Combined Antitumor Effects of Sorafenib and GPC3-CAR T Cells in Mouse Models of Hepatocellular Carcinoma.

Abstract

Our previous study indicated that GPC3-targeted chimeric antigen receptor (CAR) Tcell therapy has a high safety profile in patients with hepatocellular carcinoma (HCC). However, theresponse rate requires further improvement. Here, we analyzed the combined effect of GPC3-CAR Tcells and sorafenib in both immunocompetent and immunodeficient mouse models of hepatocellular carcinoma. In immunocompetent mouse model, mouse CAR (mCAR) Tcells induced regression of small tumors (approximately 130mm3 tumor volume) but had no effect on large, established tumors (approximately 400mm3 tumor volume). Sorafenib, at a subpharmacologic but not a pharmacologic dose, augmented the antitumor effects of mCAR Tcells, in part by promoting IL12 secretion in tumor-associated 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) Tcells invitro and showed synergistic effects with huCAR Tcells invivo, 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 Tcell research and demonstrated the clinical potential of combining sorafenib with GPC3-targeted CAR Tcells against HCC.