Treatment Of Small-molecule Targeted Agents Combined With Immune Checkpoint Inhibitors In Advanced Solid Tumors And The Relevant Mechanisms

Purpose:Small-molecule anti-angiogenic multitarget drugs and immune checkpoint inhibitors both showed good efficacy in the clinical treatment of various solid tumors,with significantly lower side effects than chemotherapeutic drugs and good compliance.For patients with solid tumors,these drugs both show superior effects over chemotherapy in terms of efficacy and survival,respectively.However,the prospective studies on the two-drug combination are less frequently reported.Because these two kinds of drugs are completely different in treatment mechanism,they theoretically have the basis for combination.This study was designed to treat advanced solid tumors with the multitarget TKI drug Anlotinib combined with anti-PD-1 antibodies,which has not been reported in the literature and is well innovative.In China,the incidence of gastric cancer ranks among the highest in the world.According to the statistical data in 2020,the number of new cases and death ranks third of the malignant tumors in China.Although chemotherapy and targeted therapy can improve the survival rate of gastric cancer to some extent,the prognosis has not been improved significantly as a result of the toxicity of chemotherapy drugs,the low proportion of people benefiting from targeted drugs and drug resistance.Therefore,how to improve the outcome of patients with advanced gastric cancer and the biomarkers that can predict the treatment effect are the research hotspots at present.In this paper,the efficacy of immune checkpoint inhibitors enhanced by multiple-targets TKI and the mechanism of regulating the c GAS/STING pathway were thoroughly investigated.Methods:First,we evaluated the efficacy and safety of Anlotinib in combination with PD-1 mab in advanced solid tumors.We also measured serum cytokine levels and peripheral blood T lymphocyte numbers before and after treatment,confirming that Anlotinib can modulate the suppressing tumor immune microenvironment,thus enhancing the activity of immune checkpoint inhibitors.Secondly,through the detection of cf DNA and CIN before and after treatment in peripheral blood of patients with metastatic gastric cancer,the possibility of cf DNA-based CIN dynamic detection was explored as an evaluation indicator of therapeutic efficacy and drug resistance in patients with metastatic gastric cancer.Thirdly,in vitro and in vivo experiments were conducted to verify that Anlotinib inhibited the proliferation,migration and immune escape of gastric cancer cells through the c GAS/STING pathway.Results:The first part of the experimental results showed that Anlotinib combined with PD-1 antibodies showed good anti-tumor efficacy and tolerable toxicity in patients with various advanced tumors.The interplay of anti-angiogenesis and immunotherapy makes it a promising novel therapeutic model that warrants further validation in clinical studies with large samples.Changes in cytokine levels and T lymphocyte subsets in peripheral blood appear to be associated with clinical benefit.The increased release of IFN may suggest the activation of the upstream pathway,the c GAS/STING signaling pathway,further research is needed to confirm.The second part indicated that CIN dynamic detection based on plasma cf DNA can be used as a biomarker for the evaluation of efficacy and chemoresistance in metastatic gastric cancer.Rapid CIN clearance after treatment suggests a better prognosis and survival benefit.Our study evaluated the role of CIN test,which deserves validation in prospective,controlled studies with large samples.The third part of the results showed that Anlotinib can effectively inhibit the proliferation,migration and immune escape of gastric cancer cells by activating the c GAS/STING/IFN-βpathway.The data in vivo showed that Anlotinib significantly inhibited gastric cancer cell growth and activated the c GAS/STING/IFN-β pathway to enhance the efficacy of PD-1 antibody.Meanwhile,Anlotinib combined with PD-1 antibody has better safety in the treatment of gastric cancer,and has no significant toxic reactions of important organs such as lung,liver,cerebral cortex and kidney.Conclusions:1.Anlotinib combined with anti-PD-1 antibody has good efficacy and safety in the treatment of advanced tumors,and can promote the phenotypic changes of T lymphocytes and the release of IFN and other pro-inflammatory cytokines.2.Through CIN detection based on cf DNA,we verified the high chromosomal instability of advanced gastric cancer,which is closely related to the treatment efficacy and prognosis of patients.3.Anlotinib can significantly inhibit the growth of gastric cancer cells,down-regulate the expression of PD-L1 in tumor cells,activate the c GAS/STING/IFN-βpathway,and enhance the efficacy of anti-PD-1 antibody.