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) 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.

Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion

“…Tumor angiogenesis is crucial for tumor growth and metastasis, thus blocking or inhibiting tumor angiogenesis could potentiate antitumor activities (42). In this study, we observed that Author Manuscript Published OnlineFirst on August 14, 2020; DOI: 10.1158/1078-0432.CCR-20-0777 CAR-T cells (43). Thus, the property of angiogenesis inhibition may enhance the antitumor activities of 7×21 CAR-T cells.…”

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

“…Patients who met all screening criteria underwent leukapheresis to obtain peripheral blood mononuclear cells (PBMC) for the generation of autologous CAR-GPC3 T cells. As described previously (36), CAR-GPC3 T cells (product code Y035) consisted of a humanized anti-GPC3 single-chain variable fragment, CD8a hinge domain, CD8a transmembrane domain, CD28 intracellular domain, and CD3z intracellular signaling domain that were cloned into a lentiviral backbone (Fig. 1A).…”

“…Indeed, anti-GPC3 mAbs had good safety profiles in previous studies (34,35), although significant clinical benefit has yet to be established in phase II clinical trials. Recently, we demonstrated that GPC3targeted CAR T cells could eliminate GPC3 þ HCC cells in vitro and eradicate GPC3 þ HCC tumor xenografts in mice (36)(37)(38). Therefore, in the present prospective phase I studies, we explored the safety and potential efficacy of CAR-GPC3 T-cell therapy in adult Chinese patients with advanced GPC3 þ HCC.…”

Immunotherapy for Hepatocellular Carcinoma: A 2021 Update

“…Chimeric antigen receptor T cells (CAR-T): Recent studies of HCC tumor xenografts in mice and in vitro demonstrated that engineered CAR-T cells expressing a GPC3 CAR could eliminate GPC3-positive HCC cells [ 141 , 142 , 143 , 144 ]. Therefore, phase I clinical studies designed to evaluate the safety and efficacy of CAR-GPC3 T-cell therapy alone (NCT03980288, NCT04121273, NCT03884751) or in combination with cyclophosphamide and fludarabine (NCT02905188) or other treatment options (NCT04093648, NCT03198546) are currently ongoing and in recruiting status [ 145 , 146 , 147 , 148 , 149 , 150 ].…”