CN114306616B - New application of bacteroides fragilis and immune checkpoint inhibitor - Google Patents
New application of bacteroides fragilis and immune checkpoint inhibitor Download PDFInfo
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- CN114306616B CN114306616B CN202210030390.1A CN202210030390A CN114306616B CN 114306616 B CN114306616 B CN 114306616B CN 202210030390 A CN202210030390 A CN 202210030390A CN 114306616 B CN114306616 B CN 114306616B
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- bacteroides fragilis
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- immune checkpoint
- lymphoma
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Abstract
The invention relates to a new application of bacteroides fragilis and an immune checkpoint inhibitor. The application of the combination of the bacteroides fragilis and the immune checkpoint inhibitor in preparing medicaments for preventing and treating lymphoma is provided, wherein the preservation number of the bacteroides fragilis is CGMCC No.10685. Compared with the prior art, the invention has the following beneficial effects: a large number of experiments prove that the bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685 is used in combination with an immune checkpoint inhibitor, particularly with a PD-1 inhibitor, and can synergistically act on lymphoma.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to a novel application of bacteroides fragilis and an immune checkpoint inhibitor.
Background
Lymphomas (lymphomas) are malignant tumors originating in the lymphohematopoietic system and can be divided into two categories, non-hodgkin lymphomas (NHL) and Hodgkin Lymphomas (HL), where NHL is about 10 times HL in incidence and 20 times HL in mortality. The pathology of hodgkin's lymphoma is characterized by the presence of lymphocytes, eosinophils, plasma cells and specific Reed-Steinberg cells in the neoplastic tissue, HL being classified according to the pathology type into nodular lymphocyte-rich and classical types (cHL), cHL being the most common type of hodgkin's lymphoma, accounting for about 90% of which includes the main type of lymphocytes, nodular sclerosis, mixed cell types and lymphocyte depletion. NHL is the sum of a group of independent diseases with very strong heterogeneity, pathologically mainly lymphocytes, histiocytes or reticulocytes with different degrees of differentiation, and can be classified into three major clinical types, namely highly invasive, invasive and indolent lymphomas, according to the natural course of NHL. Depending on the origin of the lymphocytes, B-cell, T-cell and NK-cell lymphomas can be classified. For specific classification details reference is made to the 2016 version of WHO lymphoma classification.
The lymphatic system includes lymph nodes (glands), spleen, thymus and bone marrow. Lymphomas can affect other organs of the body in addition to the lymphatic system. Clinically, there are cachexia, fever and anemia in the late stage, which are most typical of painless lymphadenectasis, hepatosplenomegaly. Due to the differences in lesion sites and ranges, clinical manifestations are inconsistent, and the primary sites may be in lymph nodes, or in extra-nodal lymphoid tissues, such as tonsils, nasopharynx, gastrointestinal tract, spleen, bone, or skin. The primary part of the lymphoid tissue is most commonly found in NHL.
Traditional treatment methods for lymphoma are mainly combined treatment of radiotherapy and chemotherapy, and other treatment methods also comprise hematopoietic stem cell transplantation, surgical treatment, targeted treatment and immunotherapy. The treatment principle is to conduct layered treatment according to the stage and prognosis factors, and is an important examination means for the stage PET/CT. For HL, most HL patients can survive and even heal for a long time due to the progress of chemotherapy and radiotherapy, and the first-line chemotherapy scheme can select ABVD scheme (doxorubicin + bleomycin + vinca + azomethine), CHOP scheme (cyclophosphamide + doxorubicin + vincristine + prednisone), CVP scheme (cyclophosphamide + vincristine + prednisone), EPOCH scheme (etoposide + vincristine + cyclophosphamide + doxorubicin + prednisone), and targeting drug rituximab targeting CD20 is commonly used for HL combination therapy of ib and above. For relapsed/refractory HL patients (r/r HL), autologous hematopoietic stem cell transplantation (auto-HSCT) may be considered to increase the likelihood of secondary cure. Because of the multiple pathological types of NHL and strong heterogeneity, a treatment scheme needs to be formulated according to different pathological subtypes, stages, prognosis factors and treatment purposes. The combined radiotherapy and chemotherapy is the main treatment means. Several common treatments for the pathological type of NHL are presented below. (1) Diffuse large B-cell lymphoma is the most common type of NHL, and the treatment modality is a combination of treatments including medical treatment and radiation therapy. Medical treatments include chemotherapy and biological targeting treatments. The treatment strategy should be adjusted according to age, IPI score and stage, etc., and common treatment scheme such as R-CGOP scheme, i.e. chemotherapy+local radiotherapy 30-36Gy. (2) Follicular lymphoma is the most common indolent lymphoma in the European and American regions, and standard first-line treatment regimens are rituximab combination chemotherapy, which may be selected in a variety of ways. (3) The marginal zone lymphoma originates from B cell stranguria in the marginal zone, and belongs to indolent lymphoma. Personalized treatment regimens for local radiotherapy or surgery, chemotherapy and immunotherapy are selected based on the location and stage. Where gastric mucosa-associated lymphoid tissue lymphomas are associated with HP infection, positive subjects considered anti-HP treatment. Surgical treatment is commonly used for tissue biopsy or treatment of complications, such as rejection of contraindications by patients with combined splenic hyperactivity, which may be considered as a splenectomy procedure to increase blood image, and is more conducive to later chemotherapy. If gastrointestinal lymphoma patients are complicated with gastric perforation, bleeding or obstruction, the medical treatment cannot be alleviated, and surgical treatment can be considered. However, the prior art is not yet free of probiotic products for the treatment of lymphomas.
Disclosure of Invention
Based on the above, the main purpose of the invention is to provide a new application of bacteroides fragilis and immune checkpoint inhibitor, mainly relating to the preparation of a medicine for preventing and treating lymphoma by using bacteroides fragilis with the preservation number of CGMCC No.10685 and the immune checkpoint inhibitor, having synergistic effect on lymphoma and providing a microecological medicine for treating lymphoma.
The aim of the invention can be achieved by the following technical scheme:
the application of bacteroides fragilis and immune checkpoint inhibitor in preparing medicaments for preventing and treating lymphoma is provided, wherein the preservation number of bacteroides fragilis is CGMCC No.10685.
In some embodiments, the bacteroides fragilis is selected from one or more of the following species: live bacteria of bacteroides fragilis, inactivated bacteroides fragilis with complete or incomplete morphological structure, bacteroides fragilis subjected to gene recombination, transformation or modification, attenuation, chemical treatment or physical treatment, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant.
In some of these embodiments, the immune checkpoint inhibitor is selected from one or more of a PD-1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a LAG-3 antibody, a TIM-3 antibody, a VISTA antibody, and an A2aR antibody.
In some of these embodiments, the immune checkpoint inhibitor is a PD-1 antibody or/and a PD-L1 antibody.
In some of these embodiments, the PD-1 antibody is selected from one or more of nano Wu Liyou mab, palbociclib mab, cimetidine Li Shan antibody, terlipressin Li Shan antibody, singeing Li Shan antibody, and karellib mab.
In some embodiments, the PD-L1 antibody is selected from one or more of an alt Zhu Shan antibody, an avermectin, and a divaruzumab. In some of these embodiments, the lymphoma is T-cell lymphoma.
In some embodiments, the medicament comprises one or more of the bacteroides fragilis and the immune checkpoint inhibitor, and a pharmaceutically acceptable adjuvant.
In some embodiments, the adjunct comprises one or more of a diluent, a wetting agent, a binder, a disintegrant, a lubricant, a color-flavor modulator, a solvent, a solubilizer, a co-solvent, an emulsifier, an antioxidant, a metal complexing agent, an inert gas, a preservative, a topical analgesic, a pH modulator, and an isotonic or isotonic modulator.
In some embodiments, the pharmaceutical dosage form comprises a pill, tablet, granule, capsule, powder, suspension, oral liquid, tube feeding, or enema.
In some embodiments, the mode of administration of the drug includes oral administration, enema administration, or parenteral administration.
In some embodiments, the period of administration of the drug comprises intermittent administration, periodic administration, continuous administration, or chronic administration.
A medicine for preventing and treating lymphoma comprises Bacteroides fragilis and immune checkpoint inhibitor, wherein the preservation number of the Bacteroides fragilis is CGMCC No.10685.
In some embodiments, the bacteroides fragilis is selected from one or more of the following species: live bacteria of bacteroides fragilis, inactivated bacteroides fragilis with complete or incomplete morphological structure, bacteroides fragilis subjected to gene recombination, transformation or modification, attenuation, chemical treatment or physical treatment, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant.
In some of these embodiments, the immune checkpoint inhibitor is selected from one or more of a PD-1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a LAG-3 antibody, a TIM-3 antibody, a VISTA antibody, and an A2aR antibody.
In some of these embodiments, the immune checkpoint inhibitor is a PD-1 antibody or/and a PD-L1 antibody.
In some of these embodiments, the PD-1 antibody is selected from one or more of nano Wu Liyou mab, palbociclib mab, cimetidine Li Shan antibody, terlipressin Li Shan antibody, singeing Li Shan antibody, and karellib mab.
In some embodiments, the PD-L1 antibody is selected from one or more of an alt Zhu Shan antibody, an avermectin, and a divaruzumab.
Compared with the prior art, the invention has the following beneficial effects:
a large number of experiments prove that the bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685 is used in combination with an immune checkpoint inhibitor, particularly with a PD-1 inhibitor, and can synergistically act on lymphoma.
Drawings
FIG. 1 is a graph showing colony characteristics of Bacteroides fragilis ZY-312 in example 1 of the present invention;
FIG. 2 is a view of the gram stain of Bacteroides fragilis ZY-312 according to example 1 of the present invention.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples, all of which are commercially available from ATCC, unless otherwise specified; all cell culture materials and pancreatin were purchased from Gibco; all experimental animals were purchased from Zhejiang Veitz laboratory animal technologies Co., ltd; or may be prepared by known methods. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer.
Unless defined otherwise or clearly indicated by context, all technical and scientific terms in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
In recent years, immunotherapy represented by Immune Checkpoint Inhibitors (ICIs) has been developed, and prognosis of patients with relapse difficulties is further improved, for example, immune checkpoint inhibitor PD-1 mab significantly improves prognosis of r/r cHL patients, objective remission rate (objective response rate, ORR) of a plurality of PD1 mab is 70% -80%, complete remission (complete response, CR) is 20% -30% or more, and median 10-year progression-free survival (PFS) is greater than 12 months.
Immune Checkpoint Inhibitors (ICIs) have demonstrated excellent therapeutic efficacy in the field of tumor therapy, with programmed cell death receptor-1 (PD-1) being primarily an inhibitory receptor present on T cells, interacting with programmed cell death ligand 1 (PD-L1) expressed by tumor cells, inhibiting T cell proliferation, activation and secretion of cytokines, thereby causing tumor immune escape. There is increasing evidence that PD-1/PD-L1 inhibitors have great potential in the treatment of a variety of tumors. The PD-1/PD-L1 inhibitors which are effectively obtained for Hodgkin's lymphoma in China are as follows: carilizumab (Camrelizumab), tirelizumab (islelizumab), xindi Li Shan anti (intelimab), pie An Puli mab (enpulimab).
It has been shown that Bifidobacterium (bifidobacteria) obtained by comparison and screening is a genus of bacteria positively correlated with anti-tumor immune response, wherein Bifidobacterium longum (b. Longum) and Bifidobacterium breve (b. Breve) can indirectly regulate the expression of specific genes of dendritic cells, promote maturation and secretion of IFN-gamma cytokines, further enhance infiltration of CTLs in tumor tissues and increase activity thereof, and improve anti-tumor immune response. Researchers at the tumor research center of the national institute of ancient taffeta and roxi find that antibiotic treatment weakens the ICIs treatment effect of patients with non-small cell lung cancer, renal cell carcinoma and urothelial cancer, and the strain with the greatest influence on the curative effect is mucin-Ackermans (A.muciniphila) through metagenome sequencing comparison and screening, so that the treatment effect of PD-1 inhibitors on tumor-bearing mice can be effectively improved.
Bacteroides fragilis (Bacteroides fragilis, b.fragilis) is a gram-negative, rod-shaped, both ends blunt round and concentrated, capsular, non-spore, unpowered, obligate anaerobic bacterium, which is classified into Enterotoxigenic (ETBF) and non-enterotoxigenic (NTBF), which are part of normal flora in the human and animal intestinal tracts, and normally colonize mucous membranes in the respiratory tract, gastrointestinal tract, and genitourinary tract of humans, and the like. Applicant research team explored from 2012 and isolated bacteroides fragilis b.fragilis (strain ZY-312) from healthy infant feces. However, there is no report of synergistic treatment of lymphoma using the Bacteroides fragilis and an immune checkpoint inhibitor.
The bacteroides fragilis ZY-312 adopted by the invention does not contain BFT genes, is a non-toxigenic strain, and has acute toxicity proved that the strain has no pathogenicity to normal mice and nude mice (Wang Y, deng H, li Z, tan Y, han Y, wang X, du Z, liu Y, yang R, bai Y, bi Y, zhi F.safety Evaluation of a Novel Strain of Bacteroides fragilis.front Microbiol.2017 Mar 17; 8:435.). According to patent zl2015175508. X and scientific literature Xu W, su P, zheng L, fan H, wang Y, liu Y, lin Y, zhi f.in vivo Imaging of a Novel Strain of Bacteroides fragilis via Metabolic labeling. Front microbiol.2018 Oct 1;9:2298. The strain has better tolerance to gastric acid and bile salts, and can ensure survival and effective colonization in the stomach.
The microbial strain used in the implementation process of the invention is preserved in China general microbiological culture Collection center (CGMCC) (No. 3 of North Chen West Lu 1 of the Korean area of Beijing city) in China general microbiological culture Collection center (CGMCC) of 4 months and 2 days of 2015. Classification naming: bacteroides fragilis ZY-312 (bacteroides fragilis ZY-312) with the preservation number of CGMCC No.10685. Bacteroides fragilis ZY-312 was isolated by the applicant's entity and has been under the authority of the patent protection (patent No. 2015175508. X), and under the provisions of the patent prosecution guidelines, the public was able to buy from commercial sources or has been granted without preservation, i.e. without providing proof of preservation.
The invention provides application of bacteroides fragilis and immune checkpoint inhibitor in preparing medicines for preventing and treating lymphoma, wherein the preservation number of bacteroides fragilis is CGMCC No.10685.
The bacteroides fragilis and the immune checkpoint inhibitor act on lymphoma together, so that the levels of pro-inflammatory factors IL-6, IL-8, IL-2R, TNF-alpha and IL-21 are reduced, migration of CD8+ effector T cells is increased, recruitment of Treg cells is reduced, weight of in-situ tumors is reduced, and cancer inhibition rate is increased.
In one example, the bacteroides fragilis is selected from one or more of the following species: live bacteria of bacteroides fragilis, inactivated bacteroides fragilis with complete or incomplete morphological structure, bacteroides fragilis subjected to gene recombination, transformation or modification, attenuation, chemical treatment or physical treatment, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant.
In one example, the immune checkpoint inhibitor is selected from one or more of a PD-1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a LAG-3 antibody, a TIM-3 antibody, a VISTA antibody, and an A2aR antibody.
Preferably, the immune checkpoint inhibitor is a PD-1 antibody or/and a PD-L1 antibody.
Preferably, the PD-1 antibody is selected from one or more of nano Wu Liyou mab, palbociclib mab, cimetidine Li Shan antibody, terlipressin Li Shan antibody, singeing Li Shan antibody and carrilizumab.
Preferably, the PD-L1 antibody is selected from one or more of Ab Zhu Shan antibody, ab-luronidase and Duvaluzumab.
In one example, the lymphoma is a T cell lymphoma.
In one example, the medicament comprises one or more of the bacteroides fragilis and the immune checkpoint inhibitor, and a pharmaceutically acceptable adjuvant.
It will be appreciated that the adjuvant is selected from one or more of the following adjuvant classes including, but not limited to: diluents, wetting agents, binders, disintegrants, lubricants, color and flavor modifiers, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, topical analgesics, pH modifiers, isotonic or isotonic modifiers. The diluent may be selected from the group including, but not limited to: starches, sugars, celluloses, and inorganic salts. The wetting agent may be selected from the group including, but not limited to: water and ethanol. The binder may be selected from the group including, but not limited to: starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol. The disintegrant may be selected from the group including, but not limited to: starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surfactant and effervescent disintegrating agent. The lubricant may be selected from the group including, but not limited to: talcum powder, calcium stearate, magnesium dodecyl sulfate, micro silica gel and polyethylene glycol. The color, fragrance, and taste modifier may be selected from the group consisting of, but not limited to: pigments, fragrances, sweeteners, mucilages, and flavoring agents. The solvent may be selected from the group including, but not limited to: water, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil and ethyl acetate. The solubilizing agent may be selected from the group including, but not limited to: tween, zee, polyoxyethylene fatty alcohol ethers, soaps, sulphates, sulphonates. The co-solvent may be selected from the group including, but not limited to: organic acid and salts thereof, amide and amine compounds, inorganic salts, polyethylene glycol, povidone and glycerin. The emulsifier may be selected from the group including, but not limited to: span, tween, mesitylene, benzyl, glycerol fatty acid ester, higher fatty acid salt, sulfate, sulfonate, acacia, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silica, bentonite. The suspending agent may be selected from the group including, but not limited to: glycerin, syrup, acacia, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, and thixotrope. The antioxidant may be selected from the group including, but not limited to: sulfite, metabisulfite, bisulfite, ascorbic acid, gallic acid, esters. The metal complexing agent may be selected from the group including, but not limited to: disodium edetate, polycarboxylic acid compounds. The inert gas may be selected from the group including, but not limited to: nitrogen and carbon dioxide. The preservative may be selected from the group including, but not limited to: nipagin, organic acid and salts thereof, quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oil. The topical analgesic may be selected from the group including, but not limited to: benzyl alcohol, chlorobutanol, lidocaine, procaine. The pH adjuster may be selected from the group including, but not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate, and citrate. The isotonic or isotonic modulator may be selected from the group including, but not limited to: glucose, sodium chloride, sodium citrate, sorbitol, xylitol.
It will be appreciated that the medicament may be formulated into a suitable dosage form according to clinical requirements, and that the dosage form may be selected from the group consisting of, but not limited to: pill, tablet, granule, capsule, powder, suspension, oral liquid, tube feeding preparation or enema.
It will be appreciated that the drug may be administered according to clinical requirements using a suitable route of administration which may be selected from the group including, but not limited to: oral administration, enema administration or parenteral administration.
It will be appreciated that the medicament may be administered according to clinical requirements using a suitable administration period, which may be selected from the group including, but not limited to: intermittent administration, periodic administration, continuous administration, or chronic administration.
It will be appreciated that the medicament may be a human or veterinary medicament.
As another aspect of the inventionThe invention provides a medicine for preventing and treating lymphoma, which comprises bacteroides fragilis and an immune checkpoint inhibitor, wherein the preservation number of the bacteroides fragilis is CGMCC No.10685.
In one example, the bacteroides fragilis is selected from one or more of the following species: live bacteria of bacteroides fragilis, inactivated bacteroides fragilis with complete or incomplete morphological structure, bacteroides fragilis subjected to gene recombination, transformation or modification, attenuation, chemical treatment and physical treatment, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant.
In one example, the immune checkpoint inhibitor is selected from one or more of a PD-1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a LAG-3 antibody, a TIM-3 antibody, a VISTA antibody, and an A2aR antibody.
Preferably, the immune checkpoint inhibitor is a PD-1 antibody or/and a PD-L1 antibody.
Preferably, the PD-1 antibody is selected from one or more of nano Wu Liyou mab, palbociclib mab, cimetidine Li Shan antibody, terlipressin Li Shan antibody, singeing Li Shan antibody and carrilizumab.
Preferably, the PD-L1 antibody is selected from one or more of Ab Zhu Shan antibody, ab-luronidase and Duvaluzumab.
In one example, the lymphoma is a T cell lymphoma.
Example 1: fermentation culture of bacteroides fragilis
The bacteroides fragilis ZY-312 strain is streaked and inoculated on a blood plate for anaerobic culture for 48 hours. Colony morphology, staining characteristics, size, sphere shape, distribution, etc. were observed.
Colony characteristics: after the bacteroides fragilis ZY-312 is cultured on a blood plate for 48 hours, the bacteroides fragilis ZY-312 is slightly convex, semitransparent, white, smooth in surface and free from hemolysis, and the colony diameter is between 1 and 3mm, as shown in figure 1.
Morphology under microscope: the bacteroides fragilis ZY-312 was subjected to gram-stain microscopic examination to show a typical rod shape for gram-negative bacteria, and was rounded at both ends to be densely stained, and the non-colored part in the middle of the thallus was formed as a cavitation, see FIG. 2.
And (3) selecting a single colony, inoculating the single colony into a plant source peptone liquid culture medium, fermenting and culturing for 8 hours (the temperature is 37 ℃), centrifuging and precipitating the obtained bacterial liquid at the rotating speed of 3000r/min for 15min, removing the supernatant, and collecting the precipitate to obtain the bacteroides fragilis ZY-312 bacterial sludge.
Example 2: preparation of live bacterial liquid of bacteroides fragilis
(1) The strain is streaked and inoculated on a blood plate, and anaerobic culture is carried out for 48 hours at 37 ℃.
Colony characteristics: after the bacteroides fragilis ZY-312 is cultured on a blood plate for 48 hours, the bacteroides fragilis ZY-312 is slightly convex, semitransparent, white, smooth in surface and free from hemolysis, and the colony diameter is 1-3mm.
(2) And (3) increasing bacteria: and (3) selecting a single colony from the step (1), inoculating the single colony into TSB (tryptone soybean broth containing 5% fetal bovine serum) for enrichment culture, and preserving the obtained bacterial liquid for later use.
(3) Live bacterial liquid of bacteroides fragilis: the bacterial liquid prepared in the step (1) is used for bacterial count measurement by a Murray turbidimetric tube, and diluted to 10 by normal saline 7 CFU/ml and 10 9 CFU/ml, and stored for later use.
Example 3: preparation of inactivated bacterial powder of bacteroides fragilis
(1) Taking the bacteroides fragilis fermentation liquid prepared in the example 1, centrifuging the fermentation liquid, collecting wet thalli, and mixing the thalli according to the following steps: physiological saline=1 (10-30) (m: v) physiological saline is added to resuspend and wash the bacterial mud, and the washed bacterial body is collected by centrifugation again.
(2) Adding an excipient mixed by 5 weight percent of maltodextrin and 0.9 weight percent of sodium chloride into the thalli obtained in the step (1), and mixing according to the thalli: excipient=1 (5-15) (m: m) and then heat-inactivating (20-40) ±5min at (70-100) ±5 ℃ after stirring and dispersing to obtain an inactivated bacterial liquid.
(3) And (3) centrifuging the inactivated bacterial liquid obtained in the step (2) to collect the inactivated bacterial mud.
(4) Adding an excipient into the inactivated bacterial sludge collected in the step (3) to enable the total weight to be consistent with the weight of the bacterial liquid before inactivation, and stirring to completely dissolve the bacterial liquid to obtain an inactivated bacterial stock solution.
(5) Vacuum freeze drying the inactivated bacteria stock solution obtained in the step (4), pre-freezing for 1-3 hours at minus 40+/-2 ℃, pre-freezing for 0.5-1 hour at minus 20+/-2 ℃, pre-freezing for 0.5-2 hours at minus 40+/-2 ℃ and finally, performing primary drying (-5+/-2 ℃ and 0+/-2 ℃) and analytical drying (35+/-2 ℃) under the vacuum degree of 0.25mbar to prepare the inactivated bacteria powder, wherein the bacterial count of the bacteria powder reaches 1 multiplied by 10 11 Cell/g or more.
Example 4: pharmacodynamic experiments of synergistic treatment of Bacteroides fragilis and PD-1 inhibitor on EL4 mouse T cell lymphoma line model
Infiltrating lymphocytes in the local microenvironment of a tumor play a non-trivial role in the progression of the tumor. Tumor programmed cell death receptor-1 (PD-1) can inhibit T cell activation through binding to its ligand, thereby achieving immune escape of the tumor. Cd8+ effector T cells in tumor immune response bear the main tumor killing activity, while aggregated regulatory T cells in microenvironment play a role in tumor immunosuppression. Numerous studies have shown that the number of regulatory T cells in the peripheral blood of different types of tumor patients is much higher than in normal populations, foxp3+cd4+cd25+ Treg cells are considered to be a major impediment in anti-tumor immunotherapy.
The experiment observes that the change condition of CD8+ effector T cells, regulatory T cells (Treg cells), tumor weight, tumor inhibition rate, mouse survival rate and related cytokines in the T cell lymphoma line model of the EL4 mouse treated by the Bacteroides fragilis and PD-1 inhibitor (BE 0273, bioXcell) in a synergic mode.
1. Cell culture of EL 4T lymphocyte tumor
EL4 cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum at 37℃under a gaseous atmosphere of 5% CO 2 95% air, humidity saturatedHumidity; the culture medium was changed according to the growth rate of cells and the color change of the culture medium, and passaging was digested with 0.25% trypsin. According to the growth condition of cells, preparing cells in logarithmic growth phase into single cell suspension, and regulating cell concentration to 1×10 7 /mL。
After completion of cell line expansion culture, the number of mice was counted before injection to ensure 5×10 per mouse 5 And EL4 cells.
2. Mouse tumor model establishment
(1) Tumor inoculation
Experiments were performed with 7 week male C57B6/L mice, and tumor inoculation was performed after the mice grew naturally for 1 week. All mice except the normal control group were individually vaccinated with tumor cells, the single side underarm of the mice was taken, a 6-gauge needle was subcutaneously injected with 0.2ml of the counted cell suspension, and gentle mixing was performed to ensure that the number of vaccinated cells was the same for each mouse, prior to aspiration of the cell suspension. The tumor growth of the mice was observed.
(2) Modeling success flag
Mice show signs of wasting, bowed back, listlessness, and the like, and the inoculation sites of the mice can reach the tumor.
3. In vivo experiments in mice
(1) Experimental grouping
Table 1, grouping and dosing regimen
(2) Starting administration after 7 days of tumor inoculation, counting survival time of each group of mice after 3 weeks of administration time, killing all mice, peeling off tumor mass and spleen of the mice under aseptic operation, weighing each peeled tumor mass, respectively grinding into cell suspension, filtering tissue residues by a 700-mesh filter screen, washing by PBS for 2 times, centrifugally counting, taking two-tube cell samples from each group, and respectively detecting CD8+ effector T cells, treg cell level and cytokine level by machine.
(3) Observation index
Cd8+ effector T cells, regulatory T cells (Treg cells), tumor weight, tumor rejection rate, and cytokines IL-6, IL-8, IL-2R, TNF- α, IL-21, and the like.
4. Experimental results
(1) Tumor weight and tumor inhibition rate
TABLE 2 weight of each group of tumors and tumor suppression ratio
n＝8)
Note that: compared with the model group, P is less than 0.05, P is less than 0.01, and P is less than 0.001
Tumor inhibition = 100% (mean weight of tumors in model group-mean weight of tumors in dosing group)/mean weight of tumors in model group.
As shown in Table 2, the average tumor weight of the model group was significantly higher than that of the other groups (P < 0.01), and ZY-312 group was slightly higher than PD-1 group (P < 0.05); the weight of tumors in the low, medium and high dose bacteroides fragilis ZY-312 combined PD-1 inhibitor group is lower than that of the PD-1 inhibitor group (P is less than 0.05), wherein the weight of tumors in the high dose bacteroides fragilis ZY-312 combined PD-1 inhibitor group is the lowest; the combined PD-1 inhibitor groups of the medium and high dose Bacteroides fragilis ZY-312 are lower than that of the PD-1 inhibitor group (P is less than 0.05), wherein the tumor weight of the combined PD-1 inhibitor group of the high dose Bacteroides fragilis ZY-312 is the lowest, and the combined PD-1 inhibitor group of the low dose ZY-312 is slightly lower than that of the PD-1 group, but has no statistical difference.
In terms of tumor inhibition rate, the concentration of Bacteroides fragilis ZY-312 and the concentration of the inactivated bacteria combined PD-1 inhibitor are higher than those of a single PD-1 inhibitor (P is less than 0.05), and the ZY-312 is slightly lower than that of the PD-1 inhibitor, but no statistical difference exists.
(2) Cd8+ effector T cells
The spleen and tumor mass were each analyzed for cd8+ effector T cell fraction after 3 weeks of treatment using flow cytometry, as shown in table 3.
In spleen, the model group is higher than normal saline blank control group, the PD-1 inhibitor group is higher than model group, and there is statistical difference (P < 0.01), ZY-312 group is higher than model group (P < 0.05), slightly lower than PD-1 inhibitor group, but there is no statistical difference; the low, medium and high dose of Bacteroides fragilis ZY-312 combined with PD-1 inhibitor group is higher than the PD-1 inhibitor group (P < 0.05), wherein the medium dose of Bacteroides fragilis ZY-312 combined with PD-1 inhibitor group has the highest CD8+ effector T cell ratio; the combination of the low, medium and high doses of the Bacteroides fragilis ZY-312 inactivated bacteria and the PD-1 inhibitor group is higher than the PD-1 inhibitor group (P is less than 0.05), wherein the combination of the medium doses of the Bacteroides fragilis ZY-312 inactivated bacteria and the PD-1 inhibitor group has the highest CD8+ effector T cell ratio.
In tumor, the model group is higher than the normal saline blank control group, the PD-1 inhibitor group is higher than the model group, all have statistical difference (P is less than 0.05), and the ZY-312 group is higher than the model group, but no statistical difference; the low, medium and high dose of Bacteroides fragilis ZY-312 combined PD-1 inhibitor group is higher than the PD-1 inhibitor group (P < 0.05), and the high and medium dose of Bacteroides fragilis ZY-312 combined PD-1 inhibitor group has the highest CD8+ effector T cell ratio; the combination of the low, medium and high doses of the Bacteroides fragilis ZY-312 inactivated bacteria and the PD-1 inhibitor group is higher than the PD-1 inhibitor group (P is less than 0.05), and the high and medium doses of the Bacteroides fragilis ZY-312 inactivated bacteria and the PD-1 inhibitor group have the highest CD8+ effector T cell ratio.
(3) Regulatory T cells (Treg cells)
Flow cytometry was used to detect Treg cell fractions in spleen and tumor mass as shown in table 3.
In the spleen, the model group is significantly higher than the normal saline blank group (P < 0.001), the PD-1 inhibitor group is lower than the model group (P < 0.05), and the ZY-312 group has no statistical difference from the PD-1 inhibitor group; the low, medium and high dose of Bacteroides fragilis ZY-312 combined PD-1 inhibitor group is lower than the PD-1 inhibitor group (P < 0.05), wherein the medium dose of Bacteroides fragilis ZY-312 combined PD-1 inhibitor group has the lowest Treg cell ratio; the low, medium and high dose of Bacteroides fragilis ZY-312 inactivated bacteria combined with PD-1 inhibitor group is lower than the PD-1 inhibitor group (P < 0.05), wherein the low dose of Bacteroides fragilis ZY-312 inactivated bacteria combined with PD-1 inhibitor group has the lowest Treg cell ratio, but is higher than the normal saline blank group (P < 0.05).
In tumor bodies, the model group is significantly higher than the normal saline blank control group (P < 0.001), the PD-1 inhibitor group is lower than the model group (P < 0.05), and the ZY-312 group has no statistical difference from the PD-1 inhibitor group; the low, medium and high dose of Bacteroides fragilis ZY-312 combined with PD-1 inhibitor group is lower than the PD-1 inhibitor group (P < 0.05), wherein the low dose of Bacteroides fragilis ZY-312 combined with PD-1 inhibitor group has the lowest CD8+ effector T cell ratio; the combination of the low, medium and high doses of inactivated Bacteroides fragilis ZY-312 and the PD-1 inhibitor is lower than that of the PD-1 inhibitor (P < 0.05).
TABLE 3 percent of immune cells per group%
n＝8)/>
Note that: compared to the model group, P < 0.05, P < 0.01, P < 0.001.
(4) Cytokines and methods of use
TABLE 4 cytokines of each group
n＝8)
The levels of cytokines such as IL-6, IL-8, IL-2R, TNF-alpha, IL-21, IL-10, etc. in the mouse model of EL4 lymphoma were detected using the luminex technique. As shown in Table 4, the pro-inflammatory factors such as IL-6, IL-8, IL-2R, TNF- α, IL-21 were significantly increased in the model group compared to the normal control group. PD-1 inhibitor can effectively regulate the above cytokines, down-regulate the levels of proinflammatory factors such as IL-6, IL-8, IL-2R, TNF-alpha, IL-21 and the like, similar effects are observed in ZY-312 group, and Bacteroides fragilis ZY-312 can strengthen the PD-1 inhibitor effect.
In conclusion, the bacteroides fragilis and the immune checkpoint inhibitor are used together, so that the growth of the lymphoma can be effectively inhibited, and the compound has a remarkable effect of treating the lymphoma.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (9)
1. The application of bacteroides fragilis and immune checkpoint inhibitors in preparing medicaments for treating lymphoma is provided, wherein the preservation number of bacteroides fragilis is CGMCC No.10685 bacteroides fragilis ZY-312;
the immune checkpoint inhibitor is a PD-1 inhibitor BE0273;
the lymphoma is T cell lymphoma.
2. The use according to claim 1, wherein the bacteroides fragilis is selected from one or more of the following species: live bacteria of bacteroides fragilis and inactivated bacteroides fragilis with complete or incomplete morphological structure.
3. The use according to claim 1 or 2, wherein the medicament comprises the bacteroides fragilis and the immune checkpoint inhibitor, and pharmaceutically acceptable excipients.
4. The use according to claim 3, wherein the adjuvant comprises one or more of diluents, wetting agents, binders, disintegrants, lubricants, color and flavor modifiers, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, local analgesics, pH modifiers and isotonic or isotonic modifiers.
5. The use according to any one of claims 1, 2 and 4, wherein the pharmaceutical dosage form comprises a pill, tablet, granule, capsule, powder, suspension, oral liquid, tube feeding or enema.
6. The use according to any one of claims 1, 2 and 4, wherein the mode of administration of the medicament comprises oral administration, enema administration or parenteral administration.
7. The use according to any one of claims 1, 2 and 4, wherein the administration cycle of the medicament comprises intermittent administration, periodic administration, continuous administration or chronic administration.
8. A drug for treating lymphoma, which is characterized by comprising bacteroides fragilis and an immune checkpoint inhibitor, wherein the bacteroides fragilis has a preservation number of CGMCC No.10685, namely bacteroides fragilis ZY-312;
the immune checkpoint inhibitor is a PD-1 inhibitor BE0273;
the lymphoma is T cell lymphoma.
9. The medicament for treating lymphoma according to claim 8, wherein the bacteroides fragilis is selected from one or more of the following species: live bacteria of bacteroides fragilis and inactivated bacteroides fragilis with complete or incomplete morphological structure.
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| CN115960738A (en) * | 2021-10-12 | 2023-04-14 | 广州知易生物科技有限公司 | Bacteroides fragilis inactivated bacteria powder and preparation method thereof |
| CN114306616B (en) * | 2022-01-12 | 2023-04-28 | 广州知易生物科技有限公司 | New application of bacteroides fragilis and immune checkpoint inhibitor |
| CN114344338B (en) * | 2022-01-12 | 2023-08-04 | 广州知易生物科技有限公司 | Novel application of bacteroides fragilis and/or zwitterionic capsular polysaccharide thereof |
| CN114306615B (en) * | 2022-01-12 | 2023-11-17 | 广州知易生物科技有限公司 | Novel application of bacteroides fragilis capsular polysaccharide A and immune checkpoint inhibitor |
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| CN106399141B (en) * | 2015-07-31 | 2019-07-05 | 广州知易生物科技有限公司 | A kind of bacteroides fragilis and its application |
| KR102530297B1 (en) * | 2016-09-27 | 2023-05-10 | 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 | Methods for Augmenting Immune Checkpoint Blockade Therapy by Modifying the Microbiome |
| CN109528775A (en) * | 2017-09-22 | 2019-03-29 | 中山大学 | Bacteroides fragilis is preparing the application in the drug for treating and preventing tumour |
| CN109793761B (en) * | 2017-11-17 | 2021-03-05 | 瑞微（深圳）生物科技有限公司 | Composition for enhancing T cell immune function and preparation method thereof |
| CN110496140B (en) * | 2018-05-18 | 2022-05-31 | 瑞微（深圳）生物科技有限公司 | Application of bacteroides fragilis or Ackmann myxobacterium in preparation of drugs for preventing or treating tumors |
| CN112472803A (en) * | 2019-09-11 | 2021-03-12 | 上海美迪西生物医药股份有限公司 | Application of combination of anti-PD-1 antibody and anti-CTLA-4 antibody in preparation of medicine for treating kidney cancer |
| CN113244385A (en) * | 2020-02-07 | 2021-08-13 | 上海君实生物医药科技股份有限公司 | Use of anti-PD-1 antibodies in the treatment of malignant tumors |
| CN112877268A (en) * | 2021-04-22 | 2021-06-01 | 上海耀旦生物科技有限公司 | Lactobacillus casei strain for enhancing treatment effect of immune checkpoint inhibitor and application thereof |
| CN114306616B (en) * | 2022-01-12 | 2023-04-28 | 广州知易生物科技有限公司 | New application of bacteroides fragilis and immune checkpoint inhibitor |
| CN114344338B (en) * | 2022-01-12 | 2023-08-04 | 广州知易生物科技有限公司 | Novel application of bacteroides fragilis and/or zwitterionic capsular polysaccharide thereof |
| CN114306615B (en) * | 2022-01-12 | 2023-11-17 | 广州知易生物科技有限公司 | Novel application of bacteroides fragilis capsular polysaccharide A and immune checkpoint inhibitor |
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