Antitumor effect potentiator

Abstract

Provided is a means for activating immune response in tumor immunotherapy using an immune checkpoint inhibitor. This antitumor effect potentiator uses an immune checkpoint inhibitor and comprises Bifidobacterium bifidum YIT10347 (FERM BP-10613) as an active ingredient.

Description

Antitumor effect enhancer

[0001] The present invention relates to an antitumor effect enhancer and a tumor immunity activator that activate tumor immune responses and thereby enhance antitumor effects.

[0002] Tumor immunotherapy is a therapy that inhibits or treats cancer progression by acting on the cancer patient's inherent immune surveillance mechanism and strengthening the patient's anti-cancer immunity. In recent years, it has been revealed that cancer cells themselves possess a system for evading the immune surveillance mechanism, and immune checkpoint molecules, such as CTLA-4, PD-1, and their ligand PD-L1, are known to be utilized by such evasion systems. It has also been reported that immune checkpoint inhibitors, which inhibit the function of these immune checkpoint molecules, are extremely useful for strengthening the patient's anti-cancer immunity (Patent Document 1). However, there are cancer patients for whom sufficient therapeutic effects are not observed even when the immune system is activated using immune checkpoint inhibitors, etc., and the development of further therapeutic methods is needed.

[0003] On the other hand, lactic acid bacteria such as Lactobacillus bacteria and Bifidobacterium bacteria have been shown to have various effects such as improving intestinal flora, improving fecal quality, improving intestinal function, protecting against infection, and stimulating the immune system. These bacteria are thought to contribute to human health by improving the intestinal environment, and are known as probiotics.

[0004] Non-Patent Document 1 reports that, when multiple Bifidobacterium bifidum strains were examined to see whether they affected the effects of immune checkpoint inhibitors, three of these Bifidobacterium bifidum strains, KCTC3357, KCTC3418, and MG731, and particularly KCTC3357, enhanced the antitumor effect of anti-PD-1 antibodies.

[0005] Patent No. 5885764

[0006] Se-Hoon Lee et al. Nat Microbiol. 6(3), 277-288, 2021

[0007] The present invention relates to providing a new means for activating immune responses in tumor immunotherapy using immune checkpoint inhibitors.

[0008] In light of these problems, the present inventors conducted extensive research and found that when specific bacteria belonging to Bifidobacterium bifidum are used in combination with immune checkpoint inhibitors, the antitumor effect is significantly enhanced and tumor immunity is activated.

[0009] That is, the present invention relates to the following 1) to 15). 1) An agent for enhancing the antitumor effect of an immune checkpoint inhibitor, comprising Bifidobacterium bifidum YIT 10347 (FERM BP-10613) as an active ingredient. 2) The agent for enhancing the antitumor effect of 1), wherein the immune checkpoint inhibitor is one or more selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, and an anti-CTLA-4 antibody. 3) An agent for activating tumor immunity, comprising Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor as active ingredients. 4) The agent for activating tumor immunity according to 3), which activates tumor immunity by increasing cytotoxic T cells. 5) A pharmaceutical comprising a combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor. 6) A pharmaceutical composition for combination with an immune checkpoint inhibitor, comprising Bifidobacterium bifidum YIT 10347. 7) Use of Bifidobacterium bifidum YIT 10347 for producing an agent for enhancing the anti-tumor effect of an immune checkpoint inhibitor. 8) Use of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for producing an agent for activating tumor immunity. 9) Use of a combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for producing a medicine. 10) Bifidobacterium bifidum YIT 10347 for use in enhancing the anti-tumor effect of an immune checkpoint inhibitor. 11) Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for use in activating tumor immunity. 12) A combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for use in a medicine. 13) A method for enhancing the antitumor effect of an immune checkpoint inhibitor, comprising administering Bifidobacterium bifidum YIT 10347 to a subject in need thereof. 14) A method for activating tumor immunity, comprising administering Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor to a subject in need thereof.15) A method for inhibiting the progression or recurrence of cancer or for treating cancer, comprising administering Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor to a subject in need thereof.

[0010] According to the present invention, tumor immunity can be activated, and it becomes possible to suppress the progression and recurrence of cancer or to treat cancer.

[0011] Antitumor effect of Bifidobacterium bifidum YIT 10347 or KCTC3357 in combination with immune checkpoint inhibitors. Effect of Bifidobacterium bifidum YIT 10347 or KCTC3357 in combination with immune checkpoint inhibitors on tumor-related T cells. Effect of Bifidobacterium bifidum YIT 10347 or KCTC3357 in combination with immune checkpoint inhibitors on the intestinal flora. Antitumor effect of Bifidobacterium bifidum YIT 10347 in combination with immune checkpoint inhibitors. Antitumor effect of Bifidobacterium bifidum YIT 10347 in combination with immune checkpoint inhibitors.

[0012] The bacterium belonging to Bifidobacterium bifidum used in the present invention is Bifidobacterium bifidum YIT 10347 (FERM BP-10613). In the present invention, Bifidobacterium bifidum YIT 10347 may be live or killed.

[0013] As the viable bacteria of Bifidobacterium bifidum YIT 10347, it is preferable to use a preparation (enterobacteria preparation) containing viable bacteria of Bifidobacterium bifidum YIT 10347. The content of Bifidobacterium bifidum YIT 10347 in such a preparation is not particularly limited, but may be, for example, 2 x 10 10 ~2 x 10 17 cells, preferably 2 x 10 11 ~2 x 10 16 cells.

[0014] The above-mentioned preparation may contain other ingredients within the scope that does not impair the effects of the present invention. Examples of other ingredients include minerals such as calcium, magnesium, zinc, iron, and dolomite, or salts thereof; acids such as citric acid, malic acid, ascorbic acid, lactic acid, acetic acid, and amino acids; additives such as collagen, chondroitin sulfate, hydroxyproline, flavones, flavonols, isoflavones, anthocyanins, catechins, and proanthocyanidins; and various vitamins such as vitamin A, vitamin B, vitamin C, vitamin E, vitamin D, vitamin K, beta-carotene, retinoic acid, and folic acid. These can be used alone or in combination of two or more.

[0015] Killed Bifidobacterium bifidum YIT 10347 cells can be obtained by subjecting live Bifidobacterium bifidum YIT 10347 cells to, for example, heat treatment, treatment with a drug such as an antibiotic, treatment with a chemical such as formalin, treatment with ultraviolet light, or treatment with radiation such as gamma rays. Of these treatments, ultrasonic treatment, enzyme treatment, and heat treatment are particularly preferred.

[0016] The dosage form of Bifidobacterium bifidum YIT 10347 is not particularly limited, and examples thereof include oral and enteral dosage forms, with oral dosage forms being preferred. Oral dosage forms include, for example, tablets (including sugar-coated tablets, enteric-coated tablets, and buccal tablets), powders, capsules (including enteric-coated capsules and soft capsules), granules (including coated granules), pills, lozenges, encapsulated liposomes, liquids, and pharmaceutical preparations such as sustained-release preparations thereof.

[0017] In formulating the formulation, additives such as carriers and excipients (e.g., lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, etc.), binders (e.g., starch, gelatin, glucose, galactose, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, etc.), disintegrants (e.g., starch, agar, gelatin, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, etc.), lubricants (e.g., magnesium stearate, hydrogenated vegetable oil, macrogol, etc.), stabilizers, flavorings, diluents, surfactants, solvents, etc. that are commonly used in ordinary pharmaceutical formulations can be used.

[0018] In the present invention, the term "immune checkpoint inhibitor" refers to a molecule that inhibits the function of immune checkpoint molecules such as CTLA-4, PD-1, or their ligand PD-L1. Examples of immune checkpoint inhibitors include anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab), PD-1 antagonists (e.g., AUNP-12), anti-CTLA-4 antibodies (e.g., ipilimumab and tremelimumab), and anti-LAG-3 antibodies (e.g., BMS-986016 and LAG525). Among these, from the viewpoint of enhancing the antitumor effect, an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, or an anti-CTLA-4 antibody is preferred, and an anti-PD-1 antibody or an anti-PD-L1 antibody is more preferred.

[0019] As shown in the Examples below, when used in combination with an immune checkpoint inhibitor, Bifidobacterium bifidum YIT 10347 enhances the antitumor effect of the immune checkpoint inhibitor. Therefore, Bifidobacterium bifidum YIT 10347 can serve as an enhancer of the antitumor effect of an immune checkpoint inhibitor. This enhancing effect is far superior to that of Bifidobacterium bifidum KCTC3357 (Non-Patent Document 1), which has been reported to enhance the antitumor effect of an anti-PD-1 antibody. Furthermore, the combined use of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor enhances CD8 expression in T cells in tumors. + T cells and Granzyme B + CD8 + Increases the proportion of T cells and IFN-γ in T cells + CD8 + T cells and Perforin + CD8 + Shows a tendency to increase the proportion of T cells. CD8 + T cells act as cytotoxic T cells and induce apoptosis in target cells such as cancer cells. One of the mechanisms of this action is the CD8 + It is known that T cells recognize specific antigens on target cells, become activated, and secrete cytotoxic granules containing granzymes, perforin, etc.; perforin polymerizes on the target cells to form pores; granzymes then invade the target cells and induce apoptosis. Specifically, the combined use of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor activates tumor immunity. Therefore, the combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor can serve as an antitumor immunity activator. Such an antitumor effect enhancer and tumor immunity activator using an immune checkpoint inhibitor can be used to inhibit cancer progression, prevent recurrence, and treat cancer. Furthermore, the antitumor effect enhancer and tumor immunity activator using an immune checkpoint inhibitor of the present invention can also reduce the dosage of the immune checkpoint inhibitor and alleviate side effects.

[0020] The cancers targeted by the antitumor effect enhancer or antitumor immunity activator using an immune checkpoint inhibitor of the present invention are not particularly limited and include any solid cancer and blood cancer, such as head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, gallbladder and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, testicular cancer, bone and soft tissue sarcoma, malignant lymphoma, leukemia, cervical cancer, skin cancer, and brain tumor. Of these, cancers for which tumor immunotherapy using an immune checkpoint inhibitor is effective are preferred.

[0021] In the present invention, Bifidobacterium bifidum YIT 10347 and the immune checkpoint inhibitor may be administered simultaneously, or Bifidobacterium bifidum YIT 10347 may be administered first, followed by the immune checkpoint inhibitor, or the immune checkpoint inhibitor may be administered first, followed by Bifidobacterium bifidum YIT 10347. The administration periods of Bifidobacterium bifidum YIT 10347 and the immune checkpoint inhibitor may be the same or different. For example, Bifidobacterium bifidum YIT 10347 is administered preferably before administration of the immune checkpoint inhibitor, more preferably at least one week before administration, even more preferably at least two weeks before administration, and even more preferably at least four weeks before administration. Furthermore, Bifidobacterium bifidum YIT 10347 is administered preferably until the end of administration of the immune checkpoint inhibitor, more preferably until one week after the end of administration, even more preferably until two weeks after the end of administration, and even more preferably until four weeks after the end of administration. The administration forms of Bifidobacterium bifidum YIT 10347 and the immune checkpoint inhibitor may be the same or different, as long as they are administered in a form appropriate for each. Furthermore, Bifidobacterium bifidum YIT 10347 and the immune checkpoint inhibitor can also be combined into a single pharmaceutical preparation as a kit.

[0022] In the antitumor effect enhancer or tumor immunity activator using an immune checkpoint inhibitor of the present invention, the dose of Bifidobacterium bifidum YIT 10347 varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 2 × 10 per day for an adult. 9 ~2 x 10 16 cells, preferably 2 x 10 10 ~2 x 10 15 It is preferable to administer the compound in a dose of 100 mg / kg / day or in divided doses several times a day within the range of 100 mg / kg / day.

[0023] The dose of the immune checkpoint inhibitor can be appropriately selected based on the dose used in clinical practice. In addition, any two or more immune checkpoint inhibitors may be administered in combination.

[0024] The present invention will be described in more detail by the following examples, but the scope of the present invention is not limited thereto. <Test samples> 1) Bifidobacterium bifidum Bifidobacterium bifidum YIT 10347 (FERM BP-10613) Bifidobacterium bifidum KCTC3357 (Korean Collection for Type Cultures) 2) Anti-PD-1 antibody "GoInVivo" TM Purified anti-mouse CD279 (PD-1) Antibody (BioLegend) (control antibody "InVivoMAb rat IgG2a isotype control, anti-trinitrophenol" (Bio X Cell)) 3) Anti-PD-L1 antibody "Ultra-LEAF" TM Purified anti-mouse CD274 (B7-H1, PD-L1) Antibody (BioLegend) (Control antibody "Rat IgG2b Isotype Control - Purified in vivo GOLD TM "Functional Grade" (Leinco Technologies)

[0025] Example 1 Antitumor Effect of Bifidobacterium bifidum Combined with Immune Checkpoint Inhibitor in MCA205 Cancer-Bearing Mouse Model Four-week-old female C57BL / 6NJcl mice were transplanted with the mouse fibrosarcoma cell line MCA205 cells to create a cell line transplanted mouse model. The mice were divided into a control (Vehicle) group, an anti-PD-1 antibody administration group, a Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group, and a Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group (n = 13). For Bifidobacterium bifidum, 1 × 10 9 CFU or more / mouse were orally administered daily for 36 days, and anti-PD-1 antibodies were administered intraperitoneally at 10 mg / kg every 3 days for 4 doses starting from the 7th day after tumor inoculation. Tumor volume was measured using a vernier caliper (Dunnett's test). Tumor volume was calculated by measuring the long and short diameters of the tumor and then multiplying the tumor volume by {(long diameter) × (minor diameter)}. 2 Using the tumor volume on day 7 after tumor inoculation as the reference, the relative tumor volume (%) was calculated using the formula (tumor volume at each measurement time point) / (tumor volume on day 7 after tumor inoculation) × 100.

[0026] The results are shown in Figure 1. Figure 1 shows that the relative tumor volume was significantly smaller in the Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group compared to the anti-PD-1 antibody administration group. On the other hand, no significant decrease in relative tumor volume was observed in the Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group. Bifidobacterium bifidum KCTC3357 has been reported to enhance the anti-tumor effect of anti-PD-1 antibodies in a mouse model transplanted with the mouse colon cancer cell line MC38 cells (Non-Patent Document 1), but it can be determined that Bifidobacterium bifidum YIT 10347 exerts a stronger enhancing effect than Bifidobacterium bifidum KCTC3357.

[0027] Example 2: Effect of combined use of Bifidobacterium bifidum and immune checkpoint inhibitor on tumor-bearing T cells in an MCA205 cancer-bearing mouse model Four-week-old female C57BL / 6NJcl mice were transplanted with the mouse fibrosarcoma cell line MCA205 cells to create a cell line transplanted mouse model. Mice were divided into a control (vehicle) group, an anti-PD-1 antibody administration group, a Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group, and a Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group. Bifidobacterium bifidum was administered at 1 x 10 once daily starting 14 days before cancer cell transplantation. 9 CFU or more / mouse were orally administered daily for 36 days, and anti-PD-1 antibody was administered intraperitoneally at 10 mg / kg every 3 days starting from the 7th day after tumor implantation. At the time of dissection, the tumor was collected and the cells were separated into single cells. The separated cells were labeled with antibodies specific to various immune cell marker proteins and identified using a flow cytometer. From the identification data, CD8 + T cells (CD3 + CD8 + ), IFN-γ + CD8 + T cells (CD3 + CD8 + IFN-γ + ), Granzyme B + CD8 + T cells (CD3 + CD8 + Granzyme B + ), Perforin + CD8 + T cells (CD3 + CD8 + Perforin + The proportion of cells in each cell population was measured (n=7, Dunnett's test).

[0028] The results are shown in Figure 2. As shown in Figure 2, CD8 + T cells and Granzyme B + CD8 +It was confirmed that the proportion of T cells was significantly increased in the Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group compared to the anti-PD-1 antibody administration group. On the other hand, no significant increase was observed in the Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group. In the Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group, IFN-γ in T cells was significantly increased. + CD8 + T cells, Perforin + CD8 + There was a tendency for the proportion of T cells to increase. Therefore, it was suggested that the effect of the combined use of Bifidobacterium bifidum YIT 10347 and anti-PD-1 antibody was mediated by an increase in the proportion and activation of cytotoxic T cells among T cells.

[0029] Example 3: Effect of Bifidobacterium bifidum / Immune Checkpoint Inhibitor Combination on Intestinal Microbiota in an MCA205 Cancer-Bearing Mouse Model Four-week-old female C57BL / 6NJcl mice were transplanted with the mouse fibrosarcoma cell line MCA205 cells to create a cell line transplanted mouse model. Mice were divided into a control (Vehicle) group, an anti-PD-1 antibody administration group, a Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group, and a Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group. Bifidobacterium bifidum was administered at 1 x 10 once daily starting 14 days before cancer cell transplantation. 9 CFU or more / mouse were orally administered daily for 36 days. For anti-PD-1 antibodies, the anti-PD-1 antibody was administered intraperitoneally at 10 mg / kg every three days for four doses starting on day 7 after tumor inoculation. Feces were collected the day before dissection, and 16S rRNA gene sequence data was obtained and analyzed using the Miseq system (Illumina Inc.) {n = 11 (Vehicle group), n = 13 (Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group), n = 13 (Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group), Steel's test}.

[0030] The results are shown in Figure 3. Figure 3 shows that, compared to the anti-PD-1 antibody administration group, the occupancy rate of the Rikenellaceae family in the intestinal flora increased and the occupancy rate of the Tannerellaceae family decreased in both the Bifidobacterium bifidum KCTC3357 + anti-PD-1 antibody administration group and the Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group. It was shown that the occupancy rate of the Eggerthellaceae family decreased only in the Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group. It has been reported that bacteria belonging to the Eggerthellaceae family occupy a lower rate in the intestinal flora in immune checkpoint inhibitor responders compared to non-responders (Park EM et al. Nat Med. 28(4), 690-703, 2022). The results in Figure 3 are consistent with these findings and support the activation of tumor immunity by the combined use of Bifidobacterium bifidum YIT 10347 and anti-PD-1 antibody.

[0031] Example 4 Antitumor Effect of Bifidobacterium bifidum YIT 10347 / Immune Checkpoint Inhibitor Combination in an MC38 Cancer-Bearing Mouse Model Five-week-old female C57BL / 6NCrl mice were transplanted with the mouse colon cancer cell line MC38 cells to create a cell line transplanted mouse model. Mice were divided into a control (Vehicle) group, an anti-PD-1 antibody administration group, and a Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group (n = 13). Bifidobacterium bifidum YIT 10347 (FERM BP-10613) was administered at a dose of 1 x 10 once daily starting 14 days before cancer cell transplantation. 9 CFU or more / mouse were orally administered daily for 36 days, and anti-PD-1 antibody was administered intraperitoneally at 10 mg / kg every 3 days for 5 doses starting from the 7th day after tumor implantation. Tumor volume was measured using calipers (Tukey's test). Tumor volume was calculated by measuring the long and short diameters of the tumor and then multiplying the tumor volume by {(long diameter) × (minor diameter)}. 2} / 2.

[0032] The results are shown in Figure 4. Figure 4 shows that the tumor volume was significantly smaller in the Bifidobacterium bifidum YIT 10347 + anti-PD-1 antibody administration group compared to the anti-PD-1 antibody administration group. Therefore, it can be concluded that Bifidobacterium bifidum YIT 10347 enhances the anti-tumor effect of the anti-PD-1 antibody.

[0033] Example 5 Antitumor Effect of Bifidobacterium bifidum YIT 10347 / Immune Checkpoint Inhibitor Combination in an MC38 Cancer-Bearing Mouse Model Eight-week-old female C57BL / 6NJ mice were transplanted with the mouse colon cancer cell line MC38 cells to create a cell line transplanted mouse model. Mice were divided into a control (Vehicle) group, an anti-PD-L1 antibody administration group, a Bifidobacterium bifidum YIT 10347 administration group, and a Bifidobacterium bifidum YIT 10347 + anti-PD-L1 antibody administration group (n = 10). Bifidobacterium bifidum YIT 10347 was administered at 1 x 10 once daily starting 14 days before cancer cell transplantation. 9 The anti-PD-L1 antibody was administered intraperitoneally at 2.5 mg / kg once every three days for a total of four doses starting from day 7 after cancer cell inoculation. On day 18 after cancer cell inoculation, the mice were dissected, and the tumors were excised and their weights (g) were measured.

[0034] The results are shown in Figure 5. Figure 5 shows that the tumor weight was significantly smaller in the Bifidobacterium bifidum YIT 10347 + anti-PD-L1 antibody administration group compared to the control group. On the other hand, no significant decrease in tumor weight was observed in the anti-PD-L1 antibody administration group or the Bifidobacterium bifidum YIT 10347 administration group. Therefore, it can be concluded that Bifidobacterium bifidum YIT 10347 enhances the anti-tumor effect of the anti-PD-L1 antibody.

Claims

1. An antitumor effect enhancer of immune checkpoint inhibitors, with Bifidobacterium bifidum YIT 10347 (FERM BP-10613) as the active ingredient.

2. The antitumor effect enhancer according to claim 1, wherein the immune checkpoint inhibitor is one or more selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, a PD-1 antagonist, and an anti-CTLA-4 antibody.

3. A tumor immunity activator containing Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor as active ingredients.

4. The tumor immunity activator according to claim 3, which activates tumor immunity by increasing cytotoxic T cells.

5. A medicine comprising a combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor.

6. A pharmaceutical composition containing Bifidobacterium bifidum YIT 10347 for use in combination with an immune checkpoint inhibitor.

7. Use of Bifidobacterium bifidum YIT 10347 for producing an agent that enhances the antitumor effect of immune checkpoint inhibitors.

8. Use of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for the production of an antitumor immune activator.

9. Use of a combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for the manufacture of a medicine.

10. Bifidobacterium bifidum YIT 10347 for use in enhancing the antitumor effect of immune checkpoint inhibitors.

11. Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for use in tumor immune activation.

12. A combination of Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor for use in medicine.

13. A method for enhancing the anti-tumor effect of an immune checkpoint inhibitor, comprising administering Bifidobacterium bifidum YIT 10347 to a subject in need thereof.

14. A method for activating tumor immunity, comprising administering Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor to a subject in need thereof.

15. A method for inhibiting the progression or recurrence of cancer, or for treating cancer, which comprises administering Bifidobacterium bifidum YIT 10347 and an immune checkpoint inhibitor to a subject in need thereof.

Images