CN114425080B - Application of bacteroides fragilis and PD-1 or PD-L1 antibody combined medicament in treatment of genitourinary system cancer - Google Patents
Application of bacteroides fragilis and PD-1 or PD-L1 antibody combined medicament in treatment of genitourinary system cancer Download PDFInfo
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- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
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Abstract
The invention discloses application of bacteroides fragilis and PD-1 antibody and/or PD-L1 antibody combined drug in preventing and treating genitourinary system tumor. A large number of experiments prove that the bacteroides fragilis, in particular to the bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685, can improve the immune cell state, strengthen the anti-tumor immune response of the organism and effectively prevent and treat the genitourinary system tumor by regulating the immune factor.
Description
The microbial strain used in the implementation process of the invention is preserved in China general microbiological culture Collection center (CGMCC) (No. 3 of North Chen West Lu 1 of the Korean area of Beijing city) in China general microbiological culture Collection center (CGMCC) of 4 months and 2 days of 2015. Classification naming: bacteroides fragilis ZY-312 (Bacteroides fragilis ZY-312) with the preservation number of CGMCC No.10685. Bacteroides fragilis ZY-312 was isolated by the applicant's entity and has been under the authority of the patent protection (patent No. 2015175508. X), and under the provisions of the patent prosecution guidelines, the public was able to buy from commercial sources or has been granted without preservation, i.e. without providing proof of preservation.
Technical Field
The invention relates to an application technology of bacteroides fragilis, in particular to an application of co-medication of bacteroides fragilis and a PD-1 antibody or a PD-L1 antibody in preventing and treating genitourinary system cancer.
Background
Cancer is the first or second largest cause of death in the current 112-national population and the third or fourth largest cause of death in the 23-national population, as counted by the 2019 World Health Organization (WHO). Cancer causes a huge disease burden.
Female reproductive system cancers include breast cancer, cervical cancer, ovarian cancer, and uterine body cancer. In women, gynaecological cancers (including the reproductive organs and breasts) are the most frequently occurring and dying neoplasms, the second leading cause of death worldwide. The breast cancer can obtain better curative effect through operation treatment, but losing the breast and female characteristics often brings heavy psychological pressure to patients, and affects family life. 13% of cervical cancer patients have advanced visits, whereas the 5-year survival rate for metastatic cervical cancer is only 16.5% with a median survival time of 8-13 months. Because of the heterogeneous nature of metastatic cervical cancer, there is currently no standard treatment. Ovarian cancer is the most fatal gynaecological malignancy. Surgery and chemotherapy are the primary treatments for ovarian cancer; however, patients often relapse within a few years after initial treatment due to chemotherapy resistance.
Urinary and male reproductive system cancers mainly include prostate cancer, bladder cancer, kidney cancer, and testicular cancer. According to the latest cancer statistics, prostate cancer, bladder cancer and kidney cancer respectively occupy the second, sixth and ninth of the global cancer incidence spectrum in 2020. Despite improvements in primary prevention, early detection and treatment, urinary system cancers are still characterized by increased morbidity and mortality worldwide and poor prognosis. Prostate cancer (PCa) is a major health problem in the world's elderly male population and is the fifth leading cause of cancer-related death worldwide. Androgen receptor plays a critical role in the development of PCa, androgen deprivation therapy being the first line treatment of newly diagnosed PCa patients. However, most patients develop castration resistant PCa, often associated with metastasis. Male bladder cancer (BCa) is three times more frequent than female. The more common surgical method for bladder tumors is transurethral bladder tumor electrotomy, and the postoperative patients need to be treated by conventional chemical drug infusion. MVAC (methotrexate, vincristine, pirarubicin and cisplatin) regimens are the first line of current bladder cancer chemotherapy (hereinafter referred to as chemotherapy), but the efficacy of bladder perfusion chemotherapy is not quite satisfactory. Although the disease condition of the patient can be effectively relieved and even cured after the conventional postoperative bladder perfusion chemotherapy, the recurrence rate is still as high as 60 percent. The malignancy of recurrent bladder tumor gradually increases, and finally, the recurrent bladder tumor develops into myometrial invasive bladder tumor. The incidence of Renal Cell Carcinoma (RCC) is steadily increasing in most parts of the world. Total or partial nephrectomy is the best primary treatment. However, RCC recurs in 20-40% of patients after resection, which is associated with worse tumor staging and grading. Some urinary tract malignancies are age-related and therefore, the incidence of them is highly likely to continue to rise due to aging of the global population.
For patients with tumor of reproductive system and urinary system without the opportunity of radical treatment or breast cancer patients with strong breast-protecting willingness and permission of physical condition, comprehensive treatment mainly comprising systemic drug treatment is adopted at present. Systemic drug therapy mainly includes chemotherapeutic drugs, molecular targeting drugs, and immunotherapeutic drugs.
Immunotherapeutic drugs are currently the most popular means of tumor treatment. Tumor immunotherapy mainly includes immune vaccine, immune checkpoint inhibitor therapy, adoptive immune cell therapy, cytokine therapy, and the like, wherein immune checkpoint inhibitor therapy has been attracting attention with its remarkable clinical efficacy.
The immune check point is a molecule with a protective function in the human immune system, has a brake-like function, and can prevent inflammatory injury caused by excessive activation of T cells. By utilizing the characteristic of the human immune system, the tumor cells inhibit the reaction of the human immune system by over-expressing immune checkpoint molecules, escape from the human immune monitoring and killing, thereby promoting the growth of the tumor cells. Inhibiting the expression of immune checkpoint molecules and ligands thereof can enhance the killing effect of T cells on tumors, thereby achieving the purpose of resisting tumors. Among the immune checkpoints that have been published are CTLA-4, PD-1/PD-L1, LAG-3, TIM-3, VISTA, A2aR, and the like.
Programmed cell death protein 1 (PD-1) is expressed on a variety of lymphocytes, especially on tumor-specific T cells. In the tumor microenvironment, it leads to expansion of malignant cells by interfering with the protective immune response. It has two ligands, programmed cell death ligands 1 and 2 (PD-L1, PD-L2), where PD-L1 is expressed by tumor cells to escape the anti-tumor response of the immune system to it. Blocking the action between PD-1 and PD-L1 can maintain T cell response after T cells enter tumor microenvironment, and ensure the anti-tumor action of T cells. Antibodies to PD-1/PD-L1 have been Nivolumab (Nivolumab), pembrolizumab (Pembrolizumab), JQ1, atuzumab (Atezolizumab), avistuzumab (Avelumab), and cimetiab Li Shan (Cemiplimab). These monoclonal antibodies are approved for the treatment of breast cancer, lung cancer, colorectal cancer, bladder cancer, pancreatic cancer, prostate cancer, and diffuse large B-cell lymphoma (DLBCL).
Although PD-1/PD-L1 antibodies have significant anti-cancer efficacy (overall progression free survival reaches 80%), clinical studies have shown that only 20-45% of patients respond to them. Intestinal microorganisms can affect the immune system of the host and even the efficacy of immune checkpoint inhibitors by their surface molecules (e.g. capsular polysaccharides, flagella, surface proteins, etc.) and metabolites (e.g. short chain fats, indoles, inosines, etc.). It has been reported that bifidobacteria play a promoting role in the efficacy of PD-1/PD-L1 antibodies. The combination of the bifidobacterium breve-bifidobacterium longum-PD-1 antibody may allow the melanoma growth to be almost completely stopped. Furthermore, high levels of a.mucinophilia and f.prausnitzii in the gut are associated with good response to PD-1 treatment.
Bacteroides fragilis (Bacteroides fragilis) are gram-negative, rod-shaped, round and dense at both ends, and have capsule, no spore, unpowered obligate anaerobic bacteria, which are divided into Enterotoxigenic (ETBF) and non-enterotoxigenic (NTBF), are part of normal flora in human and animal intestinal tracts, mainly exist in colon, and mucous membranes of respiratory tract, gastrointestinal tract and genitourinary tract can also colonize and grow. Researches show that the non-enterotoxigenic bacteroides fragilis (NTBF) has important probiotic effect. The cytokine IL-10, which regulates T cell expansion and produces a cell that blocks the development of pathogenic Th17 cells, has an anti-inflammatory effect and is considered to be a potential new generation of probiotics. Several studies have shown that NTBF is capable of secreting the anti-inflammatory cytokine IL-10, promoting Th1/Th2 cell balance, and is resistant to intestinal inflammation, and has therapeutic effects on DSS-induced colitis.
Although there is a good interaction between the intestinal flora and the PD-1/PD-L1 antibodies, no probiotics have emerged that have been developed specifically to enhance the efficacy of PD-1/PD-L1 antibodies. Therefore, it is necessary to explore the use of Bacteroides fragilis together with PD-1/PD-L1 antibodies to combat tumors of the reproductive and urinary systems.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an application of bacteroides fragilis and PD-1 antibody and/or PD-L1 antibody combined in preventing and treating genitourinary system tumor. A large number of experiments prove that the bacteroides fragilis, in particular to the bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685, can improve the immune cell state, strengthen the anti-tumor immune response of the organism and effectively prevent and treat the genitourinary system tumor by regulating the immune factor.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect, there is provided the use of bacteroides fragilis and an immune checkpoint inhibitor in the manufacture of a product for the prevention and/or treatment of a neoplasm of the genitourinary system.
In some embodiments, the bacteroides fragilis is one or more of a live bacterium, an inactivated bacterium with complete morphological structure, or an inactivated bacterium with incomplete morphological structure.
In some embodiments, the bacteroides fragilis is one or more of live bacteroides fragilis, inactivated, genetically recombined, engineered or modified, attenuated, chemically treated, physically treated or inactivated bacteroides fragilis, bacteroides fragilis lysate, bacteroides fragilis liquid culture supernatant.
In some embodiments, the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No. 10685.
In some of these embodiments, the genitourinary system tumor refers to a tumor that is diseased in the urinary system and/or reproductive system. Including breast and genital tumors in women, genital tumors in men, and urinary tumors. Preferably, one or more selected from breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, renal cancer, bladder cancer, testicular cancer.
In some of these embodiments, the immune checkpoint inhibitor comprises at least one of PD-1, PD-L2, CTLA-4, LAG-3, TIM-3, VISTA, A2aR antibodies; preferably, the immune checkpoint inhibitor is a PD-1 antibody and/or a PD-L1 antibody.
In some embodiments, the PD-1 antibodies include nano Wu Liyou mab (Nivolumab), palbociclizumab (Pembrolizumab), cimipp Li Shan mab (Cemiplimab), terlipp Li Shan mab (Torilimiab), xindi Li Shan mab (Cindilimab), carrilizumab (Camrelizumab), and other substances capable of binding to PD-1, blocking PD-1/PD-L1 signaling pathways, up-regulating T cell activation, and activating an endogenous anti-tumor immune response.
In some embodiments, the PD-L1 antibodies include Ab Zhu Shankang (Atezolizumab), avelumab (Avelumab), durvalumab (Durvalumab) and other substances capable of binding to PD-L1, blocking PD-1/PD-L1 signaling pathways, up-regulating T-cell activation, activating an endogenous anti-tumor immune response.
According to the invention, the product is a food or pharmaceutical product.
In some of these embodiments, the food product comprises milk powder, cheese, curd, yogurt, ice cream, or a fermented cereal. The food product may also be an animal food product, such as a feed or the like.
In some embodiments, the dosage form of the pharmaceutical product comprises a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation. The medicine comprises human medicine or animal medicine. In some of these embodiments, the drug administration cycle may be intermittent administration, periodic administration, continuous administration, or long-term administration.
In some of these embodiments, the bacteroides fragilis is administered concurrently with the PD-1 antibody and/or the PD-L1 antibody.
In some of these embodiments, the bacteroides fragilis is administered separately from the PD-1 antibody and/or the PD-L1 antibody.
In some embodiments, the bacteroides fragilis is administered orally or enemaically.
In a second aspect, a pharmaceutical composition for preventing and treating a tumor of the genitourinary system is provided, wherein the pharmaceutical composition comprises bacteroides fragilis and a PD-1 antibody and/or a PD-L1 antibody.
In some embodiments, the bacteroides fragilis is one or more of a live bacterium, an inactivated bacterium with complete morphological structure, or an inactivated bacterium with incomplete morphological structure.
In some embodiments, the bacteroides fragilis is one or more of live bacteroides fragilis, inactivated, genetically recombined, engineered or modified, attenuated, chemically treated, physically treated or inactivated bacteroides fragilis, bacteroides fragilis lysate, bacteroides fragilis liquid culture supernatant.
In some embodiments, the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No. 10685.
In some of these embodiments, the genitourinary system tumor comprises a female breast and reproductive organ tumor, a male reproductive organ tumor, and a urinary organ tumor. Preferably, one or more selected from breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, renal cancer, bladder cancer, testicular cancer.
In some embodiments, the PD-1 antibodies include nano Wu Liyou mab (Nivolumab), palbociclizumab (Pembrolizumab), cimipp Li Shan mab (Cemiplimab), terlipp Li Shan mab (Torilimiab), xindi Li Shan mab (Cindilimab), carrilizumab (Camrelizumab), and other substances capable of binding to PD-1, blocking PD-1/PD-L1 signaling pathways, up-regulating T cell activation, and activating an endogenous anti-tumor immune response.
In some embodiments, the PD-L1 antibodies include Ab Zhu Shankang (Atezolizumab), avelumab (Avelumab), durvalumab (Durvalumab) and other substances capable of binding to PD-L1, blocking PD-1/PD-L1 signaling pathways, up-regulating T-cell activation, activating an endogenous anti-tumor immune response.
According to the invention, the composition is a medicament.
In some embodiments, the dosage form of the medicament comprises a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation. The medicine comprises human medicine or animal medicine.
In some of these embodiments, the bacteroides fragilis is administered concurrently with the PD-1 antibody and/or the PD-L1 antibody.
In some of these embodiments, the bacteroides fragilis is administered separately from the PD-1 antibody and/or the PD-L1 antibody.
In some embodiments, the drug is administered orally or by enema.
In some of these embodiments, the drug administration period may be intermittent, periodic, continuous, or long-term.
The invention has the beneficial effects that:
a large number of experiments prove that the bacteroides fragilis, in particular to bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685, is combined with the PD-1 antibody and/or the PD-L1 antibody for application, and can improve the immune cell state, strengthen the anti-tumor immune response of an organism and effectively prevent and treat tumors of the reproductive system and the urinary system in vivo by regulating immune factors.
The bacteroides fragilis ZY-312 adopted by the invention does not contain BFT genes, is a non-toxigenic strain, and has acute toxicity proved that the strain has no pathogenicity to normal mice and nude mice (Wang Y, deng H, li Z, tan Y, han Y, wang X, du Z, liu Y, yang R, bai Y, bi Y, zhi F.safety Evaluation of a Novel Strain of Bacteroides fragilis.front Microbiol.2017Mar17; 8:435.). According to patent zl2015175508. X and scientific literature Xu W, su P, zheng L, fan H, wang Y, liu Y, lin Y, zhi f.in vivo Imaging of a Novel Strain of Bacteroides fragilis via Metabolic labeling. Front microbiol.2018oct 1;9:2298. The strain has better tolerance to gastric acid and bile salts, and can ensure survival and effective colonization in the stomach.
Drawings
FIG. 1 is a colony morphology of Bacteroides fragilis in example 1;
FIG. 2 is a gram-negative image of Bacteroides fragilis of example 1.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were all commercially available, and all cells were purchased from ATCC; all cell culture materials were purchased from Gibco; all experimental animals were purchased from Zhejiang Veitz laboratory animal technologies Co., ltd; or may be prepared by known methods. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer.
Unless defined otherwise or clearly indicated by context, all technical and scientific terms in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
EXAMPLE 1 preparation of live and inactivated Bacteroides fragilis liquid
The bacteroides fragilis ZY-312 strain is streaked and inoculated on a blood plate for anaerobic culture for 48 hours. Colony morphology, staining characteristics, size, sphere shape, distribution, etc. were observed.
Colony characteristics: after the bacteroides fragilis ZY-312 is cultured on a blood plate for 48 hours at 37 ℃, the bacteroides fragilis ZY-312 is slightly convex, semitransparent, white, smooth in surface and free from hemolysis, and the colony diameter is between 1mm and 3mm, as shown in figure 1.
Morphology under microscope: the bacteroides fragilis ZY-312 was subjected to gram-stain microscopic examination to show a typical rod shape for gram-negative bacteria, and was rounded at both ends to be densely stained, and the non-colored part in the middle of the thallus was formed as a cavitation, see FIG. 2.
And (3) selecting a single colony to inoculate in a plant source peptone liquid culture medium for fermentation culture for 8 hours (the temperature is 37 ℃) to obtain the bacterial liquid of the bacteroides fragilis ZY-312.
Obtaining the live bacterial liquid of the bacteroides fragilis ZY-312 by conventional heat inactivation to obtain the inactivated bacterial liquid of the bacteroides fragilis.
EXAMPLE 2 treatment of mouse 4T1 breast cancer transplantable tumor with Bacteroides fragilis in combination with PD-1 antibody
And (3) test design: 70 female BALB/c mice were selected and randomly divided into 7 groups according to weight interval, namely blank group, model group, ZY-312 (10) 10 CFU/alone), PD-1 antibody (PD-1 ab) group (commercial product number BE0146, available from BioXcell, hereinafter 200. Mu.g/alone), ZY-312 live bacteria-combined PD-1 antibody group, ZY-312 inactivated bacteria group (10) 10 cell/only), ZY-312 inactivated bacteria combined with PD-1 antibody, 10 per group. Except for the blank groups, the animals of each group were vaccinated under the fourth pair of mammary fat pads by 1X 10 6 4T1 cells with tumor volume up to 100-150mm 3 At (D0) start of group administration: starting from D0, animals in the blank group and the model group were orally administered 300. Mu.L of physiological saline daily, and 200. Mu.L of PBS was injected intraperitoneally twice a week; the corresponding drugs are given in the same frequency to each administration group, wherein the administration volume of the bacteroides fragilis bacterial liquid is 300 mu L, and the administration volume of the PD-1 antibody is 200 mu L. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. On day 14 post-dose (D14), all mice were euthanized and mice serum, tumor, spleen, stool, right cervical lymph, right axillary lymph were collected. All tumors were weighed and photographed. Tumors were divided into three, one frozen for cytokine detection, one fixed in formalin and one sent in vitro for flow analysis.
The detection item and method are as follows:
tumor volume and tumor growth inhibition rate: tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2 A and b represent the major and minor diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [1- (mean tumor volume at the end of dosing of a treatment group-mean tumor volume at the beginning of dosing of a treatment group)/(mean tumor volume at the end of treatment of isotype control group-mean tumor volume at the beginning of treatment of isotype control group) ]x100.
Relative tumor proliferation rate T/C (%): the calculation formula is as follows: T/C% = T RTV /C RTV ×100(T RTV : treatment group RTV; c (C) RTV : isotype control RTV). Calculating relative tumor volume (relative tumor volume, RTV) from the result of tumor measurement, the calculation formula being rtv=vt/V0, wherein V0 is the average tumor volume measured at the time of group administration (i.e. d 0), vt is the average tumor volume at a certain measurement, T RTV And C RTV The same day data was taken.
T cell subpopulations within spleen: flow cytometry analysis of intratumoral CD4 + T cells and CD8 + T cell ratio.
Cytokine detection: ELISA detects the content of IL-2 and IFN-gamma in the serum of mice.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
1. Test results
(1) Tumor volume, tumor weight and tumor growth inhibition rate
Table 1 tumor inhibition calculated based on tumor volume at day 14 after group administration
Note that:
a. mean ± SEM.
b. Tumor growth inhibition evaluation index is according to formula T/C% = T RTV /C RTV X 100% and TGI (%) = [1- (Ti-T0)/(Vi-V0)]X 100 calculation.
c. Based on tumor volume calculations, p-values between the two groups were calculated according to the unpaired t-test (one-tap) method.
TABLE 2 tumor suppression efficacy calculated based on tumor weight at day 14 after group administration
Note that:
a. mean ± SEM.
b. The tumor growth inhibition evaluation index is according to the formula T/C weight ＝TW treatment /TW Isotype control And (5) calculating.
c. Based on tumor weight calculation, the p-value between the two groups was calculated according to the unpaired t-test (one-charged) method.
From the above table, compared with the blank group, the transplanted tumor mice produced obvious tumor mass, and the molding was successful. Compared with a model group, when the PD-1 antibody and the bacteroides fragilis ZY-312 are independently used, the tumor growth speed is slowed down to a certain extent; but the tumor growth was significantly slowed down when ZY-312 was combined with PD-1 antibody. It can be seen that the combination of Bacteroides fragilis ZY-312 and PD-1 antibody can effectively inhibit tumor growth.
(2) T cell subpopulations
TABLE 3 spleen T cell subset ratio (mean+ -SD) for each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
As shown in the above table, the proportion of cd4+ T cells in the spleen to total cells was up-regulated to a different extent for each dosing group compared to the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-1 antibody group is significantly different from that of the model group, and is larger than that of the single administration group.
Each dosing group upregulated the proportion of cd8+ T cells in the spleen to total cells to a different extent than the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-1 antibody group is significantly different from that of the model group, and is larger than that of the single administration group.
It can be seen that bacteroides fragilis ZY-312 in combination with PD-1 antibody was able to up-regulate the proportion of cd4+ and cd8+ T cells in the spleen.
(3) Cytokine detection
Table 4 serum cytokine levels (mean+ -SD) for each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
As shown in the above table, serum IL-2 levels were up-regulated to varying degrees for each of the dosing groups compared to the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-1 antibody group is significantly different from that of the model group, and is larger than that of the single administration group.
The levels of serum IFN-gamma were up-regulated to varying degrees for each dosing group compared to the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-1 antibody group is significantly different from that of the model group, and is larger than that of the single administration group.
It can be seen that Bacteroides fragilis ZY-312 in combination with PD-1 antibodies was able to up-regulate the levels of cytokines IL-2 and IFN-gamma.
In conclusion, the Bacteroides fragilis ZY-312 combined PD-1 antibody can effectively prevent and treat breast cancer by enhancing the anti-tumor immunity of mice.
EXAMPLE 3 treatment of mice with Bacteroides fragilis in combination with PD-1 antibodies for ascites due to ovarian cancer in mice ID8
1. Test design and flow
70 female mice of 4-6 weeks of age C57BL/6 were randomly divided into 7 groups according to body weight interval, namely blank group, model group, ZY-312 (10) 10 CFU/only), PD-1 antibody (PD-1 ab) group (BE 0273, bioXcell 200. Mu.g/only), ZY-312 live bacteria combined PD-1 antibody group, ZY-312 inactivated bacteria group (10) 10 CFU/only), ZY-312 inactivated bacteria combined PD-1 antibody group (10) 10 CFU/only), 10 per group.
DMEM medium containing 10% calf serum, penicillin (100U/mL) and streptomycin (100U/mL) was used under conventional conditions (37 ℃, saturated humidity, 5% CO) 2 ) Culturing ID8 ovarian cancer cells to logarithmic phase, and adjusting cell concentration to 2×10 7 Each group of mice was intraperitoneally injected with 0.2mL of the cell suspension per mL, except for the blank group, which was intraperitoneally injected with 0.2mL of physiological saline.
Group dosing was started 3 weeks after inoculation (D0): starting from D0, animals in the blank group and the model group orally take 300 mu L of physiological saline every day, and 100 mu L of PBS is injected intraperitoneally every two days; the corresponding drugs are given in the same frequency to each administration group, wherein the administration volume of the bacteroides fragilis bacterial liquid is 300 mu L, the administration volume of the PD-1 antibody is 100 mu L, and the administration of the antibodies is carried out for 9 times. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. Two weeks after the last dose, all mice were euthanized and mice serum, ascites, tumors, spleen, faeces, right cervical lymph, right axillary lymph were collected. Tumors were divided into two parts, one fixed in formalin and one sent in vitro for flow analysis.
The detection item and method are as follows:
volume of ascites: 5mL syringe, 18 gauge needle to withdraw ascites.
Intratumoral T cell subpopulations: flow cytometry analysis of intratumoral CD3+CD4 + T cells and CD3+CD8 + T cell ratio.
Cytokine detection: ELISA detects the IL-2 content in ascites of mice.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Ascites volume
Table 5 ascites volume (mean.+ -. SD) of each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Mice were intraperitoneally injected with ID8 ovarian cancer cells to model ascites tumors. Compared with the blank group, the model group has obvious ascites performance and successful modeling. Compared with the model group, each administration group reduces the volume of ascites, and the volume of ascites of the PD-1 antibody group combined with the Bacteroides fragilis ZY-312 is obviously smaller than that of the model group.
(2) T cell subpopulations
TABLE 6 subsets of T cells within mice tumors (mean+ -SD)
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
The intraperitoneal tumors dispersed as small and fragile intraperitoneal nodules, attached to the mesentery of 2-7cm diameter. Tumor nodules present in each mouse were gently isolated from the mesentery and collected and made into cell suspensions for flow cytometry detection.
Compared with the model group, each administration group improves the proportion of CD3+CD8+T cells in living cells, and other groups except the ZY-312 group have obvious differences from the model group; the up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-1 antibody group is higher.
Compared with the model group, each administration group obviously improves the proportion of CD3+CD4+T cells in living cells, and the up-regulation amplitude of the bacteroides fragilis ZY-312 combined PD-1 antibody group is higher. This demonstrates that both PD-1 antibody and Bacteroides fragilis ZY-312 can increase the proportion of infiltrating T cells within the tumor.
(3) Cytokines and methods of use
TABLE 7 IL-2 content in ascites of mice in each group (mean.+ -. SD)
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
IL-2 is an immune activator, whose levels are responsive to effector T cell function. Compared with the model group, each administration group obviously improves the IL-2 level in ascites, and the up-regulation amplitude of the bacteroides fragilis ZY-312 combined PD-1 antibody group is higher. This suggests that both PD-1 antibody and Bacteroides fragilis ZY-312 can enhance effector T cell function.
In conclusion, the bacteroides fragilis can improve the ratio of infiltrating T cells in tumors, enhance the function of effector T cells and effectively prevent and treat ovarian cancer.
EXAMPLE 4 treatment of cervical cancer transplantable tumor in mice with Bacteroides fragilis in combination with PD-1 antibody
1. Test design and flow
70 female mice of 6-8 weeks of age C57BL/6 were randomly divided into 7 groups according to the weight interval, namely blank group, model group, ZY-312 (10) 10 CFU/only), PD-1 antibody (PD-1 ab) group (BE 0273, bioXcell 200. Mu.g/only), ZY-312 live bacteria combined PD-1 antibody group, ZY-312 inactivated bacteria group (10) 10 CFU/only), ZY-312 inactivated bacteria combined PD-1 antibody group (10) 10 CFU/only), 10 per group.
DMEM medium containing 10% calf serum, penicillin (100U/mL) and streptomycin (100U/mL) was used under conventional conditions (37 ℃, saturated humidity, 5% CO) 2 ) Culturing TC-1 cells to logarithmic phase, and adjusting cell concentration to 6×10 6 Each mouse was subcutaneously injected with 0.1mL of the cell suspension in the right underarm except for the blank, which was subcutaneously injected with 0.1mL of physiological saline in the right underarm.
Group dosing was started 7 days after inoculation (D0): starting from D0, animals in the blank and model groups were orally administered 300 μl of physiological saline daily, and 100 μl of PBS was injected intraperitoneally every seven days; the corresponding drugs are given in the same frequency to each administration group, wherein the administration volume of the bacteroides fragilis bacterial liquid is 300 mu L, the administration volume of the PD-1 antibody is 100 mu L, and the administration of the antibodies is 3 times. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. After one week of the last dose, all mice were euthanized and mouse serum, tumor, spleen, faeces, right cervical lymph, right axillary lymph were collected.
The detection item and method are as follows:
tumor weight and tumor growth inhibition rate: tumor inhibition = 100% (mean weight of tumors in model group-mean weight of tumors in dosing group)/mean weight of tumors in model group.
Cytotoxicity (Cytotoxicity Assay): the cytotoxicity of spleen cells was measured using a non-radioactive cytotoxicity method.
Cytokine detection: ELISA detects the expression of Vascular Endothelial Growth Factor (VEGF) and IL-10 in mouse tumors and the levels of IFN-gamma and IL-4 in spleen lymphocyte culture supernatants.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor weight and tumor growth inhibition rate
Table 8 tumor weights and tumor suppression rates (mean+ -SD) for each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Compared with the blank group, the model group is obviously neoplastic and the modeling is successful.
The tumor weight was reduced for each dosing group compared to the model group, with a significant difference for the bacteroides fragilis ZY-312 in combination with the PD-1 antibody group. This shows that the Bacteroides fragilis can effectively inhibit the growth of cervical cancer, and the combination effect of the Bacteroides fragilis ZY-312 and the PD-1 antibody is better.
(2) Cytotoxicity (Cytotoxicity Assay)
Table 9 spleen cytotoxicity (mean+ -SD) of mice in each group
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Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Cytotoxicity reflects the ability of immune cells to kill target cells. Compared with the model group, each administration group up-regulates the cytotoxicity of spleen cells on tumor cells, and the combination of the bacteroides fragilis ZY-312 and the PD-1 antibody group has obvious difference.
(3) Cytokines and methods of use
Table 10 groups of mouse cytokines (mean+ -SD)
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Cd4+ T cells are an important component of effector T cells and are classified into Th1, th2, treg and Th17 according to the cytokines produced and the biofunctional characteristics of effector cells. Th1 mainly secretes IFN-gamma and IL-2 to promote cellular immunity, while Th2 mainly secretes IL-4, IL-5, IL-10 and IL-13 to promote humoral immunity. Tumor cells can induce a shift in the polarization balance of Th1/Th2 towards Th2, thereby up-regulating the level of immunosuppressive cells regulating T cells. VEGF is a key mechanism of tumor angiogenesis and is also a major target for anti-angiogenic therapies for a variety of malignant tumors.
In the tumor microenvironment, the levels of VEGF and IL-10 were down-regulated by different magnitudes in each of the dosing groups compared to the model group, with the combination group being significant.
In the spleen, the ratio of IL-4/IFN-gamma was down-regulated by different magnitudes for each dosing group compared to the model group, with significance for the combination group. This suggests that the combination of Bacteroides fragilis with PD-1 antibodies can regulate the balance of Th1/Th2 and inhibit Th2 polarization.
The results show that the combination of the bacteroides fragilis and the PD-1 antibody can inhibit tumor angiogenesis and promote anti-tumor immune response.
In conclusion, the bacteroides fragilis can enhance CTLs function, promote anti-tumor immune response, inhibit tumor angiogenesis and effectively prevent and treat cervical cancer.
EXAMPLE 5 treatment of mice with Tramp-C1 prostate cancer transplantations with Bacteroides fragilis in combination with PD-1 antibodies
1. Test design and flow
Preparation of prostate transplantation tumor model
(1) Adopting 1640 culture solution containing 10% calf serum, 1% penicillin and streptomycin mixed solution under conventional conditions (37deg.C, saturated humidity, 5% CO 2 ) Culturing Tramp-C1 prostate cancer cells to logarithmic phase, and adjusting cell concentration to 1×10 8 And each mL. C57BL/6 male mice, under aseptic conditions, left inguinal subcutaneous injection of 0.1mL cell suspension, when the tumor grows to 2-3cm diameter, tumor-bearing mice were sacrificed as a source of tumor for transplantation.
(2) 70C 57BL/6 male mice were randomly divided into 7 groups according to body weight interval, namely blank group, model group, ZY-312 (10) 10 CFU/only), PD-1 antibody (PD-1 ab) group (BE 0273, bioXcell 200. Mu.g/only), ZY-312 live bacteria combined PD-1 antibody group, ZY-312 inactivated bacteria group (10) 10 CFU/only), ZY-312 inactivated bacteria combined PD-1 antibody group (10) 10 CFU/only), 10 per group. Tumor sources were divided into small pieces of 0.4cm in diameter, and the left inguinal skin of each mouse was implanted except for the blank group. One week later mice developed tumors. Blank groups were subjected to the same procedure but without tumor mass implantation.
Grouping dosing was started after tumorigenesis (D0): starting from D0, animals in the blank group and the model group were orally administered 300. Mu.L of physiological saline daily, and 100. Mu.L of PBS was injected intraperitoneally once a week; the corresponding drugs are given in the same frequency to each administration group, wherein the administration volume of the bacteroides fragilis bacterial liquid is 300 mu L, the administration volume of the PD-1 antibody is 100 mu L, and the administration of the antibodies is carried out for 7 times. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. Two weeks after the last dose, all mice were euthanized and mice serum, tumor, spleen, faeces, right cervical lymph, right axillary lymph were collected. Spleen and tumor were divided into two parts, one fixed in formalin and one sent in vitro for flow analysis.
The detection item and method are as follows:
tumor weight and tumor growth inhibition rate: tumor inhibition = 100% (mean weight of tumors in model group-mean weight of tumors in dosing group)/mean weight of tumors in model group.
T cell subpopulations: flow cytometry analyzed the proportion of spleen, intratumoral cd3+cd8+ T cells.
Cytokine detection: ELISA detects the content of IL-2, IFN-gamma and TNF-alpha in the serum of mice.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor weight and tumor growth inhibition rate
Table 11 tumor weight and tumor growth inhibition (mean+ -SD) for each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Compared with the blank group, the model group is obviously neoplastic and the modeling is successful.
Compared with the model group, the tumor weight of each administration group is reduced, and the tumor weight of the combined group is obviously reduced. The result shows that the bacteroides fragilis ZY-312 can inhibit the growth of prostate tumor, and the tumor inhibition effect of the ZY-312 combined PD-1 antibody is better.
(2) T cell subpopulations
Table 12 spleen and intratumoral T cell subsets (mean+ -SD) of mice in each group
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Compared with the model group, each administration group can up-regulate the proportion of spleen CD8+ T cells in CD3+ T cells, and the bacteroides fragilis ZY-312 combined PD-1 antibody group has significance.
Compared with the model group, each administration group can up-regulate the proportion of the intratumoral infiltrating CD8+ T cells in the CD3+ T cells, and the bacteroides fragilis ZY-312 combined PD-1 antibody group has significance. The results show that the bacteroides fragilis can increase the ratio of spleen and intratumoral infiltration effector T cells, and the combination effect of the bacteroides fragilis ZY-312 and the PD-1 antibody is better.
(3) Cytokines and methods of use
Table 13 serum cytokines (mean+ -SD) of mice in each group
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
IL-2, IFN-gamma and TNF-alpha are all immune activators. Compared with the model group, each administration group up-regulates the serum cytokine level, and the bacteroides fragilis ZY-312 combined PD-1 antibody group has significance. This shows that the Bacteroides fragilis can up-regulate the level of immune activating factor, and the combination effect of the Bacteroides fragilis ZY-312 and the PD-1 antibody is better.
In conclusion, the combination of the bacteroides fragilis and the PD-1 antibody can increase the number of effector T cells, up-regulate the level of immune activating factors, enhance the anti-tumor immune response of organisms and effectively prevent and treat the prostate cancer.
EXAMPLE 6 treatment of mouse MB49 bladder cancer transplants with Bacteroides fragilis in combination with PD-1 antibodies
1. Test design and flow
70C 57BL/6 mice with age of 6-8 weeks, each half of the male and female mice, were randomly divided into 7 groups according to weight interval, namely blank group, model group, ZY-312 (10) 10 CFU/only), PD-1 antibody (PD-1 ab) group (BE 0273, bioXcell 100. Mu.g/only), ZY-312 live bacteria combined PD-1 antibody group, ZY-312 inactivated bacteria group (10) 10 CFU/only), ZY-312 inactivated bacteria combined PD-1 antibody group (10) 10 CFU/only), 10 per group.
A1640 culture solution containing 10% calf serum, penicillin (100U/mL) and streptomycin (100U/mL) was used under conventional conditions (37 ℃, saturated humidity, 5% CO) 2 ) MB49 bladder cancer cells were cultured down to log phase and cell concentration was adjusted to 1X 10 6 Each group of mice was subcutaneously injected with 0.1mL of cell suspension at the back of the hind leg except for the blank group, which was subcutaneously injected at the back of the hind leg0.1mL of physiological saline was injected.
The day of inoculation (D0) began the group dosing: starting from D0, animals in the blank group and the model group orally take 300 mu L of physiological saline every day, and 100 mu L of PBS is injected intraperitoneally every four days; the corresponding drugs are given in the same frequency to each administration group, wherein the administration volume of the bacteroides fragilis bacterial liquid is 300 mu L, the administration volume of the PD-1 antibody is 100 mu L, and the administration of the antibodies is 4 times. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. After one week of the last dose, all mice were euthanized and mice were collected for blood, tumor, spleen, stool, right cervical lymph, and right axillary lymph. Tumors were divided into two parts, one fixed in formalin and one sent in vitro for flow analysis.
The detection item and method are as follows:
tumor weight and tumor growth inhibition rate: tumor inhibition = 100% (mean weight of tumors in model group-mean weight of tumors in dosing group)/mean weight of tumors in model group.
T cell subpopulations: flow cytometry analyzed the proportion of cd4+, cd8+ T cells in peripheral blood.
Cytokine detection: ELISA detects the content of IL-10, IL-12 and IFN-gamma in the serum of mice.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor weight and tumor growth inhibition rate
Table 14 tumor weight and tumor growth inhibition (mean+ -SD) for each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Compared with the blank group, the model group is obviously neoplastic and the modeling is successful.
Compared with the model group, the tumor weight of each administration group is reduced, and the tumor weight of the combined group is obviously reduced. The result shows that the bacteroides fragilis ZY-312 can inhibit the growth of bladder tumors, and the combined use of the ZY-312 and the PD-1 antibody has better tumor inhibiting effect.
(2) T cell subpopulations
Table 15 peripheral blood T cell subsets (mean+ -SD) of mice of each group
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Compared with the model group, the peripheral blood CD4+ and CD8+ T cell proportion of each administration group is increased, and the bacteroides fragilis ZY-312 combined PD-1 antibody group has significance. The result shows that the bacteroides fragilis can up-regulate the peripheral blood effector T cell proportion, and the combination effect of the bacteroides fragilis ZY-312 and the PD-1 antibody is better.
(3) Cytokines and methods of use
Table 16 serum cytokines from mice of each group
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Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Each cytokine was elevated in the model group compared to the blank group, indicating an immune response in the body against the tumor.
IL-10 is an immunosuppressive factor, and the PD-1 antibody group has elevated IL-10 levels compared to the model group; ZY-312 and the combination group down-regulated IL-10 levels. The combined set down-regulates the amplitude more.
IL-12, IFN-gamma is an immune activator, and each of the dosing groups up-regulated IL-12 levels compared to the model group. The combination group had significance.
Compared with the model group, each administration group significantly up-regulates IFN-gamma level, and the up-regulation amplitude of the combined group is larger.
The results show that the bacteroides fragilis can down regulate the level of the immunosuppressant factors and up regulate the level of the immune activator factors, and the combination effect of the bacteroides fragilis ZY-312 and the PD-1 antibody is better.
In conclusion, the combination of the bacteroides fragilis and the PD-1 antibody can increase the number of effector T cells, lower the level of an immunosuppressive factor, up-regulate the level of an immune activating factor, enhance the anti-tumor immunity of an organism and effectively prevent and treat bladder cancer.
EXAMPLE 7 treatment of mouse Renca renal cell carcinoma transplantations with Bacteroides fragilis in combination with PD-1 antibody
1. Test design and flow
70 male BALB/c mice of 6-8 weeks old were randomly divided into 7 groups according to weight interval, namely blank group, model group, ZY-312 (10) 10 CFU/alone), PD-1 antibody (PD-1 ab) group (BE 0146, bioXcell 200. Mu.g/alone), ZY-312 live bacteria combined PD-1 antibody group, ZY-312 inactivated bacteria group (10) 10 CFU/only), ZY-312 inactivated bacteria combined PD-1 antibody group (10) 10 CFU/only), 10 per group.
A1640 culture solution containing 10% calf serum, penicillin (100U/mL) and streptomycin (100U/mL) was used under conventional conditions (37 ℃, saturated humidity, 5% CO) 2 ) Culturing Renca renal cancer cells to logarithmic phase, and adjusting cell concentration to 2×10 7 Each mouse was subcutaneously injected with 50 μl of cell suspension in the left flank except for the blank group, which was subcutaneously injected with 50 μl of physiological saline in the left flank.
Tumor volume up to 500mm3 (D0) start group dosing: starting from D0, animals in the blank group and the model group orally take 300 mu L of physiological saline every day, and 100 mu L of PBS is injected intraperitoneally every three days; the corresponding drugs are given in the same frequency to each administration group, wherein the administration volume of the bacteroides fragilis bacterial liquid is 300 mu L, the administration volume of the PD-1 antibody is 100 mu L, and the administration of the antibodies is 3 times. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. D24, all mice were euthanized and mouse blood, tumor, spleen, faeces, right cervical lymph and right axillary lymph were collected. Tumors were divided into two parts, one fixed in formalin and one sent in vitro for flow analysis.
The detection item and method are as follows:
tumor weight and tumor growth inhibition rate: tumor inhibition = 100% (mean weight of tumors in model group-mean weight of tumors in dosing group)/mean weight of tumors in model group.
T cell subpopulations: flow cytometry analyzed the proportion of cd80+, cd86+ T cells in tumor draining lymph nodes.
Cytokine detection: ELISA detects the content of IL-2, IFN-gamma, IL-4 and IL-10 in the serum of mice.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor weight and tumor growth inhibition rate
Table 17 tumor weight and tumor growth inhibition (mean+ -SD) for each group of mice
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
Compared with the blank group, the model group is obviously neoplastic and the modeling is successful.
Compared with the model group, each administration group reduces the tumor weight, and the combination of the bacteroides fragilis ZY-312 and the PD-1 antibody group has obvious difference. The result shows that the bacteroides fragilis can inhibit the growth of kidney cancer, and the effect of the bacteroides fragilis ZY-312 combined with the PD-1 antibody is better.
(2) T cell subpopulations
Table 18 tumor draining lymph node T cell subsets (mean+ -SEM) of mice of each group
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
The dendritic cells express PD-L1 ligand, which can make the dendritic cells in a non-mature state and promote the tumor cells to generate immune escape. The system can promote the maturation of dendritic cells and strengthen the anti-tumor immune response of organisms theoretically by using the PD-1 antibody. Compared with the model group, each administration group improves the proportion of mature dendritic cells in the tumor drainage lymph node, and the PD-1 antibody and the Bacteroides fragilis ZY-312 combined PD-1 antibody group have obvious differences. The result shows that the bacteroides fragilis can promote the maturation of dendritic cells and enhance the anti-tumor immune response of organisms, and the effect is better when the bacteroides fragilis ZY-312 is combined with the PD-1 antibody.
(3) Cytokines and methods of use
Table 19 serum cytokines (mean+ -SD) of mice in each group
Note that: compared to the model group, x represents a significant difference p <0.05; * Represents a very significant difference p <0.01.
IL-2, IFN-gamma is a Th1 type cytokine, IL-4, IL-10 is a Th2 type cytokine. Compared with the model group, although the effect on the Th2 type cytokine is not great, the up-regulation amplitude of the combination PD-1 antibody group of the Bacteroides fragilis ZY-312 is larger than that of the two-drug single-use group. This shows that Bacteroides fragilis can regulate Th1/Th2 balance, enhance Th1 type immune response of organism, and further enhance anti-tumor immune response, and the effect is better when Bacteroides fragilis ZY-312 is combined with PD-1 antibody.
In conclusion, the combination of the Bacteroides fragilis ZY-312 and the PD-1 antibody can promote the maturation of dendritic cells, enhance Th1 type immune response of organisms and effectively prevent and treat renal cancer.
The present invention is capable of other and further embodiments and its several details are capable of modification and variation in light of the present invention, as will be apparent to those skilled in the art, without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (15)
1. Use of bacteroides fragilis and immune checkpoint inhibitor in the preparation of a product for preventing and/or treating genitourinary system tumor;
the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No. 10685;
the immune checkpoint inhibitor is a PD-1 antibody and/or a PD-L1 antibody;
the genitourinary system tumor is selected from one or more of breast cancer, cervical cancer, ovarian cancer, prostatic cancer, renal cancer and bladder cancer.
2. The use according to claim 1, wherein the bacteroides fragilis is one or more of live bacteria, inactivated bacteria with complete morphological structure or inactivated bacteria with incomplete morphological structure.
3. The use according to claim 1, wherein,
The bacteroides fragilis is one or more of live bacteroides fragilis and inactivated bacteroides fragilis.
4. The use according to any one of claims 1-3, wherein the PD-1 antibody comprises nano Wu Liyou mab (Nivolumab), pamglizumab (Pembrolizumab), cimip Li Shan antibody (Cemiplimab), terlipp Li Shan antibody (Toripalimab), singedi Li Shan antibody (Cindilimab), cerilizumab (Camrelizumab), and other substances capable of binding to PD-1, blocking PD-1/PD-L1 signaling pathway, up-regulating T cell activation, activating endogenous anti-tumor immune response.
5. The use according to any one of claims 1-3, wherein the PD-L1 antibody comprises alt Zhu Shankang (Atezolizumab), avistuzumab (Avelumab), divaruzumab (Durvalumab) and other substances capable of binding to PD-L1, blocking the PD-1/PD-L1 signaling pathway, up-regulating T cell activation, activating an endogenous anti-tumor immune response.
6. Use according to any one of claims 1-3, wherein the product is a pharmaceutical product.
7. The use according to claim 6, wherein,
the dosage forms of the medicine comprise pills, tablets, granules, capsules, oral liquid or tube feeding preparations.
8. The use according to claim 6, wherein,
the medicine comprises human medicine or animal medicine.
9. The use according to claim 6, wherein,
bacteroides fragilis is administered simultaneously with the PD-1 antibody and/or the PD-L1 antibody;
or, the bacteroides fragilis is administered separately from the PD-1 antibody and/or the PD-L1 antibody.
10. The use according to claim 6, wherein,
the bacteroides fragilis is administrated orally or by enema.
11. A pharmaceutical composition for preventing and treating a tumor of the genitourinary system, wherein the pharmaceutical composition comprises bacteroides fragilis and a PD-1 antibody and/or a PD-L1 antibody;
the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No. 10685;
the composition is a medicament;
the dosage forms of the medicine comprise pills, oral liquid or tube feeding preparations.
12. The composition of claim 11, wherein the composition comprises,
the medicament comprises human medicament or animal medicament.
13. The composition of claim 11, wherein the composition comprises,
bacteroides fragilis is administered simultaneously with the PD-1 antibody and/or the PD-L1 antibody;
or, the bacteroides fragilis is administered separately from the PD-1 antibody and/or the PD-L1 antibody.
14. The composition of claim 11, wherein the composition comprises,
the medicine is administrated orally or by enema.
15. The composition of claim 11, wherein the composition comprises,
the drug administration period may be intermittent administration, periodic administration, continuous administration, or long-term administration.
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| CN202210034082.6A CN114425080B (en) | 2022-01-12 | 2022-01-12 | Application of bacteroides fragilis and PD-1 or PD-L1 antibody combined medicament in treatment of genitourinary system cancer |
| PCT/CN2022/120026 WO2023134208A1 (en) | 2022-01-12 | 2022-09-20 | Application of bacteroides fragilis and pd-1 or pd-l1 antibody drug combination in treating genitourinary system cancer |
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| CN114425080B (en) * | 2022-01-12 | 2023-08-29 | 广州知易生物科技有限公司 | Application of bacteroides fragilis and PD-1 or PD-L1 antibody combined medicament in treatment of genitourinary system cancer |
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| CN109528775A (en) * | 2017-09-22 | 2019-03-29 | 中山大学 | Bacteroides fragilis is preparing the application in the drug for treating and preventing tumour |
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