Application of sequential combination of CAR T based on improvement of tumor microenvironment in preparation of anti-tumor drugs

Abstract

The application discloses a sequential anti-tumor strategy based on improvement of tumor microenvironment (TME) combined with CAR T and application thereof, and belongs to the technical field of biological medicine, which simultaneously improves tumor fibrosis and acid microenvironment by applying tumor-related fibroblast (CAF) targeting drugs and proton pump inhibitors, and sequentially injects CAR T combined therapy for solid tumors, wherein the CAF targeting drugs are selected from tretinoin, calcipotriol, losartan and minnelide, the proton pump inhibitors are selected from lansoprazole, omeprazole, pantoprazole, rabeprazole and esomeprazole, and the CAR T receptor or ligand is selected from mesothelin, protein tyrosine kinase 7, NKG2D, CD47, B7-H3, MUC1 and HER2; the sequential administration strategy first destroys the dense physical barrier of the tumor microenvironment, improves the acidity of the tumor site, ensures the infiltration, survival and proliferation of CAR T at the tumor site, and then targets and inhibits the growth of solid tumors, especially high-malignancy triple-negative breast cancer, by using the specificity of CAR T.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to an application of sequential combination of CART in preparation of an anti-tumor drug based on improvement of a tumor microenvironment, in particular, a tumor-related fibroblast cell (CAF) targeting drug and a proton pump inhibitor synergistically improve a tumor microenvironment, and a CAR T is sequentially injected for application in treatment of a solid tumor. BACKGROUND

[0002] T cells genetically engineered to express chimeric antigen receptors on their surface (CAR T) have received extensive attention in the field of cancer immunotherapy. Six products have been approved by the FDA for the treatment of B-cell acute lymphoblastic leukemia and multiple myeloma, with a complete remission rate of up to 90% for patients with relapsed or refractory B-cell malignancies. However, despite such a remarkable therapeutic effect of CAR T cells on hematological tumors, clinical data has shown that it is essentially ineffective for solid tumors. Studies on this significant difference in therapeutic effect have increasingly found that the tumor microenvironment (TME) associated with solid tumors has an inescapable far-reaching impact. The tumor microenvironment is defined as a complex and rich multicellular environment for tumorigenesis. Unlike hematological tumors, the TME of solid tumors presents a specific niche that is conducive to tumor progression, which includes physical barriers, multiple immune suppression mechanisms, and various biochemical factors. Therefore, CAR T therapy for solid tumors faces greater challenges. Specifically, the dense extracellular matrix, abnormal tumor vasculature, and elevated interstitial pressure in the TME hinder the infiltration of CAR T cells. In addition, the accumulation of nutrient deficiencies and metabolic waste (such as lactic acid and H + ) within the tumor tissue forms an immunosuppressive environment that inhibits the activity of CAR T cells. Therefore, there is an urgent need for innovative technical methods or therapeutic strategies to enable CAR T cells to overcome these obstacles and improve therapeutic efficacy.

[0003] Currently, CAR T research in solid tumors mainly focuses on selecting the best target (especially tumor-specific antigens), modifying the CAR structure, or combining immunological drugs to enhance the efficacy of CAR T T cell response , but there is almost no research on improving the tumor microenvironment to enhance the infiltration, survival, and proliferation of CAR T at the tumor site.

[0004] Tumor-associated fibroblasts (CAFs), as a hub for communication between various cells in the tumor stroma, are a type of stromal cell present in the interstitial space of tumor tissue. When CAFs are activated by various inflammatory cytokines produced by cancer cells, immune cells, and stromal cells, CAFs rapidly proliferate and produce extracellular matrix within the closed tumor space, forming a physical barrier. Therefore, modulating CAFs appears to be a promising strategy to overcome the physical barriers of the TME to increase the infiltration of CAR T at the tumor site.

[0005] However, adjusting a single factor is not enough to improve the complex TME. The acidic microenvironment, as a driving factor of cancer, can induce macrophages to polarize into the M2 phenotype of immunosuppression, thereby promoting tumor invasion and resisting solid tumor treatment. In addition, the acidic TME induced by cancer cell anaerobic metabolism will reduce the production of cytokines, perforin and granzyme B, thereby directly weakening the activity and function of effector T cells.

[0006] Therefore, by combining CAF-targeted drugs and proton pump inhibitors, respectively for improving tumor fibrosis and acidic microenvironment, followed by sequential injection of CAR T to play a specific anti-tumor effect, the feasibility of this treatment strategy of improving the microenvironment before anti-tumor is verified, which provides strategic reference for strengthening the efficacy of CAR T, provides valuable insights and practical guidance for other solid cancer treatments based on CAR T cells, and has important clinical significance. SUMMARY

[0007] Objectives of the invention:

[0008] By combining CAF-targeted drugs and proton pump inhibitors, the fibrosis and acidity of TME are synergistically improved, and the survival, proliferation and immunotherapy effect of CAR T cells in the tumor site are promoted.

[0009] Technical solutions:

[0010] An application of sequential combination of CAR T based on improvement of tumor microenvironment in the preparation of anti-tumor drugs, characterized by CAF-targeted drugs or pharmaceutically acceptable salts thereof and proton pump inhibitors or pharmaceutically acceptable salts thereof to improve tumor fibrosis and acidic microenvironment, followed by sequential injection of CAR T for combined treatment of solid tumors.

[0011] The CAF-targeted drug binds to the receptor on the nucleus of CAF, re-regulates the function of CAF, restores the activated CAF to the resting state or reduces the activation of CAF; and the proton pump inhibitor binds to ATPase on tumor cells and inhibits the efflux of H + to improve the acidic environment in the tumor site.

[0012] At the same time, the CAF-targeted drug reduces the generation of extracellular matrix and alpha-SMA, increases the effectiveness of drug delivery and immunotherapy, and the proton pump inhibitor can cause intracellular acidification and accumulation of intracellular reactive oxygen species in tumor cells, hinder the proliferation and migration of cancer cells, and synergistically improve the tumor microenvironment and CAR T anti-tumor function.

[0013] In one aspect, the CAF-targeting drug is selected from at least one of all-trans retinoic acid, calcipotriol, losartan and minnelide, or a pharmaceutically acceptable salt thereof; preferably all-trans retinoic acid (ATRA).

[0014] The proton pump inhibitor is selected from one of lansoprazole, omeprazole, pantoprazole, rabeprazole and esomeprazole, or a pharmaceutically acceptable salt thereof; preferably lansoprazole (LPZ).

[0015] The ligand or receptor of CAR T is selected from one of mesothelin, protein tyrosine kinase 7, NKG2D, CD47, B7-H3, MUC1, HER2; preferably NKG2D.

[0016] In another aspect, the single dose of the CAF-targeting drug is 0.01-400 mg / kg, preferably the single dose of all-trans retinoic acid is 0.1-50 mg / kg; more preferably 2.5 mg / kg.

[0017] The single dose of the proton pump inhibitor is 0.01-500 mg / kg, preferably the single dose of lansoprazole is 0.1-100 mg / kg; more preferably 2.5 mg / kg.

[0018] The single dose of CAR T is 1000-2x10 7 cells per gram, preferably the single dose of NKG2D-CAR T is 1x10 4 -2x10 6 cells per gram; more preferably 1x10 5 cells per gram.

[0019] The pharmaceutical composition is a CAF-targeting drug, a proton pump inhibitor and a pharmaceutically acceptable excipient in the form of an oral liquid, granules, capsules, pills, tablets, patches or injections.

[0020] The pharmaceutically acceptable excipient is selected from one or more of diluents, excipients, fillers, binders, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants.

[0021] The pharmaceutical composition is preferably all-trans retinoic acid, a proton pump inhibitor, poloxamer 407 and poloxamer 188 in the form of an injection.

[0022] The sequential administration is by injection, specifically by peritumoral injection of the pharmaceutical composition, followed by intratumoral injection of NKG2D-CAR T cells after two days.

[0023] The tumor is a solid tumor; preferably, it is triple-negative breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, prostate cancer, lung cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, primary peritoneal cancer or colon cancer, and most preferably, it is triple-negative breast cancer.

[0024] Specifically, using the individual mechanisms of all-trans retinoic acid and lansoprazole, a poloxamer warm gel (ATRA / LPZ@gel) is prepared, and peritumoral injection is used to improve tumor fibrosis and acidic microenvironment, and intratumoral injection of NKG2D-CAR T / ATRA / LPZ is performed after two days, so as to achieve targeted treatment of triple-negative breast cancer. Among them, NKG2D is frequently expressed in breast cancer patient samples, and is expressed at a lower level or not expressed in healthy tissues thereof, thereby minimizing the clinical risk of non-tumor targeting toxicity of CAR-T therapy; co-culture of all-trans retinoic acid and lansoprazole and NKG2D-CAR T realizes significant proliferation of CAR T and secretion of cytokines, and promotes CAR T to CD8 + CAR T transformation, enhanced immune response.

[0025] Beneficial effects: compared with the prior art, the present application has the following advantages: (1) can simultaneously improve the tumor microenvironment including fibrosis, acidity and various ecological niches, and synergistically enhance the function of CAR T; (2) remodeling the tumor microenvironment at a safe drug concentration, and combining CAR T specific targeting of tumor cells, shows excellent safety and efficacy, and has clinical significance; (3) the present application has low cost, and is not limited to the currently preferred drugs or tumor models, and has wide application. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 It is an inverted fluorescence graph of the inhibition of ATRA on activated CAF in Example 1;

[0027] Figure 2 It is a Western blot result of the inhibition of LPZ on V-ATPase expression in Example 1; a is the WB result, and b is the statistical result;

[0028] Figure 3 It is a flow cytometry result of the NKG2D-CAR T proliferation experiment in Example 2; wherein a is the flow cytometry detection result, and b is the statistical result;

[0029] Figure 4 It is a cytokine determination result in Example 2; a is TNF-alpha, b is IFN-gamma, and c is IL-2;

[0030] Figure 5 It is a result of the ATRA and LPZ combined with NKG2D-CAR T pharmacodynamic experiment in Example 2;

[0031] Figure 6Scanning electron microscope image of the temperature-sensitive gel in Example 3; a is Gel, b is ATRA / LPZ@gel

[0032] Figure 7 Release curve of ATRA (a) and LPZ (b) in the temperature-sensitive gel in Example 3;

[0033] Figure 8 Results of the influence of tumor tissue pH after treatment in different groups in Example 4;

[0034] Figure 9 Masson staining results of tumor tissue after treatment in different groups in Example 4;

[0035] Figure 10 Results of α-SMA expression in tumor tissue after treatment in different groups in Example 4;

[0036] Figure 11 Results of CD31 expression in tumor tissue after treatment in different groups in Example 4;

[0037] Figure 12 CD3 + Distribution of NKG2D-CAR T in tumor tissue results;

[0038] Figure 13 Results of the mass of tumor tissue after treatment in different groups in Example 5 and appearance pictures;

[0039] Figure 14 HE staining results of tumor tissue after treatment in different groups in Example 5;

[0040] Figure 15 TUNEL staining results of tumor tissue after treatment in different groups in Example 5;

[0041] Figure 16 CD4, CD8 staining results of tumor tissue after treatment in different groups in Example 5;

[0042] Figure 17 Results of changes in body weight of mice and evaluation results of liver and kidney function in Example 6; a is change in body weight, b is ALT, c is AST, d is BUN, and e is UA;

[0043] Figure 18 HE staining results of the main organs of mice in Example 6. DETAILED DESCRIPTION

[0044] The technical solution of the present invention will be further described below with reference to the embodiments. This description does not limit the present invention in any way. Any modifications or changes to the present invention that are easily implemented by those skilled in the art without departing from the technical solution of the present invention will fall within the scope of the claims of the present invention.

[0045] NKG2D-CAR T cells were prepared according to CN113896801A.

[0046] Example 1: Investigation into the mechanism of ATRA and LPZ

[0047] 1. Inhibitory effect of all-trans retinoic acid (ATRA) on activated CAF.

[0048] Tumor-associated fibroblasts, i.e., activated MRC-5 cells, were successfully obtained by co-incubating human embryonic lung fibroblast cell line MDC-MB-231 cells with human triple-negative breast cancer cell line MDA-MB-231. Specifically, the culture medium containing ATRA (15 μM) was changed daily, with a control group included. After 7 days, the supernatant was aspirated, and after repeated washing, each well was fixed with 4% paraformaldehyde, followed by the addition of 0.5% Triton X-100, and then blocked with 5% BSA. The blocking solution was aspirated, and each well was added with Rabbit anti-α-SMA primary antibody and incubated overnight at 4°C. The primary antibody solution was aspirated, and after repeated washing, 500 μL of Anti-Rabbit IgG was added, followed by repeated washing, and images were taken under an inverted fluorescence microscope.

[0049] Depend on Figure 1 As shown, various growth factors and cytokines secreted by tumor cells can promote the transformation of MRC-5 cells into CAF cells and promote their proliferation; ATRA can significantly inhibit the activity of activated MRC-5 cells and the expression of α-SMA.

[0050] 2. LPZ inhibits the expression of V-ATPase.

[0051] MDA-MB-231 cells in logarithmic growth phase were incubated with LPZ (10 μM) at an acidic environment (pH 6.4) for 48 h, with a control group included. Each group had three replicates. After 48 h, the supernatant was aspirated, and after repeated washing, lysis buffer was added to extract total protein. Total protein was quantified using a BCA protein assay kit, and V-ATPase expression was analyzed by Western blotting. α-tubulin was used as an internal control protein.

[0052] Depend on Figure 2 As shown, LPZ can significantly reduce the expression of V-ATPase on MDA-MB-231 cells and decrease H +The efflux of these cells helps to increase the extracellular pH, altering the tumor metabolic environment, affecting the tumor cell growth cycle, and inhibiting their proliferation.

[0053] Example 2: Synergistic effect of all-trans retinoic acid (ATRA) and lansoprazole (LPZ) on NKG2D-CAR T

[0054] 1. NKG2D-CAR T cell proliferation experiment

[0055] NGK2D-CAR T cells were stained according to the instructions of the carboxyfluorescein succinimide (CFSE) kit. Subsequently, NKG2D-CAR T cells alone or NKG2D-CAR T cells combined with target cells were seeded in 12-well plates and incubated for 48 h with different concentrations of ATRA or LPZ. Each group was configured with three replicates, and a negative control group (unstained NKG2D-CAR T cells) and a positive control group (no drug administration) were also included. After 48 h, the culture medium was collected, centrifuged at 1000 rpm for 5 min, resuspended in an appropriate amount of PBS, and intracellular fluorescence intensity was detected using flow cytometry. Lower fluorescence intensity indicated higher cell proliferation.

[0056] from Figure 3 It was found that when ATRA, LPZ, and NGK2D-CAR T cells were administered simultaneously, NGK2D-CAR T cells underwent more significant proliferation.

[0057] 2. Cytokine assay

[0058] NKG2D-CAR T cells and MDA-MB-231 cells were seeded in 12-well plates and incubated for 48 h with the optimal concentrations of ATRA and LPZ. Six replicates were performed for each concentration. After 48 h, the culture medium was collected, centrifuged, and the supernatant was analyzed according to the ELISA kit instructions. The OD values ​​of each well were measured, and TNF-α, IFN-γ, and IL-2 were quantified using a fitted standard curve.

[0059] from Figure 4 It was found that when ATRA and LPZ were co-incubated with NKG2D-CAR T, the secretion of the three pro-inflammatory factors (TNF-α, IFN-γ and IL-2) was significantly higher, further demonstrating the synergistic effect of ATRA and LPZ with NKG2D-CAR T to enhance the immune response.

[0060] 3. Evaluation of the anti-tumor effects of NKG2D-CAR T cells

[0061] NGK2D-CAR T cells and MDA-MB-231 cells were seeded in 96-well plates at ratios of 1:2, 1:1, and 2:1. A specific concentration of ATRA or LPZ was added to the NGK2D-CAR T cell group simultaneously, and the cells were incubated together for 48 hours. Each group had six replicates, and separate groups were set up for NGK2D-CAR T cell lysis alone, target cell lysis alone, and maximum target cell lysis. One hour before the predetermined detection time, LDH-releasing agent was added to the maximum target cell lysis group, and the mixture was repeatedly pipetted several times to mix thoroughly before continuing culture. After the predetermined time, the culture plates were centrifuged. 120 μL of the supernatant from each well was added to the corresponding wells of a new 96-well plate, along with 60 μL of LDH detection working solution. The absorbance of each well was measured at 490 nm using a microplate reader. Cytotoxicity was calculated as follows.

[0062]

[0063] Among them, OD c OD values ​​representing the NGK2D-CAR T cell co-incubation group with target cells, OD z OD e OD o The values ​​represent the OD values ​​of the maximum target cell lysis group, the NGK2D-CAR T cell group alone, and the target cell group alone, respectively.

[0064] The results are as follows Figure 5 As shown, the presence of ATRA and LPZ can significantly increase the toxicity of NKG2D-CAR T to tumor cells.

[0065] Example 3: Preparation and characterization of ATRA / LPZ@gel

[0066] 1. Preparation of ATRA / LPZ@gel

[0067] Accurately weigh appropriate amounts of poloxamer 407 and poloxamer 188 and place them in a beaker. Add PBS and mix. Prepare a gel using the cold dissolution method. Let it stand overnight at 4°C to obtain a homogeneous blank gel. Accurately weigh ATRA and LPZ and place them in a vial. Add anhydrous ethanol and sonicate to dissolve. Then add the blank gel, stir in an ice bath for 30 min, and let it stand at 4°C to obtain ATRA / LPZ@gel.

[0068] 2. Characterization of ATRA / LPZ@gel

[0069] The blank gel (Gel) and drug-loaded gel (ATRA / LPZ@gel) were freeze-dried, and thin slices of the freeze-dried samples were subjected to gold spraying treatment, and the microstructure of the gel was observed using a cold field electron scanning microscope (SEM). The drug-loaded gel was placed in an EP tube, PBS was added as the release medium, and stirring was performed in a 37°C water bath, 100μL samples were taken at 1, 2, 4, 8, 12, 24, 48, 72, 96h respectively and the same volume of fresh medium was added at the same time. The peak area of ATRA and LPZ was detected by HPLC, and the corresponding concentration was calculated by substituting the standard curve, and finally the cumulative release percentage (Cumative release percentage, Q%) was calculated.

[0070]

[0071] wherein C1, C2, C i-1 , C i are the concentrations of ATRA / LPZ in the release medium at the 1st, 2nd, i-1, i time points, V1 represents the total volume of the release medium, V2 represents the volume of the sample taken, and M represents the dosage.

[0072] As shown in Figure 6 , the gel system has a dense network structure and can be used as an excellent drug carrier; as shown in Figure 7 , within 48h, the release curve tends to be stable with a slight downward trend, indicating that the drug is completely released within 48h, and at the same time, it is observed that the gel has been completely degraded at this time.

[0073] Example 4: Improvement of the microenvironment of ATRA / LPZ@gel

[0074] A NSG mouse tumor transplantation model was established by subcutaneously injecting 1×10 5 cells per gram of MDA-MB-231 cell suspension, and all animal operations followed the animal ethics committee of China Pharmaceutical University. When the tumor volume reached about 100mm 3 , the tumor mice were randomly divided into four groups and treated with normal saline (as a control group), ATRA@gel, LPZ@gel, and ATRA / LPZ@gel, respectively. All samples were injected at a concentration of 2.5mg / kg. Two days later, the mice were euthanized and the tumor tissue was excised. The pH value of the maximum cross-sectional area of the tumor was measured using a CK multifunctional skin pH meter. Subsequently, the tissue sections were stained using Masson staining and immunostained for α-SMA and CD31. To further evaluate the function of CAR T cells in vivo, CAR T cells were injected for the second time into the tumor two days after the first treatment, and tumor sections were analyzed by CD3 immunostaining.

[0075] As shown in Figure 8As shown, the maximum cross-sectional pH of the tumor in the control group was 6.44, indicating that the tumor tissue was acidic inside. After A / L@gel treatment, the cross-sectional pH of the tumor rose to 6.85, and the acidic microenvironment was significantly improved. Figure 9 As shown, in the negative control group, the tumor tissue was rich in blue collagen and spread throughout the tumor tissue. After A / L@gel treatment, the collagen content in the tumor tissue decreased, and the dense collagen structure was destroyed. Figure 10 and 11 As shown, after A / L@gel treatment, the expression of a-SMA in the tumor tissue decreased, indicating that the CAF in the tumor area decreased, and the fibrotic microenvironment was improved. At the same time, the expression of CD31 increased, indicating that the tumor blood vessel system expanded, and the IFP decreased. Figure 12 As shown, CD3 labeled T cells, and the CD3 fluorescence of the ATRA / LPZ@gel+NKG2D-CAR T group not only increased in expression, but also distributed more evenly in the tumor, indicating that it promoted the infiltration and survival of NKG2D-CAR T in the tumor tissue, which was beneficial to the full contact of CAR T with tumor cells and played an anti-tumor role.

[0076] Example 5: Sequential Anti-tumor Study of ATRA / LPZ@gel and NKG2D-CAR T

[0077] Tumor mice with appropriate tumor volume (100 mm 3 ) were randomly assigned to the following five groups: (1) control group: peritumoral saline injection on day 1, intratumoral saline injection on day 3; (2) ATRA / LPZ@gel group: peritumoral ATRA / LPZ@gel injection on day 1, intratumoral saline injection on day 3; (3) NGK2D-CAR T group: peritumoral saline injection on day 1, intratumoral NGK2D-CAR T cell injection on day 3; (4) ATRA / LPZ@gel+NGK2D-CAR T group: peritumoral ATRA / LPZ@gel injection on day 1, intratumoral NGK2D-CAR T cell injection on day 3; (5) ATRA / LPZ@gel+NGK2D-CAR T / ATRA / LPZ group: peritumoral ATRA / LPZ@gel injection on day 1, intratumoral NGK2D-CAR T / ATRA / LPZ injection on day 3. In the ATRA / LPZ@gel group, the concentrations of ATRA and LPZ were both 2.5 mg / kg, and the concentration of NKG2D-CAR T cells was 1×10 5 cells per gram. The tumor volume and body weight of mice in each group were measured at the designated time points. After the experiment, the tumor tissue was harvested and subjected to H&E staining, TUNEL staining, and CD4 and CD8 immunohistochemistry to evaluate the histopathological features and immune cell infiltration.

[0078] As Figure 13 , 14 and 15, the anti-tumor effect of ATRA / LPZ@gel alone was poor, and no obvious apoptosis of tumor cells occurred, mainly playing a role in improving the tumor microenvironment. The anti-tumor effect of ATRA / LPZ@gel + NKG2D-CAR T / ATRA / LPZ was the best, the dense structure of tumor stroma was destroyed, and a large area of apoptosis appeared in the tumor area, indicating that ATRA and LPZ also played a role in promoting the immune response of NKG2D-CAR T; as Figure 16 shown, after sequential administration of ATRA / LPZ@gel and NKG2D-CAR T / ATRA / LPZ, CD4 + NKG2D-CAR T cells were slightly reduced, but CD8 + NKG2D-CAR T cells were significantly increased, indicating that ATRA and LPZ promoted the transformation of NKG2D-CAR T cells to a more killer phenotype.

[0079] Example 6: In vivo safety evaluation

[0080] The body weight of mice during the experiment was weighed and the change was recorded; the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea nitrogen (BUN) and urea (UA) in the plasma of mice after the end of the experiment were determined; HE staining analysis was performed on the main tissues (heart, liver, spleen, lung, kidney) to evaluate whether the tissues were damaged.

[0081] As Figure 17 and 18 shown, after treatment of each treatment group, the body weight of mice did not change significantly, indicating that each treatment group had no obvious toxicity to mice; the levels of AST, ALT, BUN and UA did not change significantly, indicating that each treatment group had no damage to liver and kidney function; no obvious organ lesions were observed in each experimental tissue, indicating that the drugs had little damage to the body.

Claims

1. The use of a drug composition based on improving tumor microenvironment sequentially combined with CAR T cells in the preparation of an antitumor drug, characterized in that, The improved tumor microenvironment pharmaceutical composition comprises a tumor-associated fibroblast CAF targeting drug and a proton pump inhibitor; the CAF targeting drug is selected from the compound all-trans retinoic acid, and the proton pump inhibitor is selected from the compound lansoprazole; the ligand or receptor in the CAR T cell is selected from NKG2D, and the tumor is selected from triple-negative breast cancer.

2. Use according to claim 1, characterized in that, The pharmaceutical composition is in the form of an oral solution, granules, capsules, pills, tablets, patches or injections, and comprises a CAF targeting drug, a proton pump inhibitor and a pharmaceutically acceptable excipient.

3. Use according to claim 2, characterized in that, The pharmaceutically acceptable excipient is selected from one or more of diluents, fillers, binders, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants.

4. Use according to claim 3, characterized in that, The pharmaceutical composition forms a poloxamer temperature-sensitive gel.

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