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WO2020221293A1 - Flore intestinale liée à irae et procédé de traitement et de prévention d'irae - Google Patents

Flore intestinale liée à irae et procédé de traitement et de prévention d'irae Download PDF

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WO2020221293A1
WO2020221293A1 PCT/CN2020/087772 CN2020087772W WO2020221293A1 WO 2020221293 A1 WO2020221293 A1 WO 2020221293A1 CN 2020087772 W CN2020087772 W CN 2020087772W WO 2020221293 A1 WO2020221293 A1 WO 2020221293A1
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bacteria
lactobacillus
bifidobacterium
genera
genus
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袁向亮
何宝坤
于亮
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Shanghai Humap Medical Technology Co Ltd
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Shanghai Humap Medical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of immunotherapy, and specifically relates to intestinal flora related to tumor immunotherapy-related adverse reactions and treatment and prevention methods for tumor immunotherapy-related adverse reactions.
  • Immunotherapy represented by Immune Checkpoint Blockade is the latest and most effective method in the current malignant tumor treatment field.
  • ICB Immune Checkpoint Blockade
  • CAR T chimeric antigen receptor T-cells
  • immune-related adverse events Immune-Related Adverse Events, irAE
  • irAE immune-Related Adverse Events
  • a recent evaluative study on the lethal side effects of immune checkpoint inhibitors was published in the top oncology journal JAMA Oncology. The report summarized as many as 750 fatal immune-related adverse events.
  • These immune-related side effects can affect multiple organs and tissues such as the gastrointestinal tract, skin, liver, lung, cardiovascular, endocrine system, musculoskeletal and central nervous system.
  • irAE The occurrence of irAE is mainly related to the release of a large number of cytokines after immunotherapy such as ICB or CAR-T and the large infiltration of immune cells such as activated T cells in various organs.
  • the occurrence of irAE can affect or interrupt the process of ICB or CAR-T treatment, and severe cases can lead to the death of ICB or CAR-T treatment patients.
  • corticosteroids or other immunosuppressive drugs for severe irAE patients there is still a lack of targeted safe and effective treatment plans for related side effects in clinical practice.
  • digestive system toxicity that is, immune enteritis
  • irAEs digestive system toxicity
  • digestive system toxicity that is, immune enteritis
  • it is also the type of irAE that causes the most deaths and is grade 3-4.
  • ICB clinical treatment indications especially the combination of anti-CTLA-4 antibody and anti-PD-1/PDL-1 antibody, more and more patients will have irAE.
  • How to predict and treat immune-related adverse reactions induced by immunotherapy such as ICB or CAR-T is one of the clinically urgent problems to be solved. Therefore, designing a targeted treatment plan based on the occurrence mechanism of tumor immunotherapy irAE has important clinical significance for solving this problem.
  • intestinal microbes There are about 10 14 microbes living in the human intestine. These microbes are known as "intestinal flora". They affect the host's immune system, glucose and lipid metabolism and other pathophysiological processes. At the same time, changes in the intestinal flora are closely related to the effects of immunotherapy and the occurrence, severity, patient tolerance, and resistance to drug resistance.
  • the gastrointestinal irAE caused by ICB antibody is similar to inflammatory bowel disease. Diarrhea and inflammation of the small intestine and colon are the main causes, which can lead to imbalance of the intestinal flora.
  • the present invention provides at least one kind of bacteria from at least one genera of Akkermansia, Bifidobacterium, Lactobacillus, and Turicibacter, or at least two bacteria from at least two genera, or at least three bacteria from at least three genera, or all Four genera of bacteria, and optionally at least one bacteria from at least one of the genera Bacteroides, Enterococcus, Helicobacter, Parabacteroides, and Escherichia are used in the preparation of prevention or treatment of immune checkpoint inhibitors or chimeric antigens Application in bacterial products or medicines related to adverse reactions caused by tumor immunotherapy by receptor gene-modified cells.
  • the application is the application of bacteria of the genus Bifidobacterium and/or bacteria of the genus Lactobacillus in preparing a bacterial product or medicine for preventing or treating the related adverse reaction.
  • the related adverse reaction is caused by anti-PD-1 antibody/anti-PD-L1 antibody, or caused by anti-PD-1 antibody/anti-PD-L1 antibody and anti-CTLA-4 Both antibodies are co-administered or caused by CAR-T cell therapy.
  • the bacteria of the genus Bifidobacterium include B. bifidobacterium (B. bifidum), B. adolescentis (B. adolescentis), and B. infantis (B. infantis) , Bifidobacterium longum (B. longum), B. lactis (B. lactis) and B. breve (B. breve).
  • the bacteria of the genus Lactobacillus include Lactobacillus reuteri, Lactobacillus acidophilus, Lactobacillus bulgaricus, German milk Bacillus subsp. Bulgaria (Lactobicillus deibrueckii subsp, Bulgaricus), Lactobacillus brevis (Lactobicillus brevis), Lactobacillus lactis (Lactobicillus lactis), Lactobacillus rhammosus, Lactobacillus plantarum (Lactobicillus plantarum), Lactobacillus paracasei (Lactobicillus paracasei), Lactobacillus casei (Lactobicillus casei) and Lactobacillus helveticus (Lactobicillus helveticus).
  • the bacteria of the genus Lactobacillus are Lactobacillus reuteri and/or Lactobacillus rhamnosus.
  • the bacteria of the genus Bifidobacterium are Bifidobacterium breve and/or Bifidobacterium lactis.
  • the bacterium of the genus Lactobacillus is Bifidobacterium lactis, such as HN019; and the bacterium of the genus Bifidobacterium is Lactobacillus rhamnosus, such as NH001.
  • the application is that bacteria of the genus Bifidobacterium (such as Bifidobacterium breve and/or Bifidobacterium lactis) are prepared for prevention or treatment by anti-PD-1 antibody/anti-PD- Related adverse reactions caused by L1 antibody, or related adverse reactions caused by the co-administration of anti-PD-1 antibody/anti-PD-L1 antibody and anti-CTLA-4 antibody, or related adverse reactions caused by CAR-T cell therapy
  • bacteria of the genus Bifidobacterium such as Bifidobacterium breve and/or Bifidobacterium lactis
  • the present invention also provides a bacterial product or pharmaceutical composition containing at least one bacteria from at least one genera of Akkermansia, Bifidobacterium, Lactobacillus and Turicibacter, or at least two bacteria from at least two genera, or at least At least three bacteria from three genera, or bacteria from all four genera, and optionally at least one bacteria from at least one of the genera Bacteroides, Enterococcus, Helicobacter, Parabacteroides, and Escherichia.
  • the bacterial product or pharmaceutical composition contains at least Lactobacillus reuteri (Lactobaccillus reuteri) from the genus Lactobacillus.
  • the bacterial product or pharmaceutical composition does not simultaneously contain Bifidobacterium lactis HN019 and Lactobacillus rhamnosus NH001.
  • the bacterial product or pharmaceutical composition contains bacteria of the genus Bifidobacterium and bacteria of the genus Lactobacillus, wherein the bacteria of the genus Lactobacillus at least include Reus Lactobacillus (Lactobaccillus reuteri);
  • the bacterial product or pharmaceutical composition further contains any one or both of Bifidobacterium lactis (such as HN019) and Lactobacillus rhamnosus (such as NH001).
  • the bacterial product or pharmaceutical composition contains bacteria of the genus Bifidobacterium and bacteria of the genus Lactobacillus, but does not simultaneously contain Bifidobacterium lactis HN019 and rhamnose Lactobacillus NH001.
  • the bacterial product or pharmaceutical composition contains Lactobacillus reuteri, optionally Bifidobacterium breve, Bifidobacterium lactis, and rhamnose Any one or more of Lactobacillus. In some embodiments, the bacterial product or pharmaceutical composition contains Lactobacillus reuteri and Bifidobacterium breve, and optionally Bifidobacterium lactis and/or Lactobacillus rhamnosus.
  • the pharmaceutical composition further contains immune checkpoint inhibitors and/or chimeric antigen receptor gene-modified cells for tumor immunotherapy.
  • the present invention also provides a detection kit, which contains: reagents for detecting intestinal bacteria of the following genera: Escherichia/Shigella, Lactobacillus, Bacteroides, unclassified, Allobaculu, Barnesiella, Parabacteroides, Romboutsia, Enterococcus, Alistipes, Helicobacter, Olsenella , Bifidobacterium, Akkermansia, Blautia, Klebsiella, Clostridium XlVa, Parasutterella, Clostridium XVIII, Turicibacter, Veillonella, Bilophila, Desulfovibrio, Clostridium sensu stricto, Clostridium sensu stricto, Clostridium sensu stricto, Clostridium s Reagents: Akkermansia, Helicobacter, Mycoplasmataceae, Bacteroides, Dehalobacterium, Lactobacillus, Clostridium, Lachnospiraceae, Anaero
  • the present invention also provides the application of a reagent selected from the following in the preparation of a diagnostic kit for diagnosing side effects induced by immune checkpoint inhibitors or chimeric antigen receptor gene-modified cell therapy: reagents for detecting intestinal bacteria of the following genera: Escherichia/Shigella, Lactobacillus, Bacteroides, unclassified, Allobaculu, Barnesiella, Parabacteroides, Romboutsia, Enterococcus, Alistipes, Helicobacter, Olsenella, Bifidobacterium, Akkermansia, Blautia, Klebsiutterella, Clostridium as Xlophila, Clostridium as XlVa Clostridium sensu stricto, Clostridium IV, Flavonifractor, Eubacterium, and Pseudoflavonifractor; or reagents used to detect intestinal bacteria of the following genera: Akkermansia, Helicobacter, Mycoplasmataceae
  • Figure 1 is a schematic diagram of the intestinal irAE mouse model. Among them: (A) the survival rate of mice in the model control group (DSS alone) and the treatment group (DSS+ICB); (B) the cytokine content in the blood of the control group and the ICB treatment group.
  • Figure 2 shows the change analysis of intestinal flora in the intestinal irAE mouse model.
  • A normal group (Nor), model control group (Ctrl) and ICB treatment group (ICB) mice intestinal flora composition (Genus level);
  • B normal group (Nor), model control group (Ctrl) and ICB treatment group (ICB) mice intestinal flora contained the relative abundance of main bacteria (Genus level).
  • FIG. 3 is a schematic diagram of a whole body irAE mouse model. Among them: (A) the survival rate curve of the colon of wild-type mice (WT) and Foxp3 knockout (MT) mice; (B) TNF- ⁇ , IL-6, IFN- ⁇ in the blood of WT and MT mice The content of cytokines.
  • WT wild-type mice
  • MT Foxp3 knockout mice
  • Figure 4 shows the composition and change analysis of the intestinal flora in whole-body irAE mice. Among them: (A) cluster analysis of intestinal flora in wild-type (WT) and knockout (MT) mice; (B) relative abundance of main bacteria in intestinal flora in WT and MT mice ( Genus level).
  • Figure 5 is an analysis of the ability of different intestinal bacteria to classify wild-type and knockout mice.
  • Figure 6 shows the results of studies on the survival rate and intestinal inflammation of mice that supplemented with lactobacillus to improve intestinal side effects. Among them: (A) the survival rate of mice in the model control group (Ctrl) and the lactobacillus (L.reuteri) treatment group (LR); (B) the TNF- ⁇ and IL- in the blood of the control group and the lactobacillus group 6. The content of IFN- ⁇ and other cytokines.
  • Figure 7 shows the results of studies on supplementation of Bifidobacterium breve to improve the survival rate and systemic inflammation in mice with systemic side effects. Among them: (A) the survival rate of knockout mice in the control group (MTC) and B.breve (B.breve) treatment group (MTB); (B) TNF- ⁇ in the blood of mice in the MTC group and MTB group , IL-6, IFN- ⁇ and other cytokines.
  • Figure 8 shows the research results of the effect of mixed bacteria preparations on improving the survival rate and systemic inflammatory response in mice with systemic side effects.
  • A the survival rate of knockout mice in the control group (MTC) and mixed bacteria preparation (B.breve+L.reuteri) treatment group (MTBL);
  • B the survival rate of mice in the MTC group and the MTBL group TNF- ⁇ , IL-6, IFN- ⁇ and other cytokines content.
  • the present invention simulates clinical ICB or CAR-T and other treatment-related side effects, and screens key intestinal flora that affect irAE.
  • the screening and identification of these key intestinal flora that affect irAE has important clinical application value for the judgment of the side effects of clinical tumor immunotherapy and the development of treatment strategies for these key intestinal flora.
  • tumor immunotherapy refers to a treatment method that controls and eliminates tumors by restarting and maintaining the tumor-immune cycle, restoring or enhancing the body's normal anti-tumor immune response.
  • Tumor immunotherapy includes the use of therapeutic antibodies such as immune checkpoint inhibitors (ICB) represented by CTLA-4 antibodies and PD1/PD-L1 antibodies, cancer vaccines, cellular immunotherapy (such as CAR-T, etc.) and to enhance immunity Treatment with small molecule compounds for the purpose of responding or eliminating immunosuppressive reactions.
  • the present invention particularly relates to tumor immunotherapy using immune checkpoint inhibitors or CAR-T.
  • ICB includes but is not limited to anti-PD-1 antibody/anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-TIM-3 antibody, anti-CD47 antibody, anti-IL-2R antibody, anti-TIGIT Antibodies, anti-VISTA antibodies and bispecific antibodies, etc.
  • Exemplary anti-PD-1 antibodies/anti-PD-L1 antibodies include, but are not limited to, terreplimumab, nivolumab, pembrolizumab, sintilizumab, tisleli Tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, MEDI0680, BMS936559 and SHR-1210.
  • Exemplary anti-CTAL-4 antibodies include Ipilimumab, Tremelimumab, and the like.
  • ICB includes not only drugs that have been approved for marketing, but also ICB that is undergoing clinical development or preclinical research.
  • chimeric antigen receptor gene-modified cell therapy includes various CAR-T cells or CAR-NK cells that target tumor cell surface antigens known in the art, such as targeting mesothelin, Her2, MUC1, ErbB, EGFR , CD19, CD40 and Claudin18 CAR-T cells.
  • CAR-T includes both CAR-T treatments that have been approved for marketing, as well as CAR-T or CAR-NK gene-modified cell therapies that are undergoing clinical development or preclinical research.
  • the tumors described herein can be various cancers known in the art that can be treated with tumor immunotherapy.
  • Specific examples of cancers include, but are not limited to, esophageal squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, acute myelogenous leukemia, multiple Myeloma, stomach cancer, kidney cancer, ovarian cancer, liver cancer, leukemia, colon cancer, rectal cancer, endometrial cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, pleomorphism Glioblastoma, cervical cancer, brain cancer, bladder cancer, hepatocellular tumor, breast cancer, and head and neck cancer.
  • the tumor specifically includes those cancers that are routinely treated with anti-PD-1 antibodies/anti-PD-L1 antibodies and anti-CTLA-4 antibodies in the art, such as melanoma, non-small cell lung cancer, and renal Cell carcinoma, classic Hodgkin’s lymphoma, head and neck squamous cell carcinoma and bladder epithelial carcinoma.
  • cancers that are routinely treated with anti-PD-1 antibodies/anti-PD-L1 antibodies and anti-CTLA-4 antibodies in the art, such as melanoma, non-small cell lung cancer, and renal Cell carcinoma, classic Hodgkin’s lymphoma, head and neck squamous cell carcinoma and bladder epithelial carcinoma.
  • adverse events related to ICB treatment or immune-related adverse reactions (irAE) induced by chimeric antigen receptor gene-modified cells have the same meaning, and refer to ICB or chimeric antigen receptor
  • irAE immune-related adverse reactions
  • ICB or chimeric antigen receptor gene modified cells include almost all organs, including gastrointestinal tract, skin, liver, lung, cardiovascular, endocrine system, musculoskeletal and central nervous system, such as maculopapular skin rash , Vitiligo, psoriasis, Lyle syndrome, drug-related delayed hypersensitivity to multiple organs, etc., enterocolitis, gastritis, pancreatitis, celiac disease of the gastrointestinal tract, hyperthyroidism or hypothyroidism of endocrine organs, pituitary gland Inflammation, adrenal insufficiency, diabetes, etc., lung immune pneumonia, pleurisy and pulmonary sarcoma, etc., peripheral neuropathy of the peripheral and central nervous system, aseptic meningitis, Guillain-Barre syndrome, cranial neuropathy, myelitis , Meningoencephalitis and myasthenia, etc., immune hepatitis of the liver, interstitial ne
  • irAE particularly refers to irAE caused by tumor immunotherapy using anti-PD-1 antibody/anti-PD-L1 antibody and/or anti-CTLA-4 antibody.
  • subject can be used interchangeably, including any organisms, preferably animals, more preferably mammals (eg rats, mice, dogs, cats, rabbits, etc.), and most preferably humans.
  • mammals eg rats, mice, dogs, cats, rabbits, etc.
  • treatment refers to any type of intervention or process performed on a patient, or administration of an active agent to a patient, with the purpose of reversing, alleviating, improving, slowing down or preventing symptoms, complications (such as irAE) or the onset, progression, or severity of symptoms Sex or recurrence, or biochemical indicators related to the disease.
  • ICB especially anti-PD-1 antibody/anti-PD-L1 antibody and / Or anti-CTLA-4 antibody
  • chimeric antigen receptor gene modified cells such as CAR-T cells
  • the present invention finds that, using the treatment or prevention protocol described herein, such as administering a preventive dose or a therapeutically effective amount of bacteria described herein, intestinal innate lymphoid cells (ILCs), especially the first
  • ILC3 intestinal innate lymphoid cells
  • the number and function of ILC3 of the three types of innate lymphocytes have been significantly reduced, so the local and systemic excessive inflammation of the intestinal tract can be significantly reduced, thus realizing the prevention or treatment of immunotherapy-related adverse reactions such as ICB or CAR-T.
  • the present invention provides a bacterial product containing bacteria (also referred to herein as "active bacteria") including at least one bacteria from at least one of the genus Akkermansia, Bifidobacterium, Lactobacillus, and Turicibacter , Or at least two bacteria from at least two genera, or at least three bacteria from at least three genera, or bacteria from all four genera.
  • active bacteria also referred to herein as "active bacteria”
  • the various and genus names related to bacteria are names commonly used in the art, and the range of strains covered by them is a range well known in the art.
  • Bifidobacterium bacteria may include Bifidobacterium bifidum, Bifidobacterium adolescentis (B.adolescentis), B. infantis (B.infantis), Bifidobacterium longum (B.longum), Bifidobacterium lactis (B. lactis) and B. breve (B. breve).
  • Bacteria of the genus Lactobacillus may include Lactobacillus reuteri, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus deibrueckii subsp (Bulgaricus), Lactobacillus brevis (Lactobicillus brevis), Lactobacillus lactis (Lactobicillus lactis), Lactobacillus rhamnosus (Lactobicillus rhammosus), Lactobacillus plantarum (Lactobicillus plantarum), Lactobacillus paracasei (Lactobicillus paracasei), Lactobacillus casei (Lactobicillus casei), Swiss milk Bacillus (Lactobicillus helveticus) and so on.
  • bacterial suitable for the present invention may also be various subspecies well known in the art, including various bacteria deposited in various depository units.
  • Bifidobacterium breve may include the deposit number ATCC 15698, ATCC 15700 and ATCC 15701 Bifidobacterium breve.
  • the bacterial product of the present invention may contain bacteria from the same genus and species, or two or more bacteria from the same genus and different species.
  • the bacteria contained in the bacterial products described herein include probiotics.
  • probiotics are designated as the general term for active and beneficial microorganisms that are planted in the human intestines and reproductive system, which can produce definite health effects to improve the host's microecological balance and exert beneficial effects.
  • Probiotics in humans and animals include but are not limited to bacteria of the genus Bifidobacterium and Lactobacillus. Therefore, in some embodiments, the bacterial product of the present invention contains at least bacteria from the genus Bifidobacterium, or at least bacteria from the genus Lactobacillus.
  • the bacterial product of the present invention contains at least bacteria from the genus Bifidobacterium and bacteria from the genus Lactobacillus. In some embodiments, the bacterial product of the present invention contains at least Lactobacillus reuteri (Lactobaccillus reuteri), for example, the deposit number is ATCC 55730, ATCC 23272, ATCC PTA-4964, ATCC PTA-4965, ATCC PTA-4659, ATCC PTA- 5290, ATCC PTA-4659, ATCC 55148, ATCC 53608 and ATCC PTA-6475 any one or more of Lactobacillus reuteri.
  • the probiotic in the bacterial product of the present invention is Lactobacillus reuteri (Lactobaccillus reuteri), or Lactobacillus reuteri (Lactobaccillus reuteri) and at least one bacterium from the genus Bifidobacterium such as short A mixture of Bifidobacterium breve; in addition to the Lactobacillus reuteri and optionally bacteria from the genus Bifidobacterium, the bacterial product of the present invention may also contain one or more species from the genus Akkermansia and/or Turicibacter Bacteria of the genus.
  • the Bifidobacterium breve of the present invention is Bifidobacterium breve with the deposit number ATCC 15698, ATCC 15700, or ATCC 15701.
  • the bacterial product of the present invention may also contain any one or more bacteria from any one or more of the genera Bacteroides, Enterococcus, Helicobacter, Parabacteroides, and Escherichia.
  • the content of bacteria in the bacterial product of the present invention can range from 1 ⁇ 10 10 cfu viable bacteria/g bacterial product to 1 ⁇ 10 12 cfu viable bacteria/g bacterial product.
  • the content of various bacteria can be the same, or can be formulated according to the content of intestinal bacteria detected by the patient.
  • the content of the Bifidobacterium bacteria in the probiotic of the present invention can Higher than Lactobacillus bacteria.
  • the bacterial products described herein may also contain prebiotics, such as carbohydrates, soybeans, peas, oats, asparagus, artichokes, onions, wheat, chicory, pectin, guar gum, gum arabic or their random combination.
  • prebiotics such as carbohydrates, soybeans, peas, oats, asparagus, artichokes, onions, wheat, chicory, pectin, guar gum, gum arabic or their random combination.
  • Any suitable carbohydrate can be used, such as sucrose, lactose, glucose, fructose, corn syrup solids, sucrose, maltodextrin, starch, and mixtures thereof.
  • the bacterial products described herein can also be added with dietary fiber, including soluble or insoluble.
  • Suitable sources of dietary fiber include but are not limited to soybeans, peas, oats, pectin, guar gum, acacia, fructooligosaccharides, galactooligosaccharides, and the like.
  • the bacterial products described herein can also contain minerals and micronutrients, including vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, and muscle Alcohol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine . Minerals are usually added in salt form.
  • the bacterial product of the present invention may be in the form of a solid dispersion or a liquid form, suspension, capsule, ready-to-drink beverage, food supplement, and the like.
  • the bacterial product of the present invention can be made into a form of medicine for the treatment or prevention of ICB (especially anti-PD-1 antibody/anti-PD-L1 antibody and/or anti-CTLA-4 antibody) or chimeric antigen receptor gene modification Cells (such as CAR-T cells) and other immunotherapy induced irAE. Therefore, in some embodiments, the application provides a medicament or pharmaceutical composition, which contains the bacteria or bacterial product described in any of the embodiments herein and a pharmaceutically acceptable carrier or excipient.
  • the active bacteria contained in the pharmaceutical composition of the present invention include at least the probiotic bacteria described herein, preferably Lactobacillus reuteri (Lactobaccillus reuteri), such as the deposit number ATCC 55730, ATCC23272, ATCC PTA-4964, ATCC PTA-4965, ATCC PTA-4659, ATCC PTA-5290, ATCC PTA-4659, ATCC 55148, ATCC 53608 and ATCC PTA-6475 any one or more of Lactobacillus reuteri , Or at least one bacterium of the genus Bifidobacterium, such as Bifidobacterium breve, such as any one or more of Bifidobacterium breve with the deposit number of ATCC 15698, ATCC 15700, and ATCC 15701, or Roy A mixture of Lactobacillus breve and Bifidobacterium breve.
  • Lactobacillus reuteri Lactobacillus reuteri
  • the pharmaceutical composition may optionally contain one or more bacteria from the genus Akkermansia and/or Turicibacter, and optionally one or more lactic acid from Lactobaccillus and Bifidobacterium. Any one or more other bacteria (such as Bifidobacterium lactis and/or Lactobacillus rhamnosus) other than Bacillus and Bifidobacterium breve, and optionally from the genus Bacteroides, Enterococcus, Helicobacter, Parabacteroides, and Escherichia Any one or more bacteria of any genus or any multiple genera in the genus.
  • bacteria from the genus Akkermansia and/or Turicibacter and optionally one or more lactic acid from Lactobaccillus and Bifidobacterium.
  • Any one or more other bacteria such as Bifidobacterium lactis and/or Lactobacillus rhamnosus
  • Bacteroides Enterococcus
  • Helicobacter Parabacter
  • pharmaceutically acceptable carriers and excipients are those conventionally used for bacterial medicines in the art, and their existence usually does not impair the activity of the active bacteria contained in the medicine.
  • Suitable pharmaceutically acceptable carriers or excipients include, but are not limited to, water, gelatin, vegetable gum, talc, sugar, starch, acacia, vegetable oil, polyalkylene glycol, flavoring agent, preservative, stabilizer Agents, emulsifiers, buffers, lubricants, colorants, wetting agents and fillers.
  • a suitable carrier or excipient can be selected according to the dosage form of the drug.
  • the drugs of the present invention are usually in oral dosage forms, such as tablets, dry powders, solutions, suspensions or capsules.
  • the active bacteria are present in a therapeutically effective amount or a preventively effective amount.
  • a therapeutically effective amount is any amount of a drug that protects the patient from the onset of disease or promotes the regression of the disease when used alone or in combination with another therapeutic agent. The regression of the disease is achieved by reducing the severity of symptoms of the disease. The increase in the frequency and duration of the asymptomatic period, or the prevention of injury or disability caused by the pain of the disease.
  • a preventive effective amount refers to an amount that is effective to achieve the desired preventive result within a necessary dose and time period.
  • a preventive effective amount refers to an amount required to prevent the occurrence of irAE or reduce the severity and/or rate of progression of irAE.
  • the prophylactically effective amount will be less than the therapeutically effective amount.
  • the preventive effective amount and the therapeutically effective amount can be determined according to relevant factors such as the patient's age, sex, disease, severity of the disease and the like.
  • the medicament provided by the present invention may also contain ICB or chimeric antigen receptor gene modified cells (such as CAR-T cells).
  • ICB and the active bacteria described herein can be provided in the form of a single mixture, or can be provided in the same medicine in the form of separate preparations.
  • the present invention also includes a method for preventing or treating irAE induced by ICB or chimeric antigen receptor gene-modified cell therapy, the method comprising administering a preventive or therapeutically effective amount of the irAE described herein to a patient suffering from or expected to suffer from irAE
  • a preventive or therapeutically effective amount of the irAE described herein to a patient suffering from or expected to suffer from irAE
  • One or more of the bacteria, or the bacterial product described herein, or the pharmaceutical composition described herein is administered orally.
  • the bacteria, bacterial products, or pharmaceutical compositions can be administered before, at the same time or after ICB therapy or chimeric antigen receptor gene-modified cell therapy.
  • the treatment or prevention method of the present invention further includes the step of detecting the intestinal bacteria of the patient.
  • the detection of intestinal bacteria includes the detection of intestinal bacteria of the following genera: Escherichia/Shigella, Lactobacillus, Bacteroides, unclassified, Allobaculu, Barnesiella, Parabacteroides, Romboutsia, Enterococcus, Alitipes, Helicobacter, Olsenella, Bifidobacterium, Akkermansia, Blautia, Klebsiella, Clostridium XlVa, Parasutterella, Clostridium XVIII, Turicibacter, Veillonella, Bilophila, Desulfovibrio, Clostridium sensu stricto, Clostridium IV, Flavonifractor, Eubacterium and Pseudoflavonifractor.
  • the detection of intestinal bacteria includes the detection of intestinal bacteria of the following genera: Akkermansia, Helicobacter, Mycoplasmataceae, Bacteroides, Dehalobacterium, Lactobacillus, Clostridium, Lachnospiraceae, Anaeroplasma, Bacteroidales S24-7 group (Bacteroidales S24-7 group) Bacteria), Turicibacter, Oscillospira, Prevotella, Aggregatibacter, Parabacteroides, Ruminococcus, Bifidobacterium, Enterococcus, Streptococcus, Sutterella, Anaerotruncus, Mucispirillum, Chlamydia, and Escherichia.
  • the detection of intestinal bacteria includes intestinal bacteria of the following genera: Akkermansia, Bacteroides, Bifidobacterium, Enterococcus, Helicobacter, Lactobacillus, Parabacteroides, Turicibacter, and Escherichia.
  • Methods known in the art can be used to detect the abundance of bacteria of each genera in the patient's body. For example, fresh feces of patients can be collected, 16s rRNA sequencing analysis of bacteria in the feces can be performed, and the relative abundance of bacteria can be calculated based on the sequencing results.
  • this document also provides a detection kit, which contains reagents for detecting intestinal bacteria of the following genera: Escherichia/Shigella, Lactobacillus, Bacteroides, unclassified, Allobaculu, Barnesiella, Parabacteroides, Romboutsia, Enterococcus, Alistipes , Helicobacter, Olsenella, Bifidobacterium, Akkermansia, Blautia, Klebsiella, Clostridium XlVa, Parasutterella, Clostridium XVIII, Turicibacter, Veillonella, Bilophila, Desulfovibrio, Clostridium sensu actor, Clostridium sensu stricto, Clostridium sensu actor, Flavonidium Pactor IV, Flavonidium actor.
  • Escherichia/Shigella Lactobacillus
  • Bacteroides unclassified, Allobaculu, Barnesiella, Parabacteroides, Romboutsia, Enterococcus
  • this document also provides a detection kit containing reagents for detecting intestinal bacteria of the following genera: Akkermansia, Helicobacter, Mycoplasmataceae, Bacteroides, Dehalobacterium, Lactobacillus, Clostridium, Lachnospiraceae, Anaeroplasma, Bacteroidales S24- 7 group, Turicibacter, Oscillospira, Prevotella, Aggregatibacter, Parabacteroides, Ruminococcus, Bifidobacterium, Enterococcus, Streptococcus, Sutterella, Anaerotruncus, Mucispirillum, Chlamydia and Escherichia.
  • this document also provides a detection kit containing reagents for detecting intestinal bacteria of the following genera: Akkermansia, Bacteroides, Bifidobacterium, Enterococcus, Helicobacter, Lactobacillus, Parabacteroides, Turicibacter, and Escherichia.
  • Detection reagents include, but are not limited to, reagents required for genetic detection methods, such as various primers that can specifically detect bacteria of the above-mentioned genera and optionally reagents required for PCR.
  • the primers can usually be used to amplify the characteristic sequence of each bacteria, so as to characterize the presence or absence and amount of the bacteria in the patient's intestine.
  • the present invention provides that the active bacteria described herein are used in the preparation of prevention or treatment of ICB (especially anti-PD-1 antibody/anti-PD-L1 antibody and/or anti-CTLA-4 antibody) or chimeric antigen receptor gene modified cells (Such as CAR-T cells)
  • ICB especially anti-PD-1 antibody/anti-PD-L1 antibody and/or anti-CTLA-4 antibody
  • CAR-T cells chimeric antigen receptor gene modified cells
  • the application further includes at least one bacteria of at least one of the genera Bacteroides, Enterococcus, Helicobacter, Parabacteroides, and Escherichia.
  • the present invention also provides prevention or treatment of ICB (especially anti-PD-1 antibody/anti-PD-L1 antibody and/or anti-CTLA-4 antibody) or chimeric antigen receptor gene-modified cell therapy-induced irAE Any one or more of the bacteria described herein or products thereof, especially any bacteria from the genus Akkermansia, Bifidobacterium, Lactobacillus and Turicibacter, especially including Lactobacillus reuteri and Bifidobacterium breve, and Optional Bifidobacterium lactis and/or Lactobacillus rhamnosus.
  • ICB especially anti-PD-1 antibody/anti-PD-L1 antibody and/or anti-CTLA-4 antibody
  • chimeric antigen receptor gene-modified cell therapy-induced irAE Any one or more of the bacteria described herein or products thereof, especially any bacteria from the genus Akkermansia, Bifidobacterium, Lactobacillus and Turicibacter, especially including Lactobacill
  • the present invention also includes the application of reagents for detecting the above-mentioned intestinal bacteria in the preparation of irAE diagnostic kits.
  • the reagents include at least reagents for detecting Akkermansia, Bacteroides, Bifidobacterium, Enterococcus, Helicobacter, Lactobacillus, Parabacteroides, Turicibacter and Escherichia bacteria in the patient's intestine.
  • the reagents include at least detecting Escherichia/Shigella, Lactobacillus, Bacteroides, unclassified, Allobaculu, Barnesiella, Parabacteroides, Romboutsia, Enterococcus, Alisipes, Helicobacter, Olsenella, Bifidobacterium, Akkermansia, Blautridiumblautia, Klostriella XlVa, Parasutterella, Clostridium XVIII, Turicibacter, Veillonella, Bilophila, Desulfovibrio, Clostridium sensu stricto, Clostridium IV, Flavonifractor, Eubacterium and Pseudoflavonifractor are reagents for bacteria.
  • this document also provides a detection kit containing reagents for detecting intestinal bacteria of the following genera: Akkermansia, Helicobacter, Mycoplasmataceae, Bacteroides, Dehalobacterium, Lactobacillus, Clostridium, Lachnospiraceae, Anaeroplasma, Bacteroidales S24- 7 Reagents for bacteria belonging to group, Turicibacter, Oscillospira, Prevotella, Aggregatibacter, Parabacteroides, Ruminococcus, Bifidobacterium, Enterococcus, Streptococcus, Sutterella, Anaerotruncus, Mucispirillum, Chlamydia and Escherichia.
  • the reagent may be a primer that can specifically amplify the characteristic sequence of each bacteria.
  • mice models, detection methods, mouse processing methods and statistical methods used in the examples are described as follows:
  • a mouse model of enteritis induced by ICB treatment of dextran sulfate sodium (DSS) was constructed to simulate the immune side effects of intestinal inflammation induced by clinical ICB treatment.
  • Modeling mice were 8-10 week old female mice of the C57BL/6 strain, purchased from Shanghai Slack Animal Co., Ltd. During the modeling period, the mice’s daily drinking water was replaced with 3% DSS (a drug that can induce colon inflammation in mice).
  • ICB drugs anti-CTLA-4 antibody 100 ⁇ g/bottle/time, anti-PD-1 antibody 250 ⁇ g/bottle/time
  • DSS dextran sulfate sodium
  • Foxp3 gene knockout mice to simulate the systemic immune-related adverse reactions caused by immunotherapy such as ICB.
  • the experimental mice were B6.129(Cg)-Foxp3 tm3(DTR/GFP)Ayr /J, purchased from Jackson Laboratory, USA.
  • Studies have confirmed that one of the key mechanisms of clinical ICB therapy (anti-CTLA-4 and PD-1/PD-L1 antibodies) is the activation of a large number of immune cells such as T lymphocytes, which infiltrate tumors and other organs and tissues. .
  • the mouse can be used to simulate the immune checkpoint blocker CTLA-4 antibody due to the deletion of Treg's important transcription factor Foxp3, the lack of regulatory T cells (Tregs) and the activation of a large number of T cells.
  • Side effects of systemic immune response caused by immunotherapy such as PD-1 antibody.
  • a long-term lack of Treg cells can lead to weight loss, chronic eyelid inflammation, decreased activity, a large number of lymphocytes and monocytes in multiple organs, spleen enlargement, lung and colon inflammation, and serum IFN- ⁇ and TNF- ⁇ significantly increased systemic inflammatory diseases.
  • the serum of each mouse was collected at the end of the experimental observation to detect the cytokine content of each group.
  • Quantitative analysis of tumor necrosis factor (TNF- ⁇ ), interleukin-6 (IL-6) and interferon in the collected serum using Luminex multiple cytokine analysis technology (Magnetic Luminex Assay Kit, R&D Systems, USA) based on the principle of magnetic beads - ⁇ (IFN- ⁇ ) and other inflammatory cytokines levels.
  • the feces of each mouse were collected at the end of the experimental observation. Then, 16S rDNA sequencing was performed on the intestinal flora of the mice, and the operation and kit instructions were followed throughout the process, and the changes in the intestinal flora were further analyzed.
  • Mouse 16S rRNA sequencing was sent to Shanghai Shenggong Bioengineering Company for determination. Follow the operation and kit instructions throughout the process.
  • the target segment for amplification is designated as the V3-V4 hypervariable region of the bacterial 16S rRNA gene.
  • KAPA HiFi Hot Start Premix (2x) (TaKaRa Bio Inc., Japan) to amplify 16S rRNA V3-V4 amplicons.
  • the reaction settings are as follows: microbial DNA (10ng/ ⁇ l) 2 ⁇ l; amplicon PCR forward specific primer (10 ⁇ M) 1 ⁇ l (CCTACGGGNGGCWGCAG, SEQ ID NO:1); amplicon PCR reverse specific primer (10 ⁇ M) 1 ⁇ l (GACTACHVGGGTATCTAATCC, SEQ ID NO: 2); 2 ⁇ KAPA HiFi hot start premix 15 ⁇ l (total 30 ⁇ l).
  • the PCR machine uses the following procedure to perform PCR: 95°C for 3 minutes; 95°C for 30s, 55°C for 30s, 72°C for 30 seconds, 20 cycles; 72°C for 5 minutes.
  • the PCR products were checked by electrophoresis in a 1% (W/V) agarose gel in TBE buffer (Tris, boric acid, EDTA) stained with ethidium bromide (EB) and visualized under UV light. .
  • Use AMPure XP magnetic beads to purify and remove free primers and primer dimers in the amplified products.
  • the samples were delivered to Sangon BioTech (Shanghai) using a universal Illumina adapter and index for library construction.
  • the Qubit 2.0 Green double-stranded DNA assay was used to determine the DNA concentration of each PCR product, and a bioanalyzer (Agilent 2100, USA) was used for quality control. According to the amplicon concentration, they are pooled in an equimolar ratio. Sequencing was performed using the Illumina MiSeq system (Illumina MiSeq, USA) according to the manufacturer's instructions.
  • mice with probiotic strains Treatment of mice with probiotic strains
  • the statistical results of the data of the present invention are all presented in the form of mean ⁇ standard error of mean (SEM).
  • SEM standard error of mean
  • Statistical analysis was performed using SPSS 13.0 statistical software and GraphPad Prism 7.0. The two groups were compared by unpaired Student's T test, and multiple groups were compared by one-way analysis of variance. When analyzing the differences in components between groups, Welch's t-test test, one-way analysis of variance and Tukey-Kramer post-hoc test were used by STAMP. Use Eta square ( ⁇ 2 ) to estimate the effect size. The difference P ⁇ 0.05 was considered statistically significant.
  • Example 1 The effect of adding ICB drugs on the body weight, survival rate and key inflammatory factors of mice based on the DSS model
  • ICB and DSS were used to jointly treat mice to establish an intestinal irAE model.
  • the survival rate of mice after the addition of ICB based on DSS induction was significantly lower than that of DSS alone (P ⁇ 0.01).
  • the levels of key inflammatory cytokines such as TNF- ⁇ , IL-2 and IFN- ⁇ in the serum of mice increased significantly after ICB treatment ( Figure 1, B).
  • the above results indicate that ICB treatment of DSS mouse model can successfully simulate the clinical side effects caused by ICB treatment.
  • Example 2 The effect of ICB drugs on the intestinal flora of mice
  • this example collected three groups, namely normal untreated mice (Nor), DSS alone group (Ctrl), and DSS combined with ICB induction
  • Normal untreated mice Neor
  • Ctrl DSS alone group
  • ICB ICB
  • 16S rDNA sequencing were used to detect the intestinal flora of mice in each group. The results showed that compared with Nor group mice in Ctrl group or ICB group, there were significant differences in the composition of intestinal bacteria in the body ( Figure 2, A and B).
  • the ICB treatment group of Lactobacillus, Alistipes, Olsenella, Turicibacter, and Clostridium sensu stricto showed a progressive decrease, while Escherichia/Shigella, Bacteroides, Veillonella, Flavonifractor, and Pseudoflavonifractor bacteria appeared.
  • the content increases. While the content of Romboutsia bacteria was significantly reduced only in the ICB group, the content of Klebsiella bacteria was significantly increased in the ICB group and significantly decreased in the Ctrl group (Figure 2, B). This not only shows that the intestinal flora of the mice treated with ICB is disordered, but also suggests that the abnormal content of these major intestinal floras is related to ICB-induced intestinal irAE.
  • Example 3 Comparison of survival period and key serum inflammatory factor content between transgenic mice and wild-type mice
  • Example 4 Analysis of the abnormality of intestinal flora in transgenic mice that can mimic irAE
  • Figure 4A shows the 11 genera with the highest relative abundance (genus level) and different changes, such as Akkermansia, Anaeroplasma, Oscillospira, and Bacteroides, Anaerotruncus, and Escherichia.
  • these changes are basically consistent with the intestinal flora disorder that occurred in the ICB treatment-induced model. Therefore, the results of these two models show that the occurrence of local irAE and systemic irAE in the intestine is indeed related to the disturbance of the intestinal flora, especially the changes in the key intestinal flora.
  • Example 5 Intestinal flora of transgenic mouse model
  • Table 1 summarizes the intestinal bacterial genera found to be differentially expressed in abundance in the two mouse models.
  • intestinal bacteria such as Akkermansia, Bacteroides, Bifidobacterium, Enterococcus, Helicobacter, Lactobacillus, Parabacteroides, Turicibacter, Escherichia, which are key intestinal bacteria that affect irAE side effects caused by ICB drug treatment Genus (the third column, and the direction of abundance change is the same in the two models).
  • Clostridium genus that recurs in the two mouse models (in bold in Table 1), and the abnormal abundance of Prevotella in the systemic side effects model (MT mice) (in bold in Table 1) may be The occurrence of irAE after the use of ICB drugs is related.
  • Table 1 Differently expressed intestinal bacteria genera and key intestinal bacteria genera of side effects in the digestive system side effect model and the systemic side effect model
  • ⁇ means that the abundance of bacteria increases after ICB treatment; ⁇ means that the abundance of bacteria decreases after ICB treatment.
  • Example 6 Supplementation of Lactobacillus improves the survival rate and intestinal inflammation of mice with ICB side effects
  • this example uses Lactobacillus reuteri (LR) to treat drug-induced model mice.
  • LR Lactobacillus reuteri
  • the results of the study showed that Lactobacillus reuteri significantly increased the survival rate of model mice ( Figure 6, A).
  • Lactobacillus reuteri also significantly reduced the levels of various inflammatory factors in mice ( Figure 6, B), and at the same time improved adverse reactions such as blood in the stool and weight loss in mice (Table 2).
  • + means that the corresponding side effect is caused, and the more + means the more serious the side effect.
  • Example 7 Supplementation of bifidobacteria improves the survival rate and systemic inflammation of MT mice
  • Bifidobacterium breve was used to treat the Foxp3 deletion transgenic mouse model.
  • the results of the study showed that Bifidobacterium breve also significantly increased the survival rate of model mice ( Figure 7, A), reduced the levels of various inflammatory factors in mice ( Figure 7, B), and at the same time improved mouse eyelid inflammation, Systemic adverse reactions such as blood in the stool and weight loss (Table 3). Therefore, supplementation of Bifidobacterium breve can also alleviate the intestinal side effects caused by ICB.
  • + means that the corresponding side effect is caused, and the more + means the more serious the side effect.
  • Example 8 The effect of supplementing the mixed bacteria preparation on improving the survival rate and systemic inflammatory response of MT mice
  • + means that the corresponding side effect is caused, and the more + means the more serious the side effect.

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Abstract

L'invention concerne une flore intestinale qui modifie les réactions indésirables associées à l'immunothérapie antitumorale. La flore intestinale peut être utilisée en tant qu'indicateur de détection pour diagnostiquer et prédire des réactions indésirables associées provoquées par une immunothérapie antitumorale, et peut être utilisée pour prévenir, soulager ou traiter des réactions indésirables associées à l'immunothérapie antitumorale.
PCT/CN2020/087772 2019-04-30 2020-04-29 Flore intestinale liée à irae et procédé de traitement et de prévention d'irae Ceased WO2020221293A1 (fr)

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