The efficacy and safety of chimeric antigen receptor T cells in digestive system cancers: a systematic review and meta-analysis.

Background: As a successful treatment for hematological malignancy, chimeric antigen receptor T cells (CAR-T cells) have been expanded to solid tumors to demonstrate their safety and efficacy, especially for digestive system cancer (DSC). Various CAR-T cell constructs used in different types of DSCs result in heterogeneous responses. Thus, we aimed to systematically summarize the clinical response of DSCs treated with CAR-T cells and investigate factors associated with heterogeneity in outcomes. Methods: Clinical studies of DSC patients treated with CAR-T cell therapy were selected from the PubMed, Cochrane, Embase, Web of Science databases before October 1, 2020. "CAR-T cell", "solid tumor" and their synonymous terms were used to construct the search strategy. Duplicates, reviews, non-English literature, articles not related to clinical studies or CAR-T cells used for digestive tumors were excluded. The included studies were assessed by the Institute of Health Economics (IHE) risk of bias tool to check the methodological quality. The inverse variance method was used to perform data pooling and subgroup analysis to clarify the causes of heterogeneity. Publication bias was examined by funnel plots and Egger's test. Results: Twelve studies were included, and the risk of bias evaluation was demonstrated as plots using Review Manager 5.3. The pooled overall response rate (ORR) was 2% (95% CI: 0-6%), and the clinical benefit rate (CBR) was 42% (95% CI: 24-61%). According to subgroup analysis, costimulation (P=0.0449), lymphodepletion (P=0.0002), persistence of CAR-T cells (P=0.0443) and transduction method (P=0.0165) were factors contributing to heterogeneity. For adverse effects, pyrexia was the most frequent (35%, 95% CI: 24-61%). No publication bias was found, and the major results were robust within a slight fluctuation for each removal of one of the 12 studies. Discussion: CAR-T cell therapy is generally beneficial for patients with DSCs though the ORR was still poor. Modified construction with more specific tumor antigens, costimulatory domain and lentiviral vectors is necessary to obtain a better antitumor response of CAR-T cell therapy. Information of survival data are needed for a more comprehensive analysis.