CN114344340A - Application of bacteroides fragilis, PD-1 and PD-L1 antibody combined medicine in treatment of respiratory system tumor - Google Patents
Application of bacteroides fragilis, PD-1 and PD-L1 antibody combined medicine in treatment of respiratory system tumor Download PDFInfo
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- CN114344340A CN114344340A CN202210034078.XA CN202210034078A CN114344340A CN 114344340 A CN114344340 A CN 114344340A CN 202210034078 A CN202210034078 A CN 202210034078A CN 114344340 A CN114344340 A CN 114344340A
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses bacteroides fragilis, in particular to bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685, which is combined with a PD-1 antibody and/or a PD-L1 antibody for application, and the application of the bacteroides fragilis ZY-312 and the PD-1 antibody and/or the PD-L1 antibody in correcting the proportion of immune cells of an organism, regulating the level of cell factors related to cancer of the organism, improving the anti-tumor immune response of the organism and effectively preventing and treating tumors of a respiratory system.
Description
The microbial strains used in the implementation process of the invention are preserved in China general microbiological culture Collection center (CGMCC) (No. 3 Hospital No.1 Xilu Beijing, Chaoyang, respectively) 4.2 days in 2015. And (3) classification and naming: bacteroides fragilis ZY-312 (bacterioides fragilis ZY-312), accession number CGMCC No. 10685. Bacteroides fragilis ZY-312 was isolated by the applicant and has been patented (patent No. 201510459408.X), as specified in the patent examination manual, commercially available or licensed to the public without storage, i.e., without providing proof of storage.
Technical Field
The invention relates to an application technology of bacteroides fragilis, in particular to an application of combined application of bacteroides fragilis and a PD-1 antibody or a PD-L1 antibody in treatment of respiratory system tumors.
Background
Respiratory tumors refer to any disease characterized by anatomical localization to malignant cells in the respiratory system, including lung cancer, nasopharyngeal carcinoma in head and neck cancer, laryngeal carcinoma, and the like.
Lung cancer is one of the most dangerous and human threatening malignancies in the world today. Globally, lung cancer is the second most prevalent and most lethal cancer. In China, the incidence and mortality of lung cancer rank the first, and in men, lung cancer is the first cancer killer. Smoking remains a major risk factor for lung cancer, but factors such as air pollution, occupational exposure and genetics also contribute.
Nasopharyngeal carcinoma is the most common malignant tumor of the head and neck, which refers to a malignant tumor that occurs from the epithelium covering the surface of the nasopharyngeal cavity, or the nasopharyngeal crypt. Nasopharyngeal carcinoma is less common than other cancers, however, the incidence rate of nasopharyngeal carcinoma is eighth of all malignant tumors in our country. Nasopharyngeal carcinoma is commonly associated with a combination of factors, including genetics, environmental pollution, exposure to toxic chemicals, and epstein barr virus infection.
Laryngeal carcinoma refers to a tumor with its primary site in the larynx, most commonly squamous cell carcinoma. The incidence of laryngeal cancer is 6/10 ten thousands of people, and the incidence is lower compared with lung cancer, gastric cancer and the like. However, in 2016 CA, the 5-year survival rate of laryngeal cancer decreased from 66% to 63% in the past 40 years, which is one of the few tumors with decreased survival rates. A variety of factors are thought to be associated with the pathogenesis of laryngeal cancer, including smoking, drinking, and exposure to certain toxic chemicals. Human Papillomavirus (HPV) infection is also considered as one of the possible factors.
Most respiratory cancers are already advanced in their development. Early lung cancer often has no obvious symptoms, and most patients are clinically diagnosed with symptoms at an advanced stage. The early diagnosis of nasopharyngeal carcinoma is very difficult, and the patient is easy to miss the optimal treatment time due to missed diagnosis or misdiagnosis. Laryngeal cancer is more commonly referred to as a "silent killer". For respiratory tumor patients without the chance of radical surgical cure, comprehensive treatment mainly including systemic drug therapy is mostly adopted at present. Systemic pharmacotherapy mainly includes chemotherapeutic drugs, molecular targeted drugs and immunotherapeutic drugs.
Immunotherapy drugs are currently the hottest treatment for tumors. The tumor immunotherapy mainly includes immune vaccine, immune checkpoint inhibitor therapy, adoptive immune cell therapy, cytokine therapy, and the like, in which the immune checkpoint inhibitor therapy is spotlighted with its remarkable clinical efficacy.
The immune check point is a molecule playing a protective role in the immune system of a human body, plays a role similar to braking, and prevents inflammatory injury and the like caused by over-activation of T cells. The tumor cells utilize the characteristics of the human immune system, inhibit the reaction of the human immune system by over-expressing immune check point molecules, escape the immune monitoring and killing of the human body, and promote the growth of the tumor cells. The expression of the molecules and the ligands thereof for inhibiting the immune check points can enhance the killing effect of T cells on tumors, thereby achieving the aim of resisting the tumors. The published immune checkpoints are CTLA-4, PD-1/PD-L1, LAG-3, TIM-3, VISTA, A2aR, etc.
Programmed cell death protein 1(PD-1) is expressed on a variety of lymphocytes, particularly on tumor-specific T cells. In the tumor microenvironment, it leads to expansion of malignant cells by interfering with a protective immune response. It has two ligands, programmed cell death ligands 1 and 2(PD-L1, PD-L2), of which PD-L1 is expressed by tumor cells to escape the anti-tumor response that the immune system carries out to it. Blocking the effect between PD-1 and PD-L1 can maintain the response of T cells after the T cells enter a tumor microenvironment, and ensure the anti-tumor effect of the T cells. Antibodies against PD-1/PD-L1 are known as Nivolumab (Nivolumab), Pembrolizumab (Pembrolizumab), JQ1, atelizumab (Atezolizumab), Avelumab (Avelumab) and cimiciprizumab (Cemipilimab). These mabs are approved for the treatment of breast, lung, colorectal, bladder, pancreatic, prostate and diffuse large B-cell lymphoma (DLBCL).
Despite the significant anticancer efficacy of the PD-1/PD-L1 antibody (overall progression-free survival rate of 80%), clinical studies have shown that only 20-45% of patients respond to it. Intestinal microorganisms can affect the immune system of the host and even the efficacy of immune checkpoint inhibitors through their surface molecules (e.g., capsular polysaccharides, flagella, surface proteins, etc.) and metabolites (e.g., short-chain fats, indoles, inosines, etc.). It has been reported that Bifidobacterium plays a promoting role in the therapeutic effect of the PD-1/PD-L1 antibody. The combination of the bifidobacterium breve-bifidobacterium longum-PD-1 antibody can cause the melanoma growth to be almost completely stopped. In addition, high levels of a.mucophilia and f.praussnitzii in the gut were associated with a good response to PD-1 treatment.
Bacteroides fragilis (Bacteroides fragilis) is an obligate anaerobic bacterium which is gram-negative, rod-shaped, blunt and thick-stained at two ends, capsular, spore-free and unpowered, is divided into Enterotoxigenic (ETBF) and non-enterotoxigenic (NTBF), is a part of normal flora of human and animal intestines, mainly exists in colon, and can be colonized and grown on respiratory tract mucosa, gastrointestinal tract and genitourinary tract mucosa. Studies find that non-enterotoxigenic Bacteroides fragilis (NTBF) has an important probiotic effect. The cell factor IL-10 which can regulate the expansion of T cells and prevent the development of pathogenic Th17 cells has anti-inflammatory effect and is considered as a potential new generation of probiotics. A plurality of studies show that NTBF can secrete anti-inflammatory cytokine IL-10, promote the balance of Th1/Th2 cells, resist intestinal inflammation and has a treatment effect on DSS-induced colitis.
Despite the good interaction between intestinal flora and the PD-1/PD-L1 antibody, no probiotics developed specifically for enhancing the therapeutic effect of the PD-1/PD-L1 antibody have emerged. Therefore, there is a need to explore the use of bacteroides fragilis in combination with PD-1/PD-L1 antibodies for the treatment of respiratory tumors.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide the application of the bacteroides fragilis and the PD-1 antibody and/or the PD-L1 antibody in combination in treating the respiratory tumor. A large number of experiments prove that the bacteroides fragilis, particularly the bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685, can correct the proportion of immune cells of an organism, regulate the level of cell factors related to cancer of the organism, improve the anti-tumor immune response of the organism and effectively inhibit the growth of tumors of a respiratory system.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, there is provided a bacteroides fragilis for use in combination with an immune checkpoint inhibitor for the prevention and/or treatment of respiratory tumours.
In some of these embodiments, the immune checkpoint inhibitor comprises one or more of a PD-1 antibody, a PD-L1 antibody, a CTLA-4 antibody, a LAG-3 antibody, a TIM-3 antibody, a VISTA antibody, A2aR antibody, preferably one or more of a PD-1 antibody and/or a PD-L1 antibody, preferably a PD-1 and/or PD-L1 antibody.
In some embodiments, the bacteroides fragilis is one or more of a live bacterium, a morphologically intact killed bacterium, or a morphologically incomplete killed bacterium.
In some embodiments, the bacteroides fragilis is a living bacteroides fragilis, one or more of inactivated, genetically recombined, altered or modified, attenuated, chemically treated, physically treated, or inactivated bacteroides fragilis, a bacteroides fragilis lysate, and a bacteroides fragilis liquid culture supernatant.
In some embodiments, the bacteroides fragilis is bacteroides fragilis ZY-312 with collection number of CGMCC No. 10685.
In some of these embodiments, the respiratory tumor comprises one or more of lung cancer, head and neck squamous cell carcinoma.
In some of these embodiments, the respiratory tumor comprises one or more of small cell lung cancer, non-small cell lung cancer, laryngeal cancer, and nasopharyngeal cancer.
In some of these embodiments, the PD-1 antibody includes Nivolumab (Nivolumab), paribrizumab (Pembrolizumab), cimeprimab (cemipimab), teriprimab (toripilimumab), sedilumab (Cindilimab), carpriluzumab (Camrelizumab), and others that bind to PD-1, block the PD-1/PD-L1 signaling pathway, upregulate T cell activation, activate endogenous anti-tumor immune responses.
In some of these embodiments, the PD-L1 antibodies include atelizumab (Atezolizumab), avizumab (Avelumab), duvaluzumab (Durvalumab), and other substances that bind to PD-L1, block the PD-1/PD-L1 signaling pathway, upregulate T-cell activation, activate endogenous anti-tumor immune responses.
In some of these embodiments, the bacteroides fragilis is administered simultaneously with the PD-1 antibody and/or the PD-L1 antibody.
In some of these embodiments, the bacteroides fragilis is administered separately from the PD-1 antibody and/or the PD-L1 antibody.
In some of these embodiments, the bacteroides fragilis is administered orally or by enema.
In a second aspect, a medicament is provided, wherein the medicament comprises a pharmaceutically effective dose of bacteroides fragilis together with a PD-1 antibody and/or a PD-L1 antibody.
In some of these embodiments, the pharmaceutically effective dose is 106-1010CFU。
In some embodiments, the bacteroides fragilis is one or more of a live bacterium, a morphologically intact killed bacterium, or a morphologically incomplete killed bacterium.
In some embodiments, the bacteroides fragilis is a living bacteroides fragilis, one or more of inactivated, genetically recombined, altered or modified, attenuated, chemically treated, physically treated, or inactivated bacteroides fragilis, a bacteroides fragilis lysate, and a bacteroides fragilis liquid culture supernatant.
In some embodiments, the bacteroides fragilis is bacteroides fragilis ZY-312 with collection number of CGMCC No. 10685.
In some of these embodiments, the respiratory tumor comprises one or more of small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma.
In some of these embodiments, the PD-1 antibody includes Nivolumab (Nivolumab), paribrizumab (Pembrolizumab), cimeprimab (cemipimab), teriprimab (toripilimumab), sedilumab (Cindilimab), carpriluzumab (Camrelizumab), and others that bind to PD-1, block the PD-1/PD-L1 signaling pathway, upregulate T cell activation, activate endogenous anti-tumor immune responses.
In some of these embodiments, the PD-L1 antibodies include atelizumab (Atezolizumab), avizumab (Avelumab), duvaluzumab (Durvalumab), and other substances that bind to PD-L1, block the PD-1/PD-L1 signaling pathway, upregulate T-cell activation, activate endogenous anti-tumor immune responses.
In some of these embodiments, the bacteroides fragilis is administered simultaneously with the PD-1 antibody and/or the PD-L1 antibody.
In some of these embodiments, the bacteroides fragilis is administered separately from the PD-1 antibody and/or the PD-L1 antibody.
In some of these embodiments, the bacteroides fragilis is administered orally or by enema.
According to the invention, the medicament is used for preventing and/or treating respiratory tumors. Wherein the respiratory system tumor comprises non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma.
According to the invention, the head and neck squamous cell carcinoma is selected from nasopharyngeal carcinoma, laryngeal carcinoma.
The invention has the beneficial effects that:
a large number of experiments prove that the bacteroides fragilis, particularly the bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685, is combined with a PD-1 antibody and/or a PD-L1 antibody for application, so that the invention can correct the proportion of immune cells of an organism, adjust the level of cell factors related to cancer of the organism, improve the anti-tumor immune response of the organism and effectively prevent and treat tumors of a respiratory system.
The Bacteroides fragilis ZY-312 adopted by the invention does not contain BFT gene, is a non-toxigenic Strain, and has acute toxicity verification 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 train of bacteria from. According to the patent ZL201510459408.X and the scientific literature Xu W, Su P, Zheng L, Fan H, Wang Y, Liu Y, Lin Y, Zhi F. in vivo Imaging of a Novel train of bacteria from Metabolic laboratory. front Microbiol.2018 Oct 1; 2298, the strain has better tolerance to gastric acid and bile salt, and can ensure the survival and the effective colonization in the stomach.
Drawings
FIG. 1 is a diagram showing the colony morphology of Bacteroides fragilis ZY-312 on a blood plate according to example;
FIG. 2 is a gram-stained microscopic image of Bacteroides fragilis ZY-312 according to example.
Detailed Description
The preparation method of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples were, unless otherwise specified, commercially available raw materials and reagents used in the following examples, and all cells were purchased from ATCC; all cell culture material and pancreatin were purchased from Gibco; all experimental animals were purchased from Zhejiang vitamin Tonglihua laboratory animals technologies, Inc.; or can be prepared by known methods. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations.
Unless defined otherwise or clearly indicated by the background, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
Example preparation of live and inactivated Bacteroides fragilis solutions
The bacteroides fragilis ZY-312 strain is streaked and inoculated on a blood plate, and anaerobic culture is carried out for 48 h. Observing the morphological characteristics, staining characteristics, size, club shape, distribution and the like of colonies.
Colony characteristics: after culturing the bacteroides fragilis ZY-312 on a blood plate at 37 ℃ for 48h, the bacteroides fragilis is slightly convex, semitransparent, white, smooth in surface and non-hemolytic, and the diameter of a colony ranges from 1mm to 3mm, and the bacteroides fragilis ZY-312 is shown in figure 1.
Microscopic morphology: gram-stained bacteroides fragilis ZY-312 was used as gram-negative bacteria, and was typically rod-shaped, with blunt and densely stained ends, and non-staining areas in the middle of the cells, such as vacuoles, as shown in FIG. 2.
And selecting a single colony to inoculate in a plant source peptone liquid medium for fermentation culture for 8 hours (at the temperature of 37 ℃) to obtain the live bacteroides fragilis ZY-312 bacteria liquid.
And (3) carrying out conventional heat inactivation on the obtained live bacteroides fragilis ZY-312 liquid to obtain the inactivated bacteroides fragilis liquid.
Example use of Bacteroides fragilis in combination with PD-1 antibody for the treatment of non-small cell lung cancer
1. Materials and methods
(1) Experimental groups and dosing regimens
Selecting 70 BALB/c female mice, and randomly dividing into 7 groups according to weight interval, namely blank group, model group and ZY-312 group (10)10CFU/mouse), PD-1 antibody (PD-1 ab) group (purchased from BioXcell, trade name BE0146, same as 200. mu.g/mouse), and ZY-312 viable bacteria combined PD-1 antibody group (10)10CFU/ZY), ZY-312 inactivated group (10)10CFU/ZY), ZY-312 inactivated bacteria in combination with PD-1 antibody group (10)10CFU/one), 10 per group. Animals in each group were injected with 1X 10 injections in the back, except for the blank group6The tumor volume of LLC cells reaches 50-100mm3Group administration was started (D0): starting from D0, the animals of the blank and model groups were orally administered 300 μ L of physiological saline daily and injected intraperitoneally twice weekly with 200 μ L of PBS; each administration group was administered the corresponding drug at the same frequency, wherein the administration volume of Bacteroides fragilis solution was 300. mu.L, and the administration volume of PD-1 antibody was 200. mu.L. Observing animals dailyHealth and mortality, tumor volume was measured every three days. After the fourth dose of PD-1 antibody, all mice were euthanized and mouse serum, tumors, feces, right cervical lymph, and right axillary lymph were collected. All tumors were weighed and photographed. Tumors were divided into three portions, one portion was cryopreserved for cytokine detection, one portion was fixed in formalin, and one portion was sent in vitro for flow analysis.
The detection items and methods are as follows:
tumor volume and tumor growth inhibition rate: tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
The tumor suppressor therapeutic effect of the compound was evaluated as TGI (%) or relative tumor proliferation rate T/C (%).
TGI (%), reflecting the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) × 100% (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/(average tumor volume at the end of treatment of the isotype control group-average tumor volume at the start of treatment of the isotype control group) ].
Relative tumor proliferation rate T/C (%): the calculation formula is as follows: T/C%RTV/CRTV×100％(TRTV: treatment group RTV; cRTV: isotype control group RTV). Calculating Relative Tumor Volume (RTV) from the tumor measurement result, wherein RTV is Vt/V0, wherein V0 is mean tumor volume measured in the case of group administration (i.e. d0), Vt is mean tumor volume measured in a certain time, and T is TRTVAnd CRTVThe same day data was taken.
Intratumoral T cell subsets: flow cytometry analysis of intratumoral CD4+T cells and CD8+Proportion of T cells in CD3+ T cells.
And (3) detecting cytokines: the Luminex technology detects the content of IL-2 and IFN-gamma in mouse tumors.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor volume, tumor mass and tumor growth inhibition rate
TABLE 1 antitumor drug effect calculated based on tumor volume on day 15 after group administration
Note:
a. mean. + -. SEM.
b. The evaluation index of tumor growth inhibition is T/C%RTV/CRTVX 100% and TGI (%) [1- (Ti-T0)/(Vi-V0)]X 100% calculation.
c. P-values between groups were calculated according to the unpaired t-test (one-tailed) method, based on tumor volume.
TABLE 2 antitumor drug effect calculated based on tumor weight on day 15 after group administration
Note:
a. mean. + -. SEM.
b. The tumor growth inhibition evaluation index is according to the formula T/Cweight＝TWtreatment/TWIsotype controlsAnd (4) calculating.
c. P-values between groups were calculated according to the unpaired t-test (one-tailed) method, based on tumor weight.
According to the table, compared with the blank group, the tumor transplantation mice generate obvious tumor masses, and the molding is successful.
Compared with a model group, when the PD-1 antibody and the bacteroides fragilis are independently used, the growth speed of the tumor is slowed down to a certain degree; however, when the composition is used in combination, the tumor growth is obviously slowed down. Therefore, the Bacteroides fragilis ZY-312 combined with the PD-1 antibody can effectively inhibit the growth of tumors.
(2) T cell subsets
TABLE 3 proportion of T cell subsets (mean. + -. SD) in each group of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
CD8+ T cells (TC or CTL cells) kill target cells expressing the antigen, which are important effector cells in the protection against viral infections, acute allograft rejection and killing of tumor cells. CD4+ T cells are important immune cells in the human immune system, mainly differentiated from helper T (Th) cells, and can be combined with the non-polypeptide region of MHC class II molecules to participate in the signal transduction of antigen recognition by T cell antigen receptor (TCR). It was found that CD8+ T cells can be activated by various mechanisms after the initiation of CD4+ T cells in tumor immunity to differentiate into Cytotoxic T Lymphocytes (CTLs), while maintaining and enhancing the antitumor response of CTLs.
As shown in the above table, the ratio of CD3+ CD4+ T cells to total cells in tumors was more or less up-regulated in each administration group compared to the model group, and the ratio of CD3+ CD4+/CD3+ T cells in the PD-1 antibody and Bacteroides fragilis ZY-312 or inactivated bacteria thereof combined PD-1 antibody group was significantly larger than that in the model group. The ZY-312 combination PD-1 antibody group has a larger proportion of CD3+ CD4+/CD3+ T cells than the single group.
Compared with the model group, the proportion of CD3+ CD8+ T cells in tumors to total cells is up-regulated to different degrees in each administration group, and the proportion of CD3+ CD8+/CD3+ T cells in the Bacteroides fragilis ZY-312 combined PD-1 antibody group is obviously larger than that in the model group. The ZY-312 combination PD-1 antibody group has a larger proportion of CD3+ CD8+/CD3+ T cells than the single group.
It can be seen that the combination of Bacteroides fragilis ZY-312 with PD-1 antibody can up-regulate the ratio of CD3+ CD4+ and CD3+ CD8+ T cells within the tumor.
(3) Cytokine detection
TABLE 4 cytokine levels (mean + -SD) in tumor in groups of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
Both IFN-gamma and IL-2 are known anti-tumor immunocytokines. As shown in the above table, the administration groups each up-regulated the IL-2 level in the tumor to a different extent than the model group, and the Bacteroides fragilis ZY-312 group combined with PD-1 antibody was significantly different from the model group.
Each administration group significantly upregulated the level of IFN- γ in tumors compared to the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-1 antibody group is larger than that of the single administration group.
It can be seen that Bacteroides fragilis ZY-312 in combination with the PD-1 antibody was able to upregulate the levels of cytokines IL-2 and IFN- γ.
In conclusion, the bacteroides fragilis ZY-312 combined PD-1 antibody can enhance the anti-tumor immune response of an organism and effectively prevent and treat the non-small cell lung cancer by up-regulating the proportion of cytotoxic T cells and the level of anti-tumor cell factors.
Example use of Bacteroides fragilis in combination with PD-L1 antibody for the treatment of non-small cell lung cancer
1. Experimental design and procedure
And (3) experimental design: selecting 70 BALB/c female mice, and randomly dividing into 7 groups according to weight interval, namely blank group, model group and ZY-312 group (10)10CFU/mouse), PD-L1 antibody (PD-L1 ab) group (BE0101, BioXcell 200. mu.g/mouse), ZY-312 viable bacteria combined PD-L1 antibody group (10)10CFU/ZY), ZY-312 inactivated group (10)10CFU/ZY), ZY-312 inactivated bacteria in combination with PD-L1 antibody group (10)10CFU/one), 10 per group. Animals in each group were injected with 1X 10 injections in the back, except for the blank group6The tumor volume of LLC cells reaches 50-100mm3Group administration was started (D0): from DStarting from 0, carrying out oral administration of 300 mu L of physiological saline every day by animals in a blank group and a model group, and carrying out intraperitoneal injection of 200 mu L of PBS once every three days; each administration group was administered the corresponding drug at the same frequency, wherein the administration volume of Bacteroides fragilis solution was 300. mu.L, and the administration volume of PD-L1 antibody was 200. mu.L. Animals were observed daily for health and mortality and tumor volume was measured every three days. After four administrations of the PD-L1 antibody, all mice were euthanized and mouse serum, tumors, feces, right cervical lymph and right axillary lymph were collected. All tumors were weighed and photographed. Tumors were divided into three portions, one portion was cryopreserved for cytokine detection, one portion was fixed in formalin, and one portion was sent in vitro for flow analysis.
The detection items and methods are as follows:
tumor volume and tumor growth inhibition rate: tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
The tumor suppressor therapeutic effect of the compound was evaluated as TGI (%) or relative tumor proliferation rate T/C (%). TGI (%), reflecting the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) × 100% (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/(average tumor volume at the end of treatment of the isotype control group-average tumor volume at the start of treatment of the isotype control group) ].
Relative tumor proliferation rate T/C (%): the calculation formula is as follows: T/C%RTV/CRTV×100％(TRTV: treatment group RTV; cRTV: isotype control group RTV). Calculating Relative Tumor Volume (RTV) from the tumor measurement result, wherein RTV is Vt/V0, wherein V0 is mean tumor volume measured in the case of group administration (i.e. d0), Vt is mean tumor volume measured in a certain time, and T is TRTVAnd CRTVThe same day data was taken.
Intratumoral T cell subsets: flow cytometry analysis of intratumoral CD4+T cells and CD8+Proportion of T cells.
And (3) detecting cytokines: the luminex technology detects the content of IL-2 and IFN-gamma in mouse tumors.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor volume, tumor weight and tumor growth inhibition rate
TABLE 5 antitumor drug effect calculated based on tumor volume on day 15 after group administration
Note:
a. mean. + -. SEM.
b. The evaluation index of tumor growth inhibition is T/C%RTV/CRTVX 100% and TGI (%) [1- (Ti-T0)/(Vi-V0)]X 100% calculation.
c. P-values between groups were calculated according to the unpaired t-test (one-tailed) method, based on tumor volume.
TABLE 6 antitumor drug effect calculated based on tumor weight on day 15 after group administration
Note:
a. mean. + -. SEM.
b. The tumor growth inhibition evaluation index is according to the formula T/Cweight＝TWtreatment/TWIsotype controlsAnd (4) calculating.
c. P-values between groups were calculated according to the unpaired t-test (one-tailed) method, based on tumor weight.
According to the above chart, compared with the blank group, the transplanted tumor mouse generates obvious tumor mass, and the model is successfully made.
Compared with a model group, when the PD-L1 antibody and the bacteroides fragilis are independently used, the growth speed of the tumor is slowed down to a certain degree; however, when the composition is used in combination, the tumor growth is obviously slowed down. Therefore, the Bacteroides fragilis ZY-312 combined with the PD-L1 antibody can effectively inhibit tumor growth.
(2) T cell subsets
TABLE 7 proportion of T cell subsets (mean. + -. SD) in each group of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
CD8+ T cells (TC or CTL cells) kill target cells expressing the antigen, which are important effector cells in the protection against viral infections, acute allograft rejection and killing of tumor cells. CD4+ T cells are important immune cells in the human immune system, and CD4 is mainly expressed in helper T (Th) cells, can be combined with the non-polypeptide region of MHC class II molecules, and is involved in signal transduction of antigen recognition by a T cell antigen receptor (TCR). It was found that CD8+ T cells can be activated by various mechanisms after the initiation of CD4+ T cells in tumor immunity to differentiate into Cytotoxic T Lymphocytes (CTLs), while maintaining and enhancing the antitumor response of CTLs.
As shown in table 7 above, each administration group up-regulated the proportion of intratumoral CD3+ CD4+ T cells to CD3+ T cells to a different extent compared to the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-L1 antibody group is larger than that of the single administration group, and has a significant difference with the model group.
Compared with the model group, the proportion of CD3+ CD8+ T cells to CD3+ T cells in the tumor is remarkably increased in each administration group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-L1 antibody group is larger than that of the two single groups.
It can be seen that the combination of Bacteroides fragilis ZY-312 with PD-L1 antibody can up-regulate the proportion of intratumoral CD3+ CD4+ and CD3+ CD8+ T cells.
(3) Cytokine detection
TABLE 8 cytokine levels (mean + -SD) in tumor in groups of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
As shown in the table above, the IL-2 level in the tumor was up-regulated to different degrees in each administration group compared with the model group, and the Bacteroides fragilis ZY-312 group with the use of PD-L1 antibody high dose group and the inactivated bacteria group with the use of PD-L1 antibody were significantly different from the model group. The up-regulation amplitude of the bacteroides fragilis combined PD-L1 antibody group is larger than that of the single administration group.
Each administration group significantly upregulated the level of IFN- γ in tumors compared to the model group. The up-regulation amplitude of the Bacteroides fragilis ZY-312 combined PD-L1 antibody group is larger than that of the single administration group, and has a very significant difference with the model group.
It can be seen that Bacteroides fragilis ZY-312 in combination with the PD-L1 antibody was able to upregulate the levels of cytokines IL-2 and IFN- γ.
In conclusion, the combination of the Bacteroides fragilis ZY-312 and the PD-L1 antibody can up-regulate the proportion of cytotoxic T cells and the level of anti-tumor cytokines, enhance the anti-tumor immune response of an organism and effectively prevent and treat the non-small cell lung cancer.
Example application of Bacteroides fragilis in combination with PD-1 antibody in prevention and treatment of head and neck squamous cell carcinoma
1. Design of experiments and procedure
70C 3H/HeOuJ female mice 6-8 weeks old are randomly divided into 7 groups according to body weight interval, namely blank group, model group and ZY-312 (10)10CFU/only), PD-1 antibody (PD-1 ab) group (BE0146, BioXcell 250. mu.g/only), ZY-312 viable bacteria combined PD-1 antibody group (10)10CFU/ZY), ZY-312 inactivated group (10)10CFU/ZY), ZY-312 inactivated bacteria in combination with PD-1 antibody group (10)10CFU/one), 10 per group.
A1640 culture medium (purchased from BI, same below) containing 10% calf serum (purchased from Gibco, same below), penicillin (100U/mL) and streptomycin (100U/mL) was used under conventional conditions (37 ℃ C., saturation humidity, 5% CO)2) Subculturing SCC7 head and neckAdjusting the cell concentration to 1 × 10 from the logarithmic growth phase of the cancer cells6one/mL, except for the blank, each mouse was injected subcutaneously into the right leg of each group with 100 μ L of cell suspension, and the right leg of the blank was injected subcutaneously with 100 μ L of physiological saline.
The divided dosing started 8 days after inoculation (D0, when the tumor diameter was 2-4 mm): starting from D0, blank, model animals were orally administered 300 μ L of saline daily; starting from D3, 100 μ L PBS was intraperitoneally injected every three days; the corresponding drugs were administered to each administration group at the same frequency, wherein the volume of the bacteroides fragilis solution administered was 300. mu.L, the volume of the PD-1 antibody administered was 100. mu.L, and the antibodies were administered 3 times in total. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. D12, all mice were euthanized and mice blood, tumor, spleen, feces, right neck lymph and right axillary lymph were collected. Tumors were divided into two portions, one fixed in formalin and one sent in vitro for flow analysis.
The detection items and methods are as follows:
tumor volume and tumor growth inhibition rate: the tumor inhibition rate is 100 percent (mean tumor volume in model group-mean tumor volume in administration group)/mean tumor volume in model group.
Subpopulation of immune cells: flow cytometry analyzed the ratio of M1/M2 cells within the tumor.
And (3) detecting cytokines: luminex detects the content of IL-1 beta and IP-10 in mouse serum.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor volume and tumor growth inhibition rate
TABLE 9 tumor volume and tumor growth inhibition ratio (mean + -SD) for each group of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
Compared with the blank group, the model group has obvious tumor formation and the molding is successful.
Compared with the model group, the administration groups all reduce the tumor volume remarkably, and the bacteroides fragilis ZY-312 combined PD-1 antibody group has very remarkable difference with the model group. This indicates that Bacteroides fragilis can inhibit the growth of head and neck cancer cells, and the effect of the combination of Bacteroides fragilis ZY-312 and PD-1 antibody is better.
(2) Subpopulation of immune cells
TABLE 10 ratio of M1/M2 cells (mean. + -. SD) in groups of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
Tumor-associated macrophages (TAMs) are macrophages infiltrated in tumor tissues, are the most immune cells in the tumor microenvironment, can secrete multiple cytokines, can recognize and eliminate tumor cells at the initial stage of tumor occurrence, but play a key role in the growth, invasion and metastasis of tumors along with the occurrence and development of tumors. Under the influence of tumor microenvironment cytokines, macrophages differentiate into different types of TAMs, which are mainly classified into M1 type and M2 type, M1 type macrophages have the function of killing tumor cells, and M2 type macrophages are shown to promote tumor growth. Compared with the model group, the ratio of M1/M2 is up-regulated in each administration group, and the Bacteroides fragilis ZY-312 group combined with the PD-1 antibody group has significant difference. This shows that Bacteroides fragilis can regulate TAM ratio and promote anti-tumor immune response of organism, and the effect of combining Bacteroides fragilis ZY-312 with PD-1 antibody is better.
(3) Serum cytokines
TABLE 11 groups of mouse serum cytokines (mean. + -. SD)
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
IL-1 is a cytokine released by many cell types that acts in an autocrine and/or paracrine manner to stimulate a variety of signaling pathways. IL-1 β is an agonist in the IL-1 family, and it and its receptor have been shown to be important drivers of primary carcinogenesis and metastasis of mesenchymal and epithelial cells. IP-10 is a chemokine induced by IFN-gamma and capable of recruiting neutrophils and inhibiting tumor growth.
The model group IL-1 β was significantly elevated compared to the blank group; compared with a model group, each administration group remarkably down-regulates IL-1 beta in mouse serum, and the Bacteroides fragilis ZY-312 and the inactivated bacteria combined PD-1 antibody group thereof have extremely remarkable difference.
Compared with the blank group, the IP-10 of the model group is increased, and the spontaneous anti-tumor immune response of the organism is shown; compared with the model group, the administration groups remarkably up-regulate IP-10 in the mouse serum, and the Bacteroides fragilis ZY-312 combined PD-1 antibody group has extremely remarkable difference.
The results show that the bacteroides fragilis can regulate the immune response of the body to the tumor, and the combined effect of the bacteroides fragilis ZY-312 and the PD-1 antibody is better.
In conclusion, the bacteroides fragilis ZY-312 combined with the PD-1 antibody can enhance the anti-tumor immune response of the organism and effectively prevent and treat head and neck cancer.
Example application of Bacteroides fragilis in combination with PD-L1 antibody for preventing and treating small cell lung cancer
1. Design of experiments and procedure
(1) Trp53 at age of 6-8 weeksloxP/loxP；Rb1loxP/loxP；Rb12loxP/loxP10 mice were anesthetized by intraperitoneal injection of anesthetic, and then treated with Ad-CreCaPi (Ad-CreCaPi: titer 10)7PfU Ad-Cre 2. mu.L was added to 246.8. mu.L of MEM, followed by 1.2. mu.L of 2mol/L CaCl2From VECTOR BIOLABS) by intubationMouse trachea, about 100 μ L per mouse. When the mice have the manifestations of obvious emaciation, arch back, activity reduction and the like, the mice are euthanized, tumor tissues are dissected, HE staining is carried out to verify that the tumor tissues are small cell lung cancer, the tumor tissues are prepared into cell suspension, and the cell suspension is frozen and stored to serve as a tumor source for transplantation.
(2) 70 female mice 6-8 weeks old B6129F1 are randomly divided into 7 groups according to body weight interval, namely blank group, model group and ZY-312 (10)10CFU/mouse), PD-L1 antibody (PD-L1 ab) group (9D2, BioXcell 300. mu.g/mouse), ZY-312 viable bacteria combined PD-L1 antibody group (10)10CFU/ZY), ZY-312 inactivated group (10)10CFU/ZY), ZY-312 inactivated bacteria in combination with PD-L1 antibody group (10)10CFU/one), 10 per group.
The SCLC cell concentration was adjusted to 1X 10 by Matrigel gel (Matrigel: serum-free medium ═ 1:1, Matrigel from Solarbio)7one/mL, except for the blank, each mouse was injected subcutaneously into the right flank of each group with 50 μ L of cell suspension, and the blank was injected subcutaneously into the right flank of each group with 50 μ L of Matrigel gel.
The time at which accessible tumor nodules occurred (D0) the group administration was started: starting from D0, the animals in the blank and model groups were orally administered 300 μ L of physiological saline daily and injected intraperitoneally with 100 μ L of PBS once every 7 days; the corresponding drugs were administered to each administration group at the same frequency, wherein the volume of the bacteroides fragilis solution administered was 300. mu.L, the volume of the PD-L1 antibody administered was 100. mu.L, and the antibodies were administered 3 times in total. Animals were observed daily for health and mortality, and tumor volumes were measured every two days. D21, all mice were euthanized and mice blood, tumor, spleen, feces, right neck lymph and right axillary lymph were collected. Tumors were divided into two portions, one fixed in formalin and one sent in vitro for flow analysis.
The detection items and methods are as follows:
tumor volume and tumor growth inhibition rate: the tumor inhibition rate is 100 percent (mean tumor volume in model group-mean tumor volume in administration group)/mean tumor volume in model group.
T cell subsets: flow cytometry analyzed the proportion of CD3+ T cells, CD8+ T cells within the tumor.
Data statistics and analysis: statistical analysis was performed using SPSS statistical software 25.0.
2. Test results
(1) Tumor volume and tumor growth inhibition rate
TABLE 12 tumor volume and tumor growth inhibition ratio (mean + -SD) for each group of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
Compared with the blank group, the model group has obvious tumor formation and the molding is successful.
Compared with the model group, each administration group can reduce the tumor volume of mice, and the bacteroides fragilis ZY-312 combined PD-L1 antibody group has very significant difference. This indicates that Bacteroides fragilis ZY-312 in combination with PD-L1 antibody can effectively inhibit the growth of small cell lung cancer.
(2) T cell subsets
TABLE 13 proportion of CD3+ T cells, CD8+ T cells (mean. + -. SD) in each group of mice
Note: indicates a significant difference p <0.05 compared to model group; indicates a very significant difference p < 0.01.
Compared with a model group, the proportion of mouse tumor infiltrating CD3+ T cells and CD8+ T cells cannot be obviously improved by using the PD-L1 antibody and ZY-312 antibody singly; when the PD-L1 antibody is combined with Bacteroides fragilis ZY-312, the proportion of CD3+ T cells and CD8+ T cells is remarkably increased. This shows that the combination of Bacteroides fragilis ZY-312 and PD-L1 antibody can regulate T cell level and enhance the anti-tumor immune response of body.
In conclusion, the bacteroides fragilis ZY-312 combined PD-L1 antibody can enhance the anti-tumor immune response of the organism, inhibit the growth of tumor cells and effectively prevent and treat small cell lung cancer of mice.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The application of the bacteroides fragilis and an immune checkpoint inhibitor in synergistic prevention and/or treatment of respiratory tumors is characterized in that the bacteroides fragilis ZY-312 with the preservation number of CGMCC No. 10685.
2. Use according to claim 1, wherein the immune checkpoint inhibitor comprises one or more of a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a LAG-3 antibody, a TIM-3 antibody, a VISTA antibody, an A2aR antibody, preferably a PD-1 antibody and/or a PD-L1 antibody.
3. Use according to claim 1 or 2, wherein the respiratory tumour comprises head and neck cancer, non-small cell lung cancer, small cell lung cancer. Preferably, the head and neck cancer further comprises nasopharyngeal carcinoma, laryngeal carcinoma.
4. The use according to any one of claims 1 to 3, wherein the Bacteroides fragilis is one or more of live bacteria, killed bacteria with intact morphological structure, killed bacteria with incomplete morphological structure; and/or the bacteroides fragilis is live bacteroides fragilis, and the bacteroides fragilis is subjected to one or more of inactivation, gene recombination, modification or modification, attenuation, chemical treatment, physical treatment or inactivation, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant.
5. The use of any one of claims 1 to 4, wherein the PD-1 antibody comprises Nivolumab (Nivolumab), Pabollizumab (Pembrolizumab), Cemipril mab (Cemipilimab), Tereprimab (Torpilimab), Cendilizumab (Cindilimab), Carrilizumab (Camrelizumab), and other substances capable of binding to PD-1, blocking the PD-1/PD-L1 signaling pathway, upregulating T cell activation, activating endogenous anti-tumor immune responses.
Preferably, the PD-L1 antibody includes atelizumab (Atezolizumab), aviluzumab (Avelumab), dovuzumab (Durvalumab) and other substances capable of binding to PD-L1, blocking the PD-1/PD-L1 signaling pathway, upregulating T cell activation, activating endogenous anti-tumor immune response.
6. A medicament, wherein the medicament comprises both bacteroides fragilis and PD-1 and/or PD-L1 antibodies. Preferably, the bacteroides fragilis zwitterionic capsular polysaccharide is extracted from bacteroides fragilis ZY-312 with the deposit number of CGMCC No. 10685.
7. The medicament of claim 6, wherein the PD-1 antibody comprises Nivolumab (Nivolumab), pamrolizumab (Pembrolizumab), cimetiprizumab (semiplimab), tereprimab (Torpilimab), sillimab (Cindilizab), carpicizumab (Camrelizumab), and others capable of binding to PD-1, blocking the PD-1/PD-L1 signaling pathway, upregulating T cell activation, and activating endogenous anti-tumor immune response.
8. The medicament of claim 6 or 7, wherein the PD-L1 antibodies include Atezolizumab (Atezolizumab), avilumab (Avelumab), Durvalumab (Durvalumab) and other substances capable of binding to PD-L1, blocking the PD-1/PD-L1 signaling pathway, upregulating T-cell activation, and activating endogenous anti-tumor immune responses.
9. The use according to any one of claims 6 to 8, wherein the bacteroides fragilis is one or more of live bacteria, killed bacteria with intact morphological structure, killed bacteria with incomplete morphological structure; and/or the bacteroides fragilis is live bacteroides fragilis, and the bacteroides fragilis is subjected to one or more of inactivation, gene recombination, modification or modification, attenuation, chemical treatment, physical treatment or inactivation, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant.
10. The medicament according to any one of claims 6 to 9, wherein the respiratory tumor comprises non-small cell lung cancer, head and neck squamous cell carcinoma. The head and neck squamous cell carcinoma is selected from nasopharyngeal carcinoma and laryngeal carcinoma.
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| WO2023134204A1 (en) * | 2022-01-12 | 2023-07-20 | 广州知易生物科技有限公司 | Application of capsular polysaccharide a of bacteroides fragilis combined with pd-1 and pd-l1 antibodies in treatment of respiratory system tumors |
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