Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer.

Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4-1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and off-target toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3+CD8+ T cells and CD62L+CCR7+ central memory T cells (TCM) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the anti-tumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.

Efficacy and safety of immune checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICI) have shown promising prospects in gastroesophageal junction (G/GEJ) cancer immunotherapy, many clinical trials have been carried out. Objective: To evaluate the efficacy and safety of ICI in G/GEJ cancer. Methods: The published English articles of PubMed, Cochrane Library, Embase, Web of Science were searched up to 30/09/2018. The efficacy and safety of ICI were analyzed by meta-analysis. Results: A total of 2003 patients from nine clinical trials were included. Anti-PD-1 treatment improved the 12-month, 18-month overall survival (OS) rate (RR, 1.79 p = 0.013; 2.20 p = 0.011) and prolonged the duration of response (DOR) (MSR, 3.27 p < 0.001). The objective response rate (ORR) in PD-L1+ patients was greater than PD-L1- (RR, 4.31 p < 0.001). Microsatellite instability-high (MSI-H) patients had higher ORR and disease control rate (DCR) than microsatellite stability (MSS) (RR, 3.40 p< 0.001; 2.26 p= 0.001). The most common grade ≥3 treatment-related adverse events (TRAEs) were fatigue, aspartate aminotransferase increased, hepatitis, pneumonitis, colitis, hypopituitarism. The TRAE incidence of anti-PD-1/PD-L1 was less than chemotherapy (TRAE RR = 0.64 p< 0.001; ≥3 TRAE RR = 0.37 p < 0.001). The incidence of ≥3 TRAEs of anti-PD-1/PD-L1 treatment was less than that of anti-CTLA-4 (11.7% vs 43.9%). Conclusions: ICI treatment could improve some but not all survival endpoints to advanced or metastatic G/GEJ cancer patients suggesting modest benefit and less adverse reactions. Anti-PD-1/PD-L1 therapy was more effective to PD-L1+, MSI-H, EBV+, or high tumor mutational burden patients.