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

• Published in: Molecular therapy 2019-08, Vol.27 (8), p.1483-1494
• Main Authors: Wu, Xiuqi, Luo, Hong, Shi, Bizhi, Di, Shengmeng, Sun, Ruixin, Su, Jingwen, Liu, Ying, Li, Hua, Jiang, Hua, Li, Zonghai
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antigens; Antitumor activity; Apoptosis; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell culture; Cell Line, Tumor; Chimeric antigen receptors; Combined Modality Therapy; Cytokines; Cytokines - metabolism; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Gene expression; Glypicans - antagonists & inhibitors; GPC3; Growth factors; Hepatocellular carcinoma; Humans; Immunodeficiency; Immunoglobulins; Immunotherapy, Adoptive - methods; Inhibitor drugs; Interleukin 1; Interleukin 12; Kinases; Liver cancer; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice; Original; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - metabolism; sorafenib; Sorafenib - pharmacology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Targeted cancer therapy; tumor-associated macrophages; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.04.020

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 mm3 tumor volume) but had no effect on large, established tumors (approximately 400 mm3 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 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) 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. The efficacy of GPC3-targeted chimeric antigen receptor (CAR) T cells requires further improvement in patients with hepatocellular carcinoma (HCC). Li and colleagues combined GPC3-CAR T cells with a clinically accessible multikinase inhibitor, sorafenib. The combination’s effects were analyzed in both immunocompetent and immunodeficient mouse models of HCC.