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

Abstract

Purpose: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. Patients and Methods: In two prospective phase I studies, adult patients with advanced GPC3 þ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide-and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). Results: A total of 13 patients received a median of 19.9 Â 10 8 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. Conclusions: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

“…(2/13). Compared to CAR-T targeting CD19 for hematological malignancies, CAR-T targeting GPC3 for hepatocellular carcinoma did not show encouraging e cacy [22]. Various factors affect the therapeutic bene t of CAR-T on HCC, such as a poor tumor tissue microenvironment that limits proliferation and CAR-T cytotoxicity and the dense ECM which limits lymphocyte in ltration into tumor tissue [13,25].…”

“…First, the editing of large genes is a major limiting factor when modifying T cells, as they increase the di culty of lentivirus packaging, reduce the ability of lentivirus to infect cells, and thus increase the cost of the procedure [29,30]. Secondly, GPC3 is reported to be a very speci c target, and thus CAR-T targeting of it is thought not to have off-target toxicity [22,31,32]. Therefore, we believe that for CAR-T targeting GPC3 or other speci c solid tumor targets, increasing CAR-T's in ltration ability is better than increasing its capacity for chemotaxis.…”

“…Hepatocellular carcinoma (HCC) is a highly aggressive and fast-growing malignancy with high lethality which lacks effective treatment [20,21]. There are many clinical trials of CAR-T cell therapy for HCC [22].…”

Immunotherapy for Hepatocellular Carcinoma: A 2021 Update

“…The NCT02905188 and NCT03146234 studies ( Table 3 ) reported that patients with advanced GPC3+ HCC (Child-Pugh A), receiving autologous CAR-GPC3 T-cell therapy following cyclophosphamide and fludarabine had a tolerable toxicity profile with no grade 3/4 neurotoxicity. The OS rates at 6 months, 1 year, and 3 years were 50.3%, 42.0% and 10.5%, respectively, with a median OS of 9.1 months (95% CI: 1.5–20) [ 151 ]. The target lesions in two patients with partial response exhibited significant tumor shrinkage, while one patient with sustained stable disease was alive after 44.2 months [ 151 ].…”

“…The OS rates at 6 months, 1 year, and 3 years were 50.3%, 42.0% and 10.5%, respectively, with a median OS of 9.1 months (95% CI: 1.5–20) [ 151 ]. The target lesions in two patients with partial response exhibited significant tumor shrinkage, while one patient with sustained stable disease was alive after 44.2 months [ 151 ]. Another phase I study (NCT02395250) [ 152 ] and a phase I/II study (NCT02723942) [ 153 ] have been completed; however, no results are yet posted.…”