Our previous study indicated that GPC3-targeted chimeric antigen receptor (CAR) T cell therapy has a high safety profile in patients with hepatocellular carcinoma (HCC). However, the response rate requires further improvement. Here, we analyzed the combined effect of GPC3-CAR T cells and sorafenib in both immunocompetent and immunodeficient mouse models of hepatocellular carcinoma. In immunocompetent mouse model, mouse CAR (mCAR) T cells induced regression of small tumors (approximately 130 mm 3 tumor volume) but had no effect on large, established tumors (approximately 400 mm 3 tumor volume). Sorafenib, at a subpharmacologic but not a pharmacologic dose, augmented the antitumor effects of mCAR T cells, in part by promoting IL12 secretion in tumorassociated macrophages (TAMs) and cancer cell apoptosis. In an immunodeficient mouse model, both subpharmacologic and pharmacologic doses of sorafenib had limited impacts on the function of human CAR (huCAR) T cells in vitro and showed synergistic effects with huCAR T cells in vivo, which can at least partially be ascribed to the upregulated tumor cell apoptosis induced by the combined treatment. Thus, this study applied two of the most commonly used mouse models for CAR T cell research and demonstrated the clinical potential of combining sorafenib with GPC3-targeted CAR T cells against HCC.

There is limited success in using chimeric antigen receptor (CAR) T cells to treat solid tumors. One of the major reasons is the suppressive tumor microenvironment that impairs the infiltration, expansion and persistence of CART cells in tumor tissues. In this study, we engineered CLDN18.2 specific CART cells to co-express cytokines IL-7 and CCL21 (7×21 CART). Our studies indicated that IL-7 and CCL21 can enhance the survival of CART cells and infiltration of T cells and dendritic cells in tumor tissues. 7×21 CART cells can efficiently destroy different solid tumors with or without preconditioned lymphodepletion chemotherapy and suppress the tumor growth with heterogenous antigen expression in vitro and in vivo. These findings suggest that 7×21 could boost CART cells antitumor activity and may be served as a potential therapy strategy for solid tumors.