CXCL16-targeted monoclonal neutralizing antibody combined radiotherapy and application of combined radiotherapy and PD1 monoclonal antibody in cancer treatment

Abstract

The invention discloses a CXCL16-targeted monoclonal neutralizing antibody combined radiotherapy and application of the combined radiotherapy and a PD1 monoclonal antibody in cancer treatment, and belongs to the technical field of biological pharmacy, combined therapy can increase the CD8 < + > / CD4 < + > T cell ratio in tumor tissue and enhance the immune response of an organism to the tumor tissue; meanwhile, the infiltration of inhibitory immune cells such as MDSC and TAM in tumor tissues is reduced, so that the anti-tumor effect is enhanced.

Description

Technical Field

[0001] The present invention belongs to the technical field of biopharmaceuticals, and in particular relates to the use of a monoclonal neutralizing antibody targeting CXCL16 combined with radiotherapy and combined with radiotherapy and PD1 monoclonal antibody in treating cancer. Background Art

[0002] The incidence and mortality of malignant tumors, especially thoracic tumors, are increasing every year. Radiotherapy (RT) is an important treatment for thoracic tumors, but it has a bidirectional effect on the tumor immune microenvironment (TME). Radiation-induced DNA damage in tumor cells induces type I or type II IFN responses, which can enhance innate immunity. At the same time, the death of immunogenic cells leads to the release of damage-associated molecular patterns (DAMPs), inducing MHC I / II upregulation and promoting antigen presentation, thereby enhancing adaptive immunity. However, in addition to the immunostimulatory effect, the expression of PD-L1 on the surface of tumor cells increases after radiotherapy, activating the PD-1 / PD-L1 pathway, leading to the exhaustion of cytotoxic T cells and causing immunosuppression.

[0003] Immune checkpoints are a type of inhibitory signaling molecules in the immune system that prevent tissue damage by regulating the persistence and intensity of immune responses in peripheral tissues and participate in maintaining tolerance to self-antigens. Studies have found that one of the reasons why tumor cells can evade the body's immune system and proliferate uncontrollably is that they utilize the inhibitory signaling pathway of immune checkpoints, thereby inhibiting the activity of T lymphocytes, making it impossible for T lymphocytes to effectively kill tumors.

[0004] Programmed death 1 (PD-1) is a member of the CD28 superfamily. PD-1 is an important immune checkpoint protein and is currently an important target for tumor immunotherapy. PD-1 is expressed on activated T cells, B cells, and myeloid cells. It has two ligands, namely programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2). PD-L1 interacts with the receptor PD-1 on T cells and plays an important role in the negative regulation of immune responses. The expression of PD-L1 protein can be detected in many human tumor tissues. The microenvironment of the tumor site can induce the expression of PD-L1 on tumor cells. The expressed PD-L1 is conducive to the occurrence and growth of tumors and induces the apoptosis of anti-tumor T cells. PD-1 / PD-L1 pathway inhibitors can block the binding of PD-1 and PD-L1, block negative regulatory signals, restore T cell activity, and thus enhance the immune response. Therefore, immune regulation targeting PD-1 / PD-L1 is of great significance for tumor suppression.

[0005] The PD-1 / PD-L1 pathway is one of the immune checkpoints. In the immune microenvironment, blocking the PD-1 / PD-L1 pathway with antibodies targeting PD-1 or PD-L1 is used to block negative regulatory signals, restore T cell activity, thereby enhancing the immune response and more effectively improving the effect of inhibiting tumor occurrence and development.

[0006] Given that RT has immunomodulatory effects, and immune checkpoint inhibitors (ICIs) can improve tumor cell-induced T cell exhaustion after radiotherapy, and the combination of RT and ICI can enhance antigen presentation, thereby exerting a synergistic anti-tumor effect, the combination therapy of RT and ICI has attracted attention. However, normal tissue toxicity caused by combined therapy has become one of the main limitations of clinical application, especially when thoracic radiotherapy is combined with ICI, the risk of acute / chronic radiation lung injury (RILI) increases. Therefore, an important part of advancing the development of immunotherapy is to overcome the toxicity of combined therapy.

[0007] Chemokines play an important role in various pathogenesis mechanisms and are involved in the migration of immune cells to sites of inflammation and angiogenesis, as well as tumorigenesis and tumor metastasis. Chemokines are involved in multiple pathways, such as angiogenesis, the movement and invasion of endothelial cells and immune cells at tumor sites, and the proliferation and survival of tumor cells. CXC motif chemokine ligand 16 (CXCL16), belongs to the α chemokine subfamily. Mouse CXCL16 is 246aa long. There are two forms of CXCL16, membrane-bound (mCXCL16) and soluble (sCXCL16). mCXCL16 also consists of a CXC chemokine domain and a transmembrane domain, while sCXCL16 only has a chemokine domain. The two forms of CXCL16 have different functions. sCXCL16 is a chemokine responsible for the chemotaxis of cells carrying the CXCR6 receptor, while mCXCL16 is a transmembrane protein that is regulated by proinflammatory cytokines and plays an important role in the accumulation of immune cells at sites of inflammation. mCXCL16 also mediates the adhesion of Gram-negative and Gram-positive bacteria, directing cells expressing mCXCL16 (such as macrophages and DCs) to phagocytose bacteria. mCXCL16 can also act as a receptor to transduce extracellular signals into cells. In the tumor microenvironment, CXCL16 is considered to be a cancer-associated inflammatory marker. CXCL16 expression is found in tumor-associated cells, such as microglia and endothelial glioblastoma multiforme, fibroblasts, endothelial cells and macrophages in non-small cell lung cancer, mesenchymal stem cells in gastric cancer, myeloid-derived suppressor cells in breast cancer, cancer-associated fibroblasts (CAFs) in breast cancer brain metastasis, etc. Elevated CXCL16 levels promote tumor cell proliferation, migration and invasion through pathways such as ERG MEK. Specifically, persistently high levels of CXCL16 in tumors are associated with increased tumor growth, immune tolerance, tumor metastasis and tumor cell extracellular matrix deposition, all of which may drive cancer development and resistance to therapy.

[0008] In view of the synergistic effect of radiotherapy and ICI and the key role of CXCL16 signaling in the tumor microenvironment, we developed a monoclonal neutralizing antibody targeting CXCL16, combined with radiotherapy and PD1 monoclonal antibody to explore a new strategy of combining systemic treatment and local treatment. Summary of the invention

[0009] The purpose of the present invention is to provide a monoclonal neutralizing antibody targeting CXCL16 in combination with radiotherapy and in combination with radiotherapy and PD1 monoclonal antibody for treating cancer.

[0010] In order to achieve the above purpose, this application adopts the following technical solutions:

[0011] In a first aspect, the present invention provides use of a monoclonal neutralizing antibody targeting CXCL16 in the preparation of a drug for treating cancer, wherein the monoclonal neutralizing antibody is used in combination with radiotherapy for cancer treatment.

[0012] In the above technical solution, the monoclonal neutralizing antibody is combined with radiotherapy and PD1 monoclonal antibody for cancer treatment.

[0013] In the above technical scheme, the monoclonal neutralizing antibody achieves one or more of the following purposes: inhibiting tumor growth and prolonging patient survival; increasing the number of tumor-infiltrating cytotoxic lymphocytes in the tumor; reducing myeloid-derived suppressor cells; increasing the CD8+T / CD4+T cell ratio; anti-tumor angiogenesis; and downregulating the expression of molecules related to ECM, cell adhesion and cell migration.

[0014] In the above technical solution, the cancer is selected from one of lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and gastric cancer.

[0015] In a second aspect, the present invention provides an anti-cancer device, comprising

[0016] (a) irradiation equipment for administering radiation therapy to cancer cells; and

[0017] (b) A drug kit comprising a therapeutically effective amount of a preparation or a pharmaceutical composition, wherein the preparation or composition contains a monoclonal neutralizing antibody targeting CXCL16 as an active ingredient.

[0018] In the above technical solution, the anti-cancer device further includes an instruction manual, which records a method for using the anti-cancer device to treat cancer by administering radiation therapy and a monoclonal neutralizing antibody targeting CXCL16 to a subject in need.

[0019] In the above technical solution, the preparation or composition contains a monoclonal neutralizing antibody targeting CXCL16 and a PD1 monoclonal antibody as active ingredients.

[0020] In the above technical solution, the anti-cancer device also includes an instruction manual, which records a method for using the anti-cancer device to treat cancer by administering radiation therapy and a monoclonal neutralizing antibody targeting CXCL16 and a PD1 monoclonal antibody to a subject in need.

[0021] In a third aspect, the present invention provides a radiosensitizer, comprising a monoclonal neutralizing antibody targeting CXCL16.

[0022] The above technical solution also includes PD1 monoclonal antibody.

[0023] The beneficial effects of the present invention are as follows: the present invention has discovered the therapeutic uses of CXCL16 monoclonal neutralizing antibody combined with radiotherapy and CXCL16 monoclonal neutralizing antibody combined with radiotherapy and PD1 monoclonal antibody for cancer, and the combined treatment can increase the CD8+ / CD4+T cell ratio in tumor tissue and enhance the body's immune response to tumor tissue; while reducing the infiltration of suppressive immune cells such as MDSC and TAM in tumor tissue to enhance the anti-tumor effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 :The monoclonal neutralizing antibody of CXCL16 combined with radiotherapy and PD1 monoclonal antibody treatment inhibited the tumor growth of mice. A: Flow chart of the treatment of mice. B: Anti-tumor growth curve of each group in LLC model. C, D: In vivo imaging results and statistical charts of each group of mice in LLC model.

[0025] Figure 2 : CXCL16 monoclonal neutralizing antibody combined with radiotherapy and PD1 monoclonal antibody reverses the immunosuppressive microenvironment. A: Flow cytometry detection of myeloid-derived suppressor cells in tumor tissues of LLC-luc tumor-bearing mice. B: Flow cytometry detection of CD4+ and CD8+ T cells in tumor tissues of LLC-luc tumor-bearing mice. C: Flow cytometry detection of tumor tissue-associated macrophages in tumor tissues of LLC-luc tumor-bearing mice. D: Flow cytometry results analysis statistical chart. DETAILED DESCRIPTION

[0026] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. The present invention can be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are provided so that this disclosure will be thorough and complete, and the concept of the present invention will be fully conveyed to those skilled in the art, and the present invention will only be limited by the claims.

[0027] The terms used herein are only for describing specific embodiments and are not intended to limit the present invention. The terms "comprise", "include", etc. used herein indicate the existence of features, steps, operations and / or components, but do not exclude the existence or addition of one or more other features, steps, operations or components.

[0028] All terms (including technical and scientific terms) used herein have the meanings commonly understood by those skilled in the art, unless otherwise defined. It should be noted that the terms used herein should be interpreted as having a meaning consistent with the context of this specification, and should not be interpreted in an idealized or overly rigid manner.

[0029] In the case of using expressions such as "at least one of A, B, and C, etc.", it should generally be interpreted in accordance with the meaning of the expression generally understood by those skilled in the art (for example, "a system having at least one of A, B, and C" should include but is not limited to a system having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, C, etc.). In the case of using expressions such as "at least one of A, B, or C, etc.", it should generally be interpreted in accordance with the meaning of the expression generally understood by those skilled in the art (for example, "a system having at least one of A, B, or C" should include but is not limited to a system having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, C, etc.).

[0030] The present invention relates to a method for treating cancer, which comprises administering to an individual a monoclonal neutralizing antibody targeting CXCL16 and radiotherapy in combination, or administering to an individual a monoclonal neutralizing antibody targeting CXCL16, a PD1 monoclonal antibody and radiotherapy in combination.

[0031] 1. Methods and Materials

[0032] 1. Experimental Animals

[0033] Adult female C57BL / 6 mice were obtained from Hubei Provincial Experimental Animal Center and Hubei Biotechnology Co., Ltd. (Hubei, China). All mice were 7–8 weeks old and weighed 18–20 g. Five mice were housed per cage under standard laboratory conditions, with an unlimited supply of sterile food and water. All animal experiments were performed under specific pathogen-free grade conditions in accordance with the guidelines of the International Guiding Principles for Animal Research and approved by the Ethics Committee of Huazhong University of Science and Technology (Hubei, China).

[0034] 2. Materials

[0035] (1) Reagents

[0036] Mouse-derived CXCL16 monoclonal neutralizing antibody was scaled up and manufactured by Ibotek. Mouse-derived anti-PD-1 monoclonal antibody was provided by Selleck (USA). Both antibodies were diluted to 1 mg / ml with 0.9% sterile saline and used in in vivo experiments.

[0037] (2) Cell lines and culture media

[0038] The cell line used in this study was LLC cells (lung cancer cells), which were obtained from the Laboratory of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. LLC luciferase-positive (LLC-luc) cell line was established by stably transducing the parent LLC cell line with a lentivirus containing the luciferase GV260 and was obtained from Shanghai Gene Gene Co., Ltd. (Shanghai, China). LLC and LLC-Luc cells were cultured in DMEM medium (HyClone, Utah, USA). When culturing cells, 10% (w / v) fetal bovine serum (Gibco, New York, USA) and 1% penicillin-streptomycin (Gibco) were added to the culture medium, and the cells were incubated in a clean environment at 37°C and 5% carbon dioxide.

[0039] 3. Establishment of animal model and treatment of animals

[0040] (1) Tumor-bearing animal models

[0041] For the establishment of primary single-focal tumor models, 50 μl LLC cells were plated at 1×10 6 The cells were inoculated subcutaneously into the right hind flank of C57BL / 6 mice. Nine mice were included in each group for LLC tumor treatment experiments.

[0042] The tumor-bearing mice were randomly divided into the following 8 groups, with an equal number of mice in each group: 0.9% saline (CON) group, PD-1 monoclonal antibody (anti PD-1) group, anti-CXCL16 (CXCL16 mAb) group, radiotherapy (RT) group, radiotherapy combined with CXC16 monoclonal antibody group (RT+CXCL16 mAb), radiotherapy combined with PD-1 monoclonal antibody (RT+anti PD-1) group, and radiotherapy combined with CXC16 monoclonal antibody and PD-1 monoclonal antibody (RT+CXCL16mAb+anti PD-1) group. 7-10 days after modeling, when the primary tumor volume reached 100mm 3 Treatment was started at . On D0, D7, and D14 of the treatment, CXCL16 monoclonal antibody at a concentration of 5 mg / kg and PD-1 monoclonal antibody at a concentration of 10 mg / kg were injected intraperitoneally. For all groups involving RT, a dose of 8 Gy of radiotherapy was given only to the primary site at D0, and a 0.5 cm compensation film was given. Radiotherapy was performed using an RS2000 X-ray Biological Research irradiator (160 kV, 25 mA; Rad Source Technologies, Inc., Suwanee, GA, USA). Tumor volume was measured every three days. When the tumor volume of the mouse exceeded approximately 2000 mm 3 When the tumor volume reached 1.37 × 1.34, the mice were euthanized. The formula for calculating tumor volume is volume = length × width 2 / 2.

[0043] (2) In vivo imaging

[0044] Tumor-bearing mice were intraperitoneally injected with 10 μl / g body weight of D-luciferin potassium (MB1834, Meilun Biotechnology, Shanghai, China) at a concentration of 15 mg / ml, and then anesthetized with 1.5% pentobarbital. The fluorescent real-time imaging of mice was detected and analyzed by IVIS Spectrum Imaging System (Caliper Life Sciences, Massachusetts, USA).

[0045] (3) Flow cytometry

[0046] Primary tumors, secondary tumors, and spleens were removed en bloc from euthanized mice, and the distribution of immune cells in the tumor microenvironment was evaluated by flow cytometry (n=3). The obtained tissues were minced and digested with type IV collagenase, hyaluronidase, and DNase at 37°C for 1 hour. After rinsing and filtering, the tissues were added to the red blood cell lysate, centrifuged (1200 rpm, 5 minutes), and resuspended in PBS to obtain a cell suspension. Afterwards, the BV510 Zombie Aqua TM The cell suspension was stained using Fixable Viability Kit (423101, BioLegend, CA, USA), blocked with anti-mouse CD16 / 32 (101320, BioLegend), and light-stained with the following fluorescent antibodies: BV510 anti-mouse CD45 (, BioLegend), FITC anti-mouse CD3 (100205, BioLegend), PE anti-mouse CD4 (100407, Dakewe), PerCP / CY5.5 anti-mouse CD8a (100733, BioLegend), APC anti-mouse CD11b (101211, Dakewe), and PE / CY7 anti-mouse Ly-6G / Ly-6C (108416, BioLegend) antibodies. Flow cytometry was performed using a CytoFLEX LX flow cytometer (Beckman, CA, USA) and analyzed using FlowJo v10.8.1 software.

[0047] (4) In vivo biosafety evaluation

[0048] ALT, AST, and Cr in the serum of mice in all treatment groups were detected using a Chemray 240 automatic biochemical analyzer (Rayto Science, Shenzhen, China) to evaluate the effects of CXCL16 mAb on liver and kidney function. The hearts, livers, and kidneys of mice treated with CXCL16 mAb were fixed with 4% paraformaldehyde, sliced, and stained with HE to observe the effects of CXCL16 mAb on important organs.

[0049] (5) Statistical analysis

[0050] Data were analyzed using GraphPad Prism version 8.0. Results are expressed as mean ± standard deviation (SD) or mean ± standard error (SEM). Statistical significance was defined as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001, respectively.

[0051] 2. Experimental Results

[0052] 1. CXCL16 mAb combined with radiotherapy inhibits tumor growth in mice

[0053] In single lesion tumor burden studies, the Lewis lung carcinoma (LLC) tumor-bearing model of lung cancer was used to evaluate the efficacy of the combination therapy. Mice were treated as Figure 1 (A) shown.

[0054] In the LLC model, on day 21 after treatment, the tumor burden of mice in the RT+CXCL16 mAb group was significantly lower than that in the RT group alone (p<0.001), indicating that CXCL16 mAb has a radiosensitizing effect. The RT+CXCL16mAb+anti PD-1 group had a stronger anti-tumor growth effect than the RT group (p<0.0001) or the RT+CXCL16 mAb group (p<0.0001) and the RT+anti PD-1 group (p<0.0001). Figure 1 , B), suggesting that CXCL16mAb combined with anti PD-1 and radiotherapy has a strong anti-tumor effect.

[0055] In the LLC model, in vivo imaging results also verified the anti-tumor effect of the triple combination. Compared with the RT+anti PD-1 group, the tumor volume in the RT+CXCL16 mAb+anti PD-1 group was smaller (p<0.001)( Figure 1 , C, D), indicating that the triple therapy effect is better than the "radiotherapy + immunotherapy" regimen of radiotherapy combined with PD1 monoclonal antibody in the clinical first line.

[0056] 2. CXCL16 monoclonal neutralizing antibody combined with radiotherapy and PD1 monoclonal antibody to reverse the immunosuppressive microenvironment

[0057] After treatment, mice bearing LLC tumors were sacrificed, and LLC tumor tissues of the anti-PD-1 group, CXCL16mAb group, and CXCL16 mAb+RT group were harvested intact (3 in each group). Flow cytometry was used to detect immune cell infiltration in tumor tissues of LLC-luc tumor-bearing mice (n=3), including myeloid-derived suppressor cells (MDSC) ( Figure 2 , A), tumor-associated macrophages (TAM) ( Figure 2, B) and CD4+ and CD8+ T cells ( Figure 2 , C). MDSCs are important immunosuppressive cells in tumor immune escape. Compared with the CON group, the MDSCs in the tumors were significantly reduced in the CXCL16 mAb group (p<0.0001), the anti PD-1 group (p<0.0001), and the CXCL16 mAb+anti PD-1 combined treatment group (p<0.0001). In the RT+CXCL16 mAb treatment group, the promoting effect of RT on MDSCs was slowed down (p<0.0001) ( Figure 2 , D). The RT+CXCL16 mAb+anti PD-1 group showed the best MDSC inhibition effect, which was significantly different from the classic regimen of RT+anti PD-1 (p=0.0199).

[0058] The ratio of CD8+T to CD4+T cells was used to evaluate the activity of cytotoxic reactions in the TME. The results showed that the CD8+T / CD4+T levels in the CXCL16mAb+ and anti PD-1 groups were significantly higher than those in the CON group (p=0.0014). The CD8+T / CD4+T levels in the RT+anti PD-1 group were significantly increased after radiotherapy (p=0.0100, but there was no significant difference between the RT+CXCL16 mAb+anti PD-1 group and the RT+anti PD-1 group.

[0059] The TAM cell ratio was used to evaluate the content of tumor-associated macrophages in tumor tissue that promote tumor growth. The results showed that the CD8+T / CD4+T levels in the CXCL16 mAb+ and anti PD-1 groups were significantly higher than those in the CON group (p=0.0014). The CD8+T / CD4+T levels in the RT+anti PD-1 group were significantly increased after radiotherapy (p=0.0100), but there was no significant difference between the RT+CXCL16 mAb+anti PD-1 group and the RT+anti PD-1 group.

[0060] The TAM cell ratio is used to evaluate the content of tumor-associated macrophages that promote tumor growth in tumor tissues. The results showed that the TAM content in the CXCL16 mAb group was significantly lower than that in the CON group (p = 0.0035), but there was no difference in the TAM level between the anti PD-1 group and the CON group, while the CXCL16 mAb + anti PD-1 group was significantly lower than that in the CON group (p < 0.0001), indicating that the inhibition of CXCL16 can reduce the TAM content.

[0061] The TAM level in the RT+CXCL16 mAb+anti PD-1 group was significantly lower than that in the RT+anti PD-1 group (p<0.0001), suggesting that CXCL16 can reduce the TAM level caused by RT+anti PD-1.

[0062] The above results indicate that the combination of RT+CXCL16 mAb+anti PD-1 enhances the anti-tumor effect by increasing the CD8+T / CD4+T cell ratio in tumor tissues and reducing MDSCs and TAMs.

[0063] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. Use of a monoclonal neutralizing antibody targeting CXCL16 in the preparation of a drug for treating cancer, characterized in that: The monoclonal neutralizing antibody is used in combination with radiotherapy to treat cancer.

2. The application according to claim 1, characterized in that: The monoclonal neutralizing antibody is used in cancer treatment in combination with radiotherapy and PD1 monoclonal antibody.

3. The application according to claim 1, characterized in that: The monoclonal neutralizing antibody achieves one or more of the following purposes: inhibiting tumor growth and prolonging patient survival; increasing the number of tumor-infiltrating cytotoxic lymphocytes in the tumor; reducing myeloid-derived suppressor cells; increasing the CD8+T / CD4+T cell ratio; inhibiting tumor angiogenesis; and downregulating the expression of molecules related to ECM, cell adhesion and cell migration.

4. The application according to claim 1, characterized in that: The cancer is selected from one of lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and gastric cancer.

5. An anti-cancer device, characterized in that: include (a) irradiation equipment for delivering radiation therapy to cancer cells; and (b) A drug kit comprising a therapeutically effective amount of a preparation or a pharmaceutical composition, wherein the preparation or composition contains a monoclonal neutralizing antibody targeting CXCL16 as an active ingredient.

6. The anti-cancer device according to claim 5, characterized in that: The anti-cancer device also includes instructions, which describe a method for using the anti-cancer device to treat cancer by administering radiation therapy and a monoclonal neutralizing antibody targeting CXCL16 to a subject in need thereof.

7. The anti-cancer device according to claim 5, characterized in that: The preparation or composition contains a monoclonal neutralizing antibody targeting CXCL16 and a PD1 monoclonal antibody as active ingredients.

8. The anti-cancer device according to claim 7, characterized in that: The anti-cancer device also includes instructions, which describe a method for using the anti-cancer device to treat cancer by administering radiation therapy and a monoclonal neutralizing antibody targeting CXCL16 and a PD1 monoclonal antibody in combination to a subject in need thereof.

9. A radiotherapy sensitizer, characterized in that: Includes monoclonal neutralizing antibodies targeting CXCL16.

10. The radiotherapy sensitizer according to claim 9, characterized in that: It also includes PD1 monoclonal antibodies.

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