatment with immune checkpoint inhibitors, subsequently developed progressive disease (PD); or to subjects who, although effective in treatment with both tyrosine kinase inhibitors and immune checkpoint inhibitors, subsequently developed progressive disease (PD), and the subjects showed CXCL10 positivity in their tumors and had low CD8+ T cell counts.

6. As used in claim 5, wherein the aforementioned cancer manifestation is PD-L1.

7. A program product characterized in that: it is used to treat or prevent cancer in a patient, and causes a computer to perform the following steps: administering to the patient a first treatment using an immune checkpoint inhibitor, and / or any one or both of a dendritic cell direct activator or a dendritic cell direct activation method, wherein the dendritic cell direct activator or dendritic cell direct activation method comprises a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, wherein the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B; and determining the optimal treatment program based on the patient's response.

8. The program product as requested in item 7, wherein the patient's response is a specific change in the patient's medical images and the measured values ​​of the patient's tumor markers.

9. The use of an immune checkpoint inhibitor in the manufacture of a medicine for the prevention or treatment of cancer in a patient, characterized in that: the immune checkpoint inhibitor is administered in combination with a dendritic cell direct activator or a dendritic cell direct activating agent, wherein the dendritic cell direct activator or dendritic cell direct activating agent comprises a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, wherein the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B; and based on information on the optimal tumor marker (CEA) of the combination obtained from the patient, the method of administration and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell direct activator or dendritic cell direct activating agent with therapeutic or preventive effects are specified, and the medicine is administered based on the specified method of administration and dosage.

10. The use of a dendritic cell direct activator or dendritic cell direct activating method in the manufacture of a medicine for the prevention or treatment of cancer in a patient, characterized in that: the dendritic cell direct activator or dendritic cell direct activating method is administered in combination with an immune checkpoint inhibitor, the dendritic cell direct activator or dendritic cell direct activating method comprising a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, wherein the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B; and based on information on the optimal tumor marker (CEA) of the combination obtained from the patient, the method of administration and dosage of the combination of the immune checkpoint inhibitor and the dendritic cell direct activator or dendritic cell direct activating method having therapeutic or preventive effects are specified, and the medicine is administered based on the specified method of administration and dosage.

11. The use of an immune checkpoint inhibitor in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer, tumor, or tumor in a subject according to a specific regimen, the regimen comprising the steps of: administering the immune checkpoint inhibitor in combination with a dendritic cell direct activator, wherein the dendritic cell direct activator comprises a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, and wherein the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B.

12. The use of a dendritic cell direct activator in the manufacture of a medicine for the treatment, prevention, or recurrence prevention of cancer, tumors, or other cancers in a subject according to a specific protocol, the protocol comprising the steps of: administering the dendritic cell direct activator in combination with an immune checkpoint inhibitor, wherein the dendritic cell direct activator comprises a subcutaneous injection solution (Extract Z) containing lipoarabinomannan, nucleic acid, and lipids extracted from Mycobacterium tuberculosis, and wherein the Mycobacterium tuberculosis is Mycobacterium tuberculosis strain Aoyama B.

13. For any of the uses described in claims 1, 3, 4, 9, and 11, where the tested systems have not received treatment with immune checkpoint inhibitors, or have failed single-dose treatment with immune checkpoint inhibitors, in the specific regimens described above, the immune checkpoint inhibitor is i) nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks. The specific regimens further include: c) The procedure for implementing radiation therapy, wherein the radiation therapy is palliative irradiation other than brain metastasis, and is irradiated with 3 Gy for 10 times or with 2 Gy for 20 to 25 times, and the above Extract Z is administered by the following method: the drug solution is drawn into a 1 mL syringe and 0.05 mL of the drug solution is injected subcutaneously twice a week.

14. For any of the uses described in claims 2, 5, and 6, where the tested systems have not received treatment with immune checkpoint inhibitors, or have failed single-dose treatment with immune checkpoint inhibitors, in the specific regimens described above, the immune checkpoint inhibitor is i) nivolumab, administered at 240 mg every 2 weeks; ii) pembrolizumab, administered at 200 mg every 3 weeks, or at 400 mg every 6 weeks; or iii) atezolizumab, administered at 1200 mg every 3 weeks. The specific regimens further include: c) The procedure for implementing radiation therapy, wherein the radiation therapy is palliative irradiation other than brain metastasis, and is irradiated with 3 Gy for 10 times or with 2 Gy for 20 to 25 times, and the above Extract Z is administered by the following method: the drug solution is drawn into a 1 mL syringe and 0.05 mL of the drug solution is injected subcutaneously twice a week.

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