CN115998771A

CN115998771A - Application of bacteria in preparation of synergist of immune checkpoint inhibitor

Info

Publication number: CN115998771A
Application number: CN202211008924.7A
Authority: CN
Inventors: 徐瑞华; 赵霞
Original assignee: Sun Yat Sen University Cancer Center
Current assignee: Sun Yat Sen University Cancer Center
Priority date: 2021-07-16
Filing date: 2021-08-16
Publication date: 2023-04-25
Also published as: CN114159475B; WO2023284069A1; CN114159475A

Abstract

The invention discloses application of bacteria in preparing a synergist of an immune checkpoint inhibitor. According to the invention, the human endogenous intestinal bacteria single-bacterium oral preparation is combined with the immune checkpoint inhibitor, so that the anti-tumor immune protection response generated by the stimulation of the endogenous intestinal bacteria is obviously enhanced, the drug effect of the immune checkpoint inhibitor on a plurality of tumor species is better in safety, the overall survival time of cancer patients is prolonged, the response rate of cancer immune treatment crowds is improved, and the cancer immune treatment benefited tumor patient crowds are enlarged.

Description

Application of bacteria in preparation of synergist of immune checkpoint inhibitor

The application is a divisional application with the application number of 202110939699.8 and the application date of 2021, month and 16, and the invention name of 'application of a bacterium in preparing a synergist of an immune checkpoint inhibitor'.

Technical Field

The invention relates to the technical field of cancer treatment, in particular to application of bacteria in preparation of a synergist of an immune checkpoint inhibitor.

Background

Malignant tumors are one of the biggest problems facing the world at present, and among various lethal factors causing death every year, malignant tumors are the first. The conventional treatment scheme, such as operation treatment, radiotherapy and chemotherapy, has the defects that tumor cells are difficult to completely remove, the recurrence rate is high, and the treatment means such as radiotherapy and chemotherapy have weak targeting, kill normal cells while killing tumor cells, cause great harm to patients and seriously influence the life quality of the patients.

Compared with conventional therapies, the tumor immunotherapy aims at targets which are not tumor cells and tissues, but rather the human immune system, and eliminates tumor cells, including tumor cells transferred to a far distance, by regulating and activating the human immune system, through an autoimmune machine, has small toxic and side effects on normal cells, and greatly improves prognosis and quality of life of patients with advanced malignant tumors.

At present, tumor immunotherapy is various, wherein immune checkpoint inhibitor (immune checkpoint inhibitors, ICIs) therapy reactivates T cells by blocking immune inhibition pathways (such as PD-L1/PD-1 and CTLA-4/B7-1) hijacked by tumor cells, and the immune system of a reactivating organism has the advantages of good curative effect and lasting response on the tumor cells, thereby opening a new era of tumor therapy. ICIs therapy has led to a revolution in cancer therapy in applications due to the lack of treatment options for a variety of tumor types, becoming a new milestone for cancer therapy.

Currently, patients receiving ICIs treatment may be relieved for a long period of time after treatment interruption, increasing the hope of cure for some patients. Particularly in melanoma patients, complete remission, i.e. complete disappearance of all visible tumor metastases, can be achieved in patients. The problem of low response rate of ICIs single drugs in patients is the biggest bottleneck of current development and application, and patients capable of achieving complete remission in single drug ICIs treatment only occupy 20% -40%, so that development of a combined strategy for enhancing the efficacy of immune checkpoint inhibitors is needed. The current mainstream combination strategies comprise treatment means such as operation, chemotherapy, radiotherapy, targeted therapy and the like and ICIs combination therapies, can generate synergistic effect, enhance the persistence and the curative effect of ICIs and overcome the problem of low response rate of ICIs. Although these combination therapies may improve the efficacy and response rate of ICIs to some extent, toxicity is often increased.

Among the many combination therapies, several studies through manipulation of endogenous intestinal microbiologically assisted ICIs therapy became milestone events in the field of tumor treatment. The intestinal tract is the largest lymphoid organ in the human body, with more than 70% of T cells present, and is the residence for the vast majority of memory T cells. Intestinal flora residing in intestinal tracts promotes the development of the immune system of a human body through interaction with intestinal immune organs, balances and lays the immune foundation of the human body. For the defense system and immune system of human body, the bacteria and tumor are not already present, so the same set of defense mechanism is used in the immune response to the bacteria and tumor, and the immune response stimulated by the endogenous bacteria in intestinal tract has the potential of resisting tumor. Based on the anti-tumor immune cross theory of the intestinal flora, oncolytic enzymes secreted by certain intestinal bacteria have been used for hundreds of years for treating tumors. It is worth noting that the antitumor effect induced by the endogenous bacteria in the intestinal tract is derived from the autoimmune reaction of the organism, and has higher safety and smaller toxic and side effects compared with the combined therapy of radiotherapy and chemotherapy.

Recent two clinical studies reported that fecal transplantation in patients receiving ICIs treatment response (either to partial or complete remission) resulted in partial or complete remission of refractory metastatic melanoma patients not receiving ICIs response (Baruch E N, youngster I, ben-Betzalel G, et al Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients [ J ]. Science,371. And Davar D, dzutsev A K, mcc Ulloch J A, et al Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients[J ]. Science,2021,371 (6529):595-602.) and no toxic or side effects, demonstrating the synergistic effect of endogenous intestinal microorganisms on ICIs therapy. The fecal transplantation component is complex, the whole intestinal microorganisms play a role in the fecal transplantation, and the intestinal flora is greatly affected by environment, diet, life style and the like, and the continuous and stable source of the donor fecal is not obtained, so that the clinical application of the fecal transplantation ICIs combined immunotherapy is limited. Therefore, the identification of single-component antitumor intestinal bacteria which can be produced in standardized and quantified manner becomes a key for solving the problem. In a recent study (Mager LF, burkhard R, pett N, cooke NCA, brown K, ramayH, paik S, stagg J, groves RA, galo M, lewis IA, geuking MB, mcCoy KD. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.science.2020 Sep 18;369 (6510): 1481-1489.), researchers isolated three bacteria from ICIS treated mice models of intestinal cancer: bifidobacterium pseudolongum (Bifidobacterium pseudolongum), lactobacillus johnsonii (Lactobacillus johnsonii) and euglena (Olsenella species). These 3 specific bacteria, in combination with immune checkpoint inhibitors, respectively, can enhance the efficacy of ICIs in 4 mouse cancer models. Further studies have found that bifidobacterium pseudolongum exerts a synergistic effect of ICIs by its metabolite inosine.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, provides application of bacteria in preparing a synergist of an immune checkpoint inhibitor, relates to a combined therapy for enhancing curative effect of the immune checkpoint inhibitor, is applicable to one or more tumors, and is applicable to active whole cell African fens (Alistipes finegoldii) for the method, wherein cancer immunotherapy relates to immune checkpoint inhibitor therapy, and aims to enhance anti-tumor efficacy of the cancer immunotherapy, prolong overall survival time of cancer patients, improve response rate of cancer immunotherapy groups and enlarge benefited tumor patient groups of the cancer immunotherapy.

The treatment method provided by the invention aims at the defects of conventional treatment: the traditional Chinese medicine composition has the advantages of large toxic and side effects, easiness in transfer and recurrence, short duration, short life cycle and poor life quality, and is obviously improved; shortcomings of single medication for immune checkpoints: the range of the tumor types is limited, the drug response population is less, and the obvious improvement is realized; aiming at the defects of the immune check point combined radiotherapy and chemotherapy treatment method: has large toxic and side effects and less drug response crowd, and has obvious improvement.

The treatment method provided by the invention has good treatment effect on the following patients: treating tumor patients who can not be operated, can not use targeting drugs, and are ineffective in radiotherapy, chemotherapy and the like; treatment of tumor patients with ineffective or resistant single drug immune checkpoint inhibitors (primary, adaptive and acquired resistance); treatment of tumor patients with immune checkpoint inhibitors in combination with radiotherapy, chemotherapy, targeted therapy with ineffective or resistant (primary, adaptive and acquired resistance).

In order to achieve the above object, the present invention is realized by the following means:

use of bacteria in tumor treatment is provided.

Preferably, the use is the use as an active ingredient in the preparation of a potentiator of an immune checkpoint inhibitor.

Preferably, the application is the application of a synergist serving as an immune checkpoint inhibitor, and the effect of the immune checkpoint inhibitor on treating tumors is improved.

Preferably, the bacterial species belongs to the genus bacillus (alitispes), i.e. the 16S rDNA sequence of the bacterial species has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identity with the 16S rDNA sequence of the genus bacillus (alitispes).

Preferably, the bacterium belonging to the genus Effithitis (Alistipes) is one or more species or combination of strains of the bacterium belonging to the genus Effithitis (Alistipes).

More preferably, the bacterium belonging to the genus Equisqualis (Alistipes) is Equisqualis (Alistipes finegoldii).

Further preferred, the A.fenhnsonii (Alistipes finegoldii) comprises a 16S rDNA sequence which has at least 99% identity with the 16S rDNA sequence of the A.fensonii species (Alistipes finegoldii).

Further preferred, the A.fenhnsonii (Alistipes finegoldii) comprises a 16S rDNA sequence which is at least 99.5% or 100% identical to the 16S rDNA sequence of A.fensonii strain DSM17242 (Alistipes finegoldii DSM 17242).

Still further preferably, the method further comprises the step of, one or more of the above-mentioned Earthwest bacteria (Alistipes finegoldii) combination of strains of a. Personals (Alistipes finegoldii).

Still more preferably, the strain of Eimeria fens (Alistipes finegoldii) is a sub-class of strain in the national center for biotechnology (National Center for Biotechnology Information, NCBI) genome database (https:// www.ncbi.nlm.nih.gov/genome/browse/# ] |/prokaryotes/11196 /) having a strain name (Strain name of sub species classification) of: alistipes finegoldii DSM17242, alistipes finegoldii D53t1_180928_d3, alistipes finegoldii 2789STDY5834947, alistipes finegoldii 1001713b170207_170306_h2, alistipes finegoldii dfi.2.31, alistipes finegoldii BIOML-A1, alistipes finegoldii dfi.2.16, alistipes finegoldii dfi.2.10, alistipes finegoldii aa _0143, alistipes finegoldii 2789STDY5608890, alistipes finegoldii MGBC116453, alistipes finegoldii COPD076, or Alistipes finegoldii UBG 195.

Still further preferably, the strain of a. Fenhnsonii is a combination of one or more of the following strains:

the strain of Emblica Fensis deposited with the German collection of DSM microorganisms and cell cultures under accession number DSM 17242 (NCBI: txid679935, https:// www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi;

the strain is deposited in the Japanese JCM collection of strains (Deutsche Sammlung von Mikroorganismen und Zellkulturen = German collection of microorganisms and cell cultures) and the like, the accession number of which is JCM 16770;

the strain is deposited in Korean KCTC culture collection (Korean Collection for Type Cultures) and has the accession number KCTC 15236;

the strain of Emblica fenugreek deposited under AHN 2437 in the Heteroctyl anaerobe reference laboratory of Finland (Anaerobe Reference Laboratory, helsinki Collection, national Public health Institute, helsinki, finland);

the strain is deposited in the Swedish CCUG strain collection (Culture Collection University of Gothenburg) and has the deposit number of CCUG 46020;

the strain was deposited with the French CIP Collection (Collection de L' Institut Pasteur of Institut Pasteur) under the accession number CIP 107999.

The strain is deposited in the China center for type culture Collection of microorganisms, guangdong province, and the accession number is GDMCC 1.2324.

Preferably, the A.fenhnsonii (Alistipes finegoldii) comprises a 16S rDNA sequence which has at least 99% identity with the 16S rDNA sequence of the A.fensonii species (Alistipes finegoldii), the 16S rDNA sequence of the A.fensonii species (Alistipes finegoldii) being shown in SEQ ID NO: 1.

Most preferably, the strain of A.fenhnsonii is a strain of A.fensonii (Alistipes finegoldii) deposited with DSM accession number 17242.

Preferably, the bacteria include one or more of a live bacterium, a derivative of a bacterium, or a metabolite of a bacterium.

More preferably, the bacterium belonging to the genus Eimeria (Alistipes) and the immune checkpoint inhibitor are administered simultaneously or separately.

Preferably, the bacterial metabolites include all molecules produced or modified by the bacteria during their preparation and storage as well as during transport in the gastrointestinal tract of a mammal as a result of their growth, survival, retention, transport or presence.

More preferably, the bacterial metabolites include all organic acids, inorganic acids, bases, proteins and peptides, enzymes and coenzymes, amino acids and nucleic acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, all biologically active compounds, metabolites containing inorganic components, and all small molecules, such as nitrogen-containing molecules or sulfurous acid-containing molecules.

Preferably, the bacterial derivatives, including bacterial constituents and genetic material and related constituents thereof, examples of which include bacterial cell membranes, pili, flagella, LPS, nucleic acid material and the like, are derived from bacterial constituents.

Preferably, the live bacteria are whole bacteria.

More preferably, the live bacteria are whole live bacteria.

Preferably, the treatment of the tumor is tumor shrinkage or stabilization, overall survival time extension, non-worsening survival time extension, quality of life improvement.

Preferably, the tumors are adenomas, malignant tumors, and adenocarcinomas, wherein the tumors are classified by tissue origin or cell name, comprising: adrenal cortex cancer, bladder urothelial cancer, breast cancer, pancreatic cancer, cervical cancer, cholangiocarcinoma, colon cancer, colorectal cancer, diffuse large B-cell lymphoma, glioblastoma multiforme, glioma, head and neck cancer, kidney chromocytoma, mixed kidney cancer, leukemia, lymphoma, brain cancer, liver cancer, lung adenocarcinoma, lung squamous carcinoma, mesothelioma, ovarian cancer, pancreatic cancer, pheochromocytoma, paraganglioma, prostate cancer, rectal adenocarcinoma, sarcoma, skin melanoma, gastric cancer, esophageal cancer, testicular cancer, thyroid cancer, thymus cancer, endometrial cancer, uterine sarcoma, uveal melanoma, and soft tissue sarcoma.

In a specific embodiment of the invention, the tumor is colorectal cancer or melanoma.

Preferably, the tumor is a malignant tumor, a metastatic tumor or a non-metastatic tumor.

Preferably, herein the neoplasm includes malignant, metastatic and non-metastatic types; including any stage of cancer (clinical stage I, II, III or IV, malignant TNM classification T1-4, N0-4, or M0-1, histological grade G1, G2, G3 or G4, etc.)

More preferably, the immune checkpoint inhibitor is a combination of one or more of the blocking agents acting on T cell negative co-stimulatory (co-inhibitory) molecules and/or their respective ligands.

Further preferably, the T cell negative co-stimulatory (co-inhibitory) molecules and/or their respective ligands are selected from CTLA-4, PD-1, PD-L2, B7-1, B7-2, B7-H3, B7-H4, B7-H6, A2AR, IDO, TIM-3, BTLA, VISTA, TIGIT, LAG-3, CD40, KIR, CEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, TNFR, dcR3.

Still further preferably, the blocking agent of the ligand of the T cell negative co-stimulatory (co-inhibitor) molecule is selected from the group consisting of Na Wu Liyou mab (nivolumab, PD-1 mab), ipilimumab (ipilimumab, CTLA-4 mab), pamezole mab (pembrolizumab, PD-1 mab), atozumab (azetolizumab, PD-L1 mab), at Zhu Shankang (atezolizumab, PD-L1 mab), carpezulimab (camrelizumab, PD-L1 mab), ti Lei Lizhu mab (tisluelimab, BGB-A317), duvali You Shan mab (durvalumab, PD-L1 mab), tremelimumab (tremeliumab, CTLA-4 mab), dazulizumab (spartamab, PD-1 mab), avistuzumab (PD-L1 mab), sidilimab Li Shan (PD-1 mab), terlipressimab Li Shan (toripalimab, PD-1 mab), siemerprop Li Shan (cemiplimab, PD-1 mab), MGA012 (retifanlimab, PD-1 mab), MGD013 (tebotelimab, PD-1/LAG-3 mab), MGD019 (PD-1/A-4 mab), enbelituzumab (Enbelituzumab, B7-H3 mab), MGD009 (B7-H3 mab), MGC018 (B7-H3 mab), MEDI0680 (PD-1 mab), PDR001 (PD-1 mab) FAZ053 (PD-L1 mab), R TS022 (TIM-3 mab) MBG453 (TIM-3 mab), relatimab (BMS 986016, LAG-3 mab), LAG525 (LAG-3 mab), IMP321 (LAG-3 mab), REGN3767 (LAG-3 mab), pexidatinib (pexidatinib, CSF-1R mab), LY3022855 (CSF-1R mab), FPA008 (CSF-1R mab), BLZ945 (CSF-1R mab), GDC0919 (navoxmod, IDO mab), epacadostat (IDO mab), indoximid (IDO mab), BMS986205 (IDO mab), CPI-444 (A2 AR mab), MEDI9447 (olechamab, CD73 mab), PBF509 (A2 AR mab), lirilub (lirilub, R mab), or a combination of any of several thereof; preferably, wherein the blocking agent is selected from the group consisting of nano Wu Liyou mab, palbociclib mab, terlipressin Li Shan antibody, singal Li Shan antibody, cimipramin Li Shan antibody or a combination of any of the several.

Still further preferred, the immune checkpoint inhibitor is an inhibitor acting on the PD-1/PD-L1 signaling pathway and/or the PD-1/PD-L2 signaling pathway, wherein PD-1 refers to programmed cell death protein 1, also known as CD279, and PD-L1 (B7-H1 or CD 274) and PD-L2 (B7-DC or CD 273) are ligands for PD-1.

Still more preferably, the inhibitor of the PD-1/PD-L1 signaling pathway or PD-1/PD-L2 signaling pathway is selected from the group consisting of Na Wu Liyou mab (nivolumab, PD-1 mab), paboluzumab (pembrolizumab, PD-1 mab), atozuab (azetolizumab, PD-L1 mab), ab Zhu Shankang (atezolizumab, PD-L1 mab), cariglizumab (camrelilizumab, PD-L1 mab), ti Lei Lizhu mab (tisslizumab, B-A317), duvalizumab You Shan mab (durvalumab, PD-L1 mab), paboluzumab (spartrazumab, PD-1 mab), sidiluzumab (aviumab, PD-L1 mab), sidiscou75 (Tilizumab, PD-1 mab), west anti-28, CTLuzumab (MGuab, MGuB-3), talbuB-A (PDambuzumab, PD-1), qlauzumab (Qlazumab, PD-3), qlauzumab (Qlazumab, PD-1), qlauab (Qlauab, PD-3), qlauab (Qlauab, PD-1), qlauab (Qlauab, PD-3, PD-1, qlauab (Qlauab), or FAUG-1, qlauab (Qlauab), PDmg-3, qlizumab (Qvauab, PD-1, qbL 1).

Still more preferably, the immune checkpoint inhibitor is an inhibitor acting on the CTLA-4/B7-1 signaling pathway and/or the CTLA-4/B7-2 signaling pathway, wherein CTLA-4 refers to cytotoxic T lymphocyte protein 4, also known as CD152, B7-1 (CD 80) and B7-2 (CD 86) are ligands for CTLA-4.

Still more preferably, it may be selected from ipilimumab (CTLA-4 mab), tremelimumab (CTLA-4 mab), MGD019 (PD-1 and CTLA-4 mab), or a combination of any of them.

As a specific embodiment of the invention, the immune checkpoint inhibitor is an inhibitor acting on the PD-1/PD-L1 signaling pathway and/or the PD-1/PD-L2 signaling pathway and/or an inhibitor acting on the CTLA-4/B7-1 signaling pathway and/or the CTLA-4/B7-2 signaling pathway.

In particular, the immune checkpoint inhibitor is a PD-1 monoclonal antibody or a CTLA-4 monoclonal antibody.

Preferably, chemotherapy, immunotherapy or radiation therapy is performed simultaneously, separately or sequentially with the administration of the A.fenhnsonii.

Preferably, the subject to which the application is applied is a human being, which is an infant, a child, a adolescent, an adult or an elderly person.

Preferably, wherein the subject to which the application is administered is a non-human primate that is a mammal (e.g., dog, cat, ferret, horse, rabbit, guinea pig, gerbil, hamster, gray mouse, rat, mouse); birds; a reptile; fish; an amphibian; arthropod or livestock animal (e.g. cow, pig, sheep, goat, alpaca, donkey, camel, buffalo or mink)

Preferably, the bacteria are treated to comprise 10 of the bacteria ⁵ To 10 ¹² Between CFUs (colony forming units), or at 10 ⁷ To 10 ¹¹ Between CFUs, or 10 ⁸ To 10 ¹¹ Between CFUs, or 10 ⁹ To 10 ¹¹ Between CFUs, or 10 ¹⁰ To 10 ¹¹ The dose between the CFU is administered,more preferably, to comprise 10 of said bacteria ⁹ To 10 ¹¹ Dosage administration between CFUs.

The invention also claims the following:

a kit for tumor treatment comprising one or more of said immune checkpoint inhibitors, and said bacteria, and optionally a container;

or consist of one or more of said immune checkpoint inhibitors, and said bacteria, and optionally comprise a container.

A bacterium comprising a 16S rDNA sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to a 16S rDNA sequence of bacillus alistris (Alistipes).

A bacterium comprising a 16S rDNA sequence that is at least 99% identical to the 16S rDNA sequence of a. Fense (Alistipes finegoldii).

A bacterium comprising a 16S rDNA sequence, the 16S rDNA sequence of which has at least 99.5% or 100% identity with the 16S rDNA sequence of any one of the following strains:

Wherein the preservation number is: the 16SrDNA sequence of African fens-shibata (Alistipes finegoldii DSM 17242) of DSM17242 is shown in SEQ ID NO: 1.

A formulation, characterized in that an effective amount of a composition of one or more of the bacteria of any one of claims 32 to 33 for the treatment of tumors is formulated into a lyophilized powder, tablet, capsule, granule or injection by adding a pharmaceutically acceptable carrier and excipients.

Wherein "pharmaceutically acceptable carrier" refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered. Wherein the "adjuvant" refers to solvent, diluent or other excipient, dispersant, and surfactant.

A composition comprising a bacterium as described in any one of claims and a pharmaceutically acceptable carrier.

A composition comprising a bacterium as described in any one of the claims formulated for use as a medicament.

A composition comprising a bacterium as described in any one of claims formulated for use as a medical food.

A composition, characterized in that it comprises a mixture of two or more bacterial strains as described in any one of the claims, and optionally further comprises a pharmaceutically acceptable carrier.

A composition, characterized in that it comprises an effective amount of a mixture of two or more bacteria according to any one of the claims for tumor treatment, and optionally also a pharmaceutically acceptable carrier.

A composition comprising an effective amount of one or several compositions of a live bacterial bacterium, a bacterial derivative, or a bacterial metabolite of the bacterium described in any one of two or more of the bacteria for tumor treatment, and optionally further comprising a pharmaceutically acceptable carrier.

A food, beverage, food supplement, probiotic or health food comprising the bacterium of any one of the claims formulated as a formulation for enteral nutrition

A food, beverage, food supplement, probiotic or health food comprising a mixture of two or more bacteria as described in any one of the claims formulated for enteral nutrition.

Any bacterium or composition, wherein the bacterium or composition is formulated as a lyophilized powder, tablet, capsule, granule or injection.

The bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food of any one of claims, characterized in that the subject to which it is administered is a human.

Preferably, wherein the human is an infant, a child, a adolescent, an adult or an elderly person.

The bacterium, formulation, composition, food, beverage, food supplement, probiotic, or nutraceutical of any of claims, administered to a non-human primate that is a mammal (e.g., dog, cat, ferret, horse, rabbit, guinea pig, gerbil, hamster, gray mouse, rat, mouse); birds; a reptile; fish; an amphibian; arthropods or livestock animals (e.g. cattle, pigs, sheep, goats, alpacas, donkeys, camels, buffalo or minks).

The use of any bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food in the treatment of a tumor.

The bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food product of any one of claims, comprising an effective amount of said bacterium, for use in tumor therapy.

A bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food product according to any one of claims, comprising an effective amount of said bacterium, use in tumor therapy, characterized in that said tumor therapy is administered with a bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food product according to any one of claims.

A composition comprising an effective amount of any one of the bacteria or composition for treating cancer, and optionally further comprising a pharmaceutically acceptable carrier.

A composition comprising an effective amount of any one of two or more bacteria or compositions for treating cancer, and optionally further comprising a pharmaceutically acceptable carrier.

A composition comprising a. Fenugreek (Alistipes finegoldii) and an immune checkpoint inhibitor.

Preferably, the immune checkpoint inhibitor is a PD-1 monoclonal antibody (αpd-1) and/or a CTLA-4 monoclonal antibody (αctla 4).

The invention also claims the application of the composition in preparing medicines for treating tumor.

The invention also discloses a medicine, which comprises the composition, in particular a medicine composition with the active ingredients of the bacillus albosis (Alistipes finegoldii) and immune checkpoint inhibitor for treating tumors,

the use of one or more of a bacterial live, a bacterial derivative, or a bacterial metabolite of a bacterium belonging to the genus Alistipes (Alistipes) for the preparation of a potentiator of an immune checkpoint inhibitor for the treatment of tumors.

Preferably, the use of the a. Fenhnsonii as an active ingredient in the preparation of a potentiator of an immune checkpoint inhibitor, said potentiator being capable of enhancing the effect of the immune checkpoint inhibitor in the treatment of a tumour.

More preferably, the strain of a. Fenhnsonii is a combination of one or more of the following strains:

The invention provides an active whole cell African fens herb (Alistipes finegoldii) for treating tumor patients, which enhances the curative effect of immune checkpoint inhibitors. Specifically, the present invention proposes a combination therapy: immune checkpoint inhibition therapy will be administered simultaneously, separately or sequentially with the administration of the a.feni, thereby increasing the therapeutic effect of immune checkpoint inhibition.

The mode of administration of the A.fensii (Alistipes finegoldii) is oral.

The order of administration of the combination therapy is: the albophenocarps (Alistipes finegoldii) are administered before and/or after the immune checkpoint inhibition treatment.

In the combination therapy, dose delays and/or dose reductions and time adjustments are performed as needed, depending on the individual patient's tolerance to treatment.

The A.fenhnsonii (Alistipes finegoldii) described in the present invention may comprise an effective amount of A.fensonii (Alistipes finegoldii) typically dispersed in a pharmaceutically or pharmacologically acceptable carrier.

The term "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal (e.g., a human, if appropriate). Specific examples of pharmacologically acceptable carriers as described herein are borate buffers or sterile saline solutions.

The potentiated immune checkpoint inhibitor of the present invention is useful in immune checkpoint inhibitor refractory patients, wherein the immune checkpoint inhibitor refractory patient exhibits congenital (primary) resistance to treatment with the immune checkpoint inhibitor, manifested by a lack of response or an insufficient response to treatment with the checkpoint inhibitor for at least about 8 weeks or 12 weeks from the first dose.

The potentiated immune checkpoint inhibitor of the present invention is useful in immune checkpoint inhibitor refractory patients, wherein the immune checkpoint inhibitor refractory patients exhibit acquired (secondary) resistance to treatment with the checkpoint inhibitor as evidenced by an initial response to treatment with the checkpoint, but subsequent recurrence and development of one or more tumors.

The therapeutic effect of the combination therapies described in the present invention is assessed by measuring the enhanced therapeutic effect through increased total survival time.

The therapeutic effect of the combination therapies described in the present invention is assessed by measuring the enhanced therapeutic effect through increased progression free survival.

Evaluation of the therapeutic effect of the combination therapy described in the present invention, wherein the enhanced therapeutic effect is measured by reducing or stabilizing the tumor size of one or more of the tumors, as defined by RECIST 1.1, including disease Stabilization (SD), complete Remission (CR) or Partial Remission (PR) of the target tumor; and/or disease Stabilization (SD) or Complete Remission (CR) of one or more non-target tumors.

The therapeutic effect assessment of the combination therapy described in the present invention measures the enhanced therapeutic effect by improved overall remission rate and/or improved quality of life.

Safety assessment of combination therapy described in the present invention, the safety was measured by whether diarrhea or enteritis was induced.

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, by using the human symbiotic bacteria single-bacterium oral preparation and combining with the immune checkpoint inhibitor, the anti-tumor immune protection response generated by bacterial stimulation can obviously enhance the drug effect of the immune checkpoint inhibitor on a plurality of tumors, and the oral preparation has better safety, prolongs the overall survival time of cancer patients, improves the response rate of cancer immunotherapy crowds, and enlarges the benefited tumor patient crowds of cancer immunotherapy (immune therapy checkpoint inhibitor).

Drawings

Fig. 1 is a flowchart of example 1.

Fig. 2 is a tumor photograph (day 21).

Fig. 3 is a graph showing tumor volume change.

Fig. 4 is a statistical graph of tumor weights.

FIG. 5 is a photograph of the anus of the mouse (day 21)

FIG. 6 is a graph of HE staining of intestinal tissue of mice (day 21).

FIG. 7 shows tumor tissue immunocyte infiltration (day 21).

FIG. 8 is a graph of survival of mice.

FIG. 9 shows the distribution and relative abundance of A.fensonii in different populations.

Detailed Description

The invention will be further described in detail with reference to the drawings and specific examples, which are given solely for the purpose of illustration and are not intended to limit the scope of the invention. The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.

Example 1 therapeutic Effect of Fennella-like immune checkpoint inhibitor on tumors

1. Experimental method

1. Experimental materials

(1) Mouse strain: female C57BL/6J mice of 6 weeks of age

(2) Tumor cell lines: murine melanoma cell line (B16-OVA, ATCC), murine intestinal cancer cell line (MC 38, ATCC)

(3) Bacterial preparation: af (Alistipes finegoldii, DSM No.:17242,Type strain, 16S rDNA sequence of which is shown in SEQ ID NO: 1), abbreviated as Af, is commercially available from DSMZ German national culture Collection (official website of DSMZ: http:// www.dsmz.de).

(4) Bacterial culture medium: the liquid DSMZ104 medium mainly comprises peptone, yeast extract, beef extract, glucose, etc., and is commercially available from DSMZ Germany culture collection.

(5) Immune checkpoint inhibitors: PD-1 monoclonal antibody (alpha PD-1), clone number G4C2, and the reagent was given by Shanghai Junzhen biological medicine science and technology Co., ltd.

(6) Antibiotic combination: metronidazole 100mg/kg, vancomycin 50mg/kg, penicillin sodium 100mg/kg, neomycin sulfate 100mg/kg

2. Experimental grouping

The experimental groupings are shown in table 1,

table 1:

3. experimental procedure (flow chart is shown in FIG. 1)

(1) Bacterial culture: inoculating the Eimeria fenhnsonii to DSMZ104 liquid culture medium, culturing in an anaerobic tank at 37 ℃ for 18 hours, and centrifuging to 1X 10 ¹⁰ CFU/ml。

(2) Subcutaneous inoculation of tumor cells, MC38 cell line 1×10 ⁶ Only, B16-OVA cell line 5X 10 ⁵ /only.

(3) Day 1-3: the indigenous intestinal flora was cleared by the combination of gastric lavage antibiotics in each group of mice.

(4) IgG or alpha PD-1, 200 μg/

day

5, 8, 11, respectively, was intraperitoneally injected.

(5) Bacterial preparation treatment with Af living bacterial liquid by lavage method at

days

5, 7, 9, 11, 13, 15, 100 μl/1×10 ⁹ CFU/CFU.

(6) Tumor sizes were measured on

days

5, 8, 11, 14, 17, 21, respectively, and tumor volumes were calculated.

(7) Mice were euthanized on day 21, tumor tissues were taken out for photographing and weighing, intestinal tissues were taken for HE staining to confirm enteritis:

Measurement of tumor volume of mice, weight measurement of tumors at the final time point, immunohistochemical evaluation of infiltration of tumor tissue immune cells for effect evaluation;

adopting a mouse anus and intestinal tissue section HE staining observation to evaluate whether the Fender-like bacillus can cause enteritis or not so as to perform safety evaluation;

2. experimental results

Fig. 2 shows tumors on day 21. Fig. 3 is a graph showing tumor volume change and fig. 4 is a graph showing tumor weight statistics, in the MC38 intestinal cancer and B16-OVA melanoma mouse models, the single drug immune checkpoint inhibitor group (αpd-1) showed significant and significant (p < 0.01) tumor reduction relative to the placebo treatment group (IgG), while the combination therapy group (αpd-1+af) showed significant and significant (p < 0.01) tumor reduction relative to the single drug immune checkpoint inhibitor group (αpd-1), demonstrating that the b.Fender-like bacillus has an anti-tumor effect of enhancing αpd-1. The tumor of the Monomonas fenhnsonii treated group mice (IgG+Af) was indistinguishable from that of the placebo treated group (IgG), indicating that the anti-tumor effect of the Monomonas fensonii was dependent on αPD-1.

The anus photograph of the mice in fig. 5 and the intestinal tissue section HE staining of fig. 6 show that no enteritis phenomenon is found in the mice of the combination therapy group (αpd-1+af) and the single bacteria of the species of the bacillus fenhnsonii (igg+af), which proves the safety of the gastrointestinal administration of the bacillus fenhnsonii.

Fig. 7 shows that the experimental endpoint MC38 mouse model tumor tissue immunohistochemistry shows that the treatment group of a single bacterium of the agrobacterium fenhnsonii (igg+af) can significantly increase the cd4+ helper T cell infiltration of the tumor interstitial region, and that the combination therapy group (αpd-1+af) shows an increased tendency of the cd4+ helper T cell infiltration of the tumor interstitial region compared to the single immune checkpoint inhibitor group (αpd-1), but does not reach a statistical difference. There was also only a trend of increased cd4+ helper T cell infiltration at the end of the mice experiment in the single drug immune checkpoint inhibitor group (αpd-1) compared to placebo group (IgG), and no statistical difference was reached. This result suggests that the effects of αpd-1 monotherapy and combination therapy (αpd-1+af) on immune cell infiltration of mouse tumor tissue may be short-lived and no significant differences could be detected in tumor samples at the experimental endpoint. The effect of the Fender-like bacillus single-bacterium treatment (IgG+Af) on the immune cell infiltration of the mouse tumor tissue lasts longer, the significantly increased infiltration of CD4+ helper T cells was still present after one week of treatment cessation, confirming the modulating effect of oral administration of B.fensonii on systemic immunity.

EXAMPLE 2 extension of total survival time by different doses of Eimeria tenella in combination with different immune checkpoint inhibitors

1. Experimental method

1. Experimental materials

(1) Mouse strain: female C57BL/6J mice of 6 weeks of age

(3) Bacterial preparation: af.Fender (Alistipes finegoldii, DSM No.:17242,Type strain, 16S rDNA sequence of which is shown in SEQ ID NO: 1), abbreviated as Af, commercially available from DSMZ Germany national culture Collection.

(5) Immune checkpoint inhibitors: PD-1 monoclonal antibody (alpha PD-1), clone number G4C2, and the reagent was given by Shanghai Junzhen biological medicine science and technology Co., ltd. CTLA4 mab (αctla 4), clone number 9D9, commercially available from BioXcell, usa.

2. Experimental grouping

The experimental groupings are shown in table 2,

TABLE 2

3. Experimental procedure (flow chart is shown in FIG. 1)

(4) IgG or αpd-1 or αctla4, 200 μg/person was intraperitoneally injected every 3 days starting on day 5.

(5) Bacterial preparation treatment with different doses of Af live bacterial fluid was performed by gavage every 2 days, starting on day 5, with a low dose group (low) of 100 μl/1×10 ⁹ CFU/medium dose group (medium) 200. Mu.l/medium, 2X 10 ⁹ CFU/high dose group (high) 400. Mu.l/high, 4X 10 ⁹ CFU/CFU.

(6) Tumor size was measured every 3 days starting on day 5, and tumor volume was calculated.

(7) The treatment period was continued until the tumor of the mice grew to an ethical volume size (2000 mm) ³ ) Euthanasia was performed or the tumor ethical volume was not reached and death was natural.

(8) The death status and time of each mouse were recorded and survival plots were drawn.

2. Experimental results

FIG. 8 is a graph showing that in the MC38 intestinal cancer and B16-OVA melanoma mice models, both the medium (medium) and low (low) doses of the combination therapy (αPD-1+Af) significantly increased survival time in tumor-bearing mice relative to the single drug immune checkpoint inhibitor group (αPD-1). Af also exhibits efficacy-promoting effects on an αCTLA4 immune checkpoint inhibitor in a B16-OVA melanoma mouse model: both high (high), medium (medium) and low (low) doses of Af in combination with αctla4 significantly increase survival time in tumor-bearing mice. In the MC38 intestinal cancer mouse model, the efficacy of the alpha CTLA4 immune checkpoint inhibitor is too strong, so that the synergy of Af on the alpha CTLA4 is not observed.

Example 3A. Fengii (Alistipes finegoldii) is an endogenous gut symbiotic bacterium in humans

1. Experimental method

Four human intestinal metagenomic datasets were analyzed, containing 1396 human stool samples in total, involving 9 different types of populations. The metagenome sequencing technology can reach the accuracy of human intestinal tract strain level identification.

9 different types of people include: 1) Healthy adults; 2) Patients with colorectal adenoma; 3) Colorectal cancer patients; 4) Patients post-colorectal cancer surgery; 5) Patients with atherosclerotic disease; 6) Non-small cell lung cancer patients prior to receiving Immune Checkpoint Inhibitors (ICIs); 7) Non-small cell lung cancer patients after receiving Immune Checkpoint Inhibitors (ICIs); 8) Intestinal microbiota macrogenomic data of renal cancer patients prior to receiving Immune Checkpoint Inhibitors (ICIs); 9) Renal cancer patients after receiving Immune Checkpoint Inhibitors (ICIs).

The details of the dataset are shown in table 3.

Table 3 human intestinal metagenome public dataset:

2. experimental results

As shown in fig. 9 and table 4, the results show that the fens's bacillus (Alistipes finegoldii) exists in different populations, the relative abundance is 0.001-0.07%, and the fens' bacillus is different in different populations, wherein the relative abundance refers to the ratio of a certain strain to the total bacterial strain in the intestinal tract. According to the total bacterial species contained in the human intestinal tract of about 10 ¹⁴ CFU/ml estimation, the quantity of Eimeria fensis in human intestinal tract was about 10 ⁹ CFU/ml～10 ¹⁰ CFU/ml。

TABLE 4 relative abundance of Fennella in different populations

It should be noted that the above embodiments are merely for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and that other various changes and modifications can be made by one skilled in the art based on the above description and the idea, and it is not necessary or exhaustive to all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.

Claims

1. Use of bacteria in tumor treatment is provided.

2. The use according to claim 1, wherein the bacterial species belongs to the genus alistripes (alistripes), i.e. the 16S rDNA sequence of the bacterial species has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identity with the 16S rDNA sequence of the genus alistripes (alistripes).

3. The use according to claim 2, wherein the bacteria belonging to the genus alibacterium (Alistipes) are one or more species or combinations of strains of bacteria belonging to the genus Alistipes (Alistipes).

4. Use according to claim 3, characterized in that the bacterium belonging to the genus Alistipes (Alistipes) is alistibium fenshi (Alistipes finegoldii).

5. Use according to claim 3, characterized in that the a.fenhnsonii (Alistipes finegoldii) comprises a 16S rDNA sequence which has at least 99% identity with the 16S rDNA sequence of a a.fensonii species (Alistipes finegoldii).

6. The use according to claim 5, wherein the a.fenhnsonii (Alistipes finegoldii) comprises a 16S rDNA sequence which has at least 99.5% or 100% identity with the 16S rDNA sequence of a a.fensonii strain DSM17242 (Alistipes finegoldii DSM 17242).

7. The use according to claim 5 or 6, wherein the strain of a. Fenhnsonii (Alistipes finegoldii) is a combination of one or more strains of a. Fensonii (Alistipes finegoldii).

8. The use according to claim 7, characterized in that the strain name of the subclass classification in the strain of the strain albophenocissus (Alistipes finegoldii) is: alistipes finegoldii DSM17242, alistipes finegoldii D53t1_180928_d3, alistipes finegoldii 2789STDY5834947, alistipes finegoldii1001713B170207_170306_h2, alistipes finegoldii dfi.2.31, alistipes finegoldii BIOML-A1, alistipes finegoldii dfi.2.16, alistipes finegoldii dfi.2.10, alistipes finegoldii aa _0143, alistipes finegoldii 2789STDY5608890, alistipes finegoldii MGBC116453, alistipes finegoldii COPD076, or Alistipes finegoldii UBG 195.

9. The use according to claim 7, wherein the strain of a. Fenhnsonii is one or a combination of several of the following strains:

the strain of Eimeria tenuifolia deposited with the German collection of DSM microorganisms and cell cultures under accession number DSM 17242;

the strain is deposited in the Japanese JCM strain collection with the accession number JCM 16770;

the strain is deposited in the Korean KCTC strain collection with the accession number of KCTC 15236;

the strain is deposited in a reference laboratory of Helsinki anaerobe, finland, with accession number AHN 2437;

the bacillus dysenteriae is preserved in the sweden CCUG strain preservation center and has the preservation number of CCUG 46020;

the bacillus dysenteriae is deposited in French CIP strain collection with accession number CIP 107999.

10. The use according to claim 1, wherein the bacteria comprise one or more of live bacteria, bacterial derivatives, or bacterial metabolites.

11. The use according to claim 10, wherein the live bacteria are whole bacteria.

12. The use according to claim 10, wherein the live bacteria are whole viable bacteria.

13. The use according to claim 10, wherein the bacterial metabolites include all molecules produced or modified by the bacteria during their preparation and storage and during transit in the gastrointestinal tract of a mammal as a result of bacterial growth, survival, retention, transit or presence.

14. Use according to claim 13, wherein the bacterial metabolites comprise all organic acids, inorganic acids, bases, proteins and peptides, enzymes and coenzymes, amino acids and nucleic acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, all biologically active compounds, metabolites containing inorganic components and all small molecules, such as nitrogen-containing molecules or sulfurous acid-containing molecules.

15. The use according to claim 10, wherein the bacterial derivatives comprise bacterial constituents and genetic material and related constituents, examples of which include bacterial cell membranes, pili, flagella, LPS, nucleic acid material and the like derived from bacteria.

16. Use according to any one of claims 1 to 15, characterized in that the bacterium belonging to the genus Alistipes (Alistipes) and the immune checkpoint inhibitor are administered simultaneously or separately.

17. The use according to claim 1, wherein the treatment of a tumor is tumor shrinkage or stabilization, prolonged total survival, prolonged non-worsening survival, improved quality of life.

18. The use according to claim 1, wherein the tumors are adenomas, malignant tumors and adenocarcinomas, wherein the tumors are classified by tissue origin or cell name, comprising: adrenal cortex cancer, bladder urothelial cancer, breast cancer, pancreatic cancer, cervical cancer, cholangiocarcinoma, colon cancer, colorectal cancer, diffuse large B-cell lymphoma, glioblastoma multiforme, glioma, head and neck cancer, kidney chromocytoma, mixed kidney cancer, leukemia, lymphoma, brain cancer, liver cancer, lung adenocarcinoma, lung squamous carcinoma, mesothelioma, ovarian cancer, pancreatic cancer, pheochromocytoma, paraganglioma, prostate cancer, rectal adenocarcinoma, sarcoma, skin melanoma, gastric cancer, esophageal cancer, testicular cancer, thyroid cancer, thymus cancer, endometrial cancer, uterine sarcoma, uveal melanoma, and soft tissue sarcoma.

19. The use according to claim 1, wherein the tumor is a malignant tumor, a metastatic tumor or a non-metastatic tumor.

20. The use of claim 1, wherein the neoplasm herein comprises malignant, metastatic and non-metastatic types; including any stage of cancer.

21. The use according to claim 16, wherein the immune checkpoint inhibitor is a combination of one or more of the blocking agents acting on T cell negative co-stimulatory (co-inhibitory) molecules and/or their respective ligands.

22. The use according to claim 21, wherein the T cell negative co-stimulatory (co-inhibitory) molecules and/or their respective ligands are selected from CTLA-4, PD-1, PD-L2, B7-1, B7-2, B7-H3, B7-H4, B7-H6, A2AR, IDO, TIM-3, BTLA, VISTA, TIGIT, LAG-3, CD40, KIR, CEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, TNFR, dcR3.

23. The use of claim 22, wherein the blocker of the ligand of the T cell negative co-stimulatory (co-inhibitory) molecule is selected from the group consisting of nano Wu Liyou mab, ipilimumab, palbocuzumab, atocyzumab, alt Zhu Shan mab, caryophyllumab, ti Lei Lizhu mab, dulcis You Shan mab, tremelimumab, swadazumab, avermectin, singdi Li Shan mab, terep Li Shan mab, cim Li Shan mab, MGA012, MGD013, MGD019, enbelicumab, MGD009, MGC018, MEDI0680, PDR001FAZ053, TSR022, MBG453, relatlimab, LAG, 525, reng 321, REGN3767, pexidantinib, 3022855, FPA008, z945, GDC0919, blub, indoximid, BMS986205, CPI-444, MEDI 47, PBF509, LY monoclonal LY, or a combination of any of them; preferably, wherein the blocking agent is selected from the group consisting of nano Wu Liyou mab, palbociclib mab, terlipressin Li Shan antibody, singal Li Shan antibody, cimipramin Li Shan antibody or a combination of any of the several.

24. The use according to claim 21, wherein the immune checkpoint inhibitor is an inhibitor acting on the PD-1/PD-L1 signaling pathway and/or the PD-1/PD-L2 signaling pathway, wherein PD-1 refers to the apoptosis protein 1, PD-L1 (B7-H1 or CD 274) and PD-L2 (B7-DC or CD 273) are ligands for PD-1.

25. The use of claim 24, wherein the inhibitor of the PD-1/PD-L1 signaling pathway or the PD-1/PD-L2 signaling pathway is selected from the group consisting of sodium Wu Liyou mab, palbociclizumab, atozumab, att Zhu Shan mab, cerivizumab, ti Lei Lizhu mab, dulvalli You Shan mab, swainsomumab, avermectin, sitagliptin Li Shan mab, terep Li Shan mab, cimipn Li Shan mab, MGA012, MGD013, MGD019 (PD-1/CTLA-4 diab), MEDI0680, PDR001, FAZ053, or a combination of any of several thereof.

26. The use according to claim 23, wherein the immune checkpoint inhibitor is an inhibitor acting on CTLA-4/B7-1 signaling pathway and/or CTLA-4/B7-2 signaling pathway, wherein CTLA-4 refers to cytotoxic T lymphocyte protein 4, B7-1 (CD 80) and B7-2 (CD 86) are ligands for CTLA-4.

27. The use according to claim 26, selected from the group consisting of ipilimumab, tremelimumab, MGD019 or a combination of any of these.

28. The use according to any one of claims 16 to 27, wherein the immune checkpoint inhibitor is an inhibitor acting on the PD-1/PD-L1 signalling pathway and/or the PD-1/PD-L2 signalling pathway and/or an inhibitor acting on the CTLA-4/B7-1 signalling pathway and/or the CTLA-4/B7-2 signalling pathway.

29. The use according to claim 1, wherein the chemotherapy, immunotherapy or radiation therapy is performed simultaneously, separately or sequentially with the administration of the strain of alternaria tenuifolia.

30. The use according to claim 1, wherein the subject to which the use is administered is a human being, which is an infant, a child, a adolescent, an adult or an elderly person.

31. The use of claim 1, wherein the subject to which the use is administered is a non-human primate, the non-human primate being a mammal.

32. The use according to claim 1, wherein the bacteria are present in an amount of 10 comprising the bacteria ⁵ To 10 ¹² Between CFUs, or at 10 ⁷ To 10 ¹¹ Between CFUs, or 10 ⁸ To 10 ¹¹ Between CFUs, or 10 ⁹ To 10 ¹¹ Between CFUs, or 10 ¹⁰ To 10 ¹¹ Dosage administration between CFUs, more preferably at 10 comprising the bacteria ⁹ To 10 ¹¹ Dosage administration between CFUs.

33. Kit for tumor treatment, characterized in that it comprises one or more of the immune checkpoint inhibitors of any one of claims 16, 21 to 28 and the bacteria of any one of claims 1 to 15, and optionally a container;

or consist of one or more of the immune checkpoint inhibitor of any one of claims 16, 21 to 28 and the bacterium of any one of claims 1 to 15, and optionally comprising a container.

34. A bacterium comprising a 16S rDNA sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or 100% identical to a 16S rDNA sequence of bacillus alistripes (alistripes).

35. A bacterium comprising a 16S rDNA sequence that is at least 99% identical to the 16S rDNA sequence of a. Fense (Alistipes finegoldii).

36. A bacterium comprising a 16S rDNA sequence, which 16S rDNA sequence has at least 99.5% or 100% identity to a 16S rDNA sequence of any one of the following strains:

37. A formulation, characterized in that an effective amount of a composition of one or more of the bacteria of any one of claims 34 to 36 for the treatment of tumors is formulated into a lyophilized powder, tablet, capsule, granule or injection by adding a pharmaceutically acceptable carrier and excipients; wherein "pharmaceutically acceptable carrier" refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered. Wherein the "adjuvant" refers to solvent, diluent or other excipient, dispersant, and surfactant.

38. A composition comprising a bacterium according to any one of claims 34 to 36 and a pharmaceutically acceptable carrier.

39. A composition, characterized in that it comprises a bacterium according to any one of claims 34 to 36 formulated for use as a medicament.

40. A composition, characterized in that it comprises a bacterium according to any one of claims 34 to 36 formulated for use as a medical food.

41. A composition, characterized in that it comprises a mixture of two or more bacteria according to any one of claims 34 to 36, and optionally further comprises a pharmaceutically acceptable carrier.

42. A composition, characterized in that it comprises an effective amount of a mixture of two or more bacteria according to any one of claims 34 to 36 for the treatment of tumors, and optionally also a pharmaceutically acceptable carrier.

43. A composition comprising an effective amount of one or several of the bacterial live bacteria, bacterial derivatives, or bacterial metabolites of two or more bacteria of any one of claims 34 to 36 for tumor treatment, and optionally further comprising a pharmaceutically acceptable carrier.

44. A food, beverage, food supplement, probiotic or health food comprising the bacterium of any one of claims 34 to 36 formulated for enteral nutrition.

45. A food, beverage, food supplement, probiotic or health food product comprising a mixture of two or more bacterial strains according to any one of claims 34 to 36 formulated for enteral nutrition.

46. The bacterium, formulation, or composition of any one of claims 34 to 43, wherein said bacterium or composition is formulated as a lyophilized powder, tablet, capsule, granule, or injection.

47. The bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food according to any one of claims 34 to 45, characterized in that the subject to which it is administered is a human.

48. The bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food according to any one of claims 34 to 45, wherein the human is an infant, a child, a adolescent, an adult, or an elderly person.

49. The bacterium, composition, food, beverage, food supplement, probiotic, or nutraceutical of any one of claims 34 to 45, administered to a non-human primate, the non-human primate being a mammal; birds; a reptile; fish; an amphibian; arthropods or livestock animals.

50. Use of a bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food according to any one of claims 34 to 45 in the treatment of a tumor.

51. The bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food of any one of claims 34 to 45, comprising an effective amount of said bacterium, for use in tumor therapy.

52. A bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food according to any one of claims 34 to 45, comprising an effective amount of said bacterium, for use in tumor therapy, characterized in that said tumor therapy is administered the bacterium, formulation, composition, food, beverage, food supplement, probiotic, or health food according to any one of claims 34 to 45.

53. A composition comprising an effective amount of the bacterium or composition of any one of claims 32 to 33 for treating cancer, and optionally further comprising a pharmaceutically acceptable carrier.

54. A composition comprising an effective amount of two or more bacteria or compositions of any one of claims 32 to 33 for treating cancer, and optionally further comprising a pharmaceutically acceptable carrier.

55. The use of one or more of a bacterial live, a bacterial derivative, or a bacterial metabolite of a bacterium belonging to the genus Alistipes (Alistipes) for the preparation of a potentiator of an immune checkpoint inhibitor for the treatment of tumors.