Abstract LB032: Preclinical evaluation of GPC3 targeting antibody-TCR T cells in HCC models with tumor rechallenging

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Glypican-3 (GPC3), highly expressed in HCC but minimally in normal tissues, is a promising target for cell therapy. ECT204, a GPC3-targeting T cell product developed using the ARTEMIS Cell Receptor Platform, incorporates an Antibody T-Cell Receptor (AbTCR) combining an antibody-derived targeting domain with a human γδ T-cell receptor effector domain and a Costimulatory Receptor (CSR)1. Previous studies have demonstrated superior anti-tumor activity, safety, and reduced exhaustion of ARTEMIS T cells compared to CAR-T cells in hematologic cancer models2. To address challenges of T-cell therapy against solid tumors, including poor tumor infiltration, T cell exhaustion, short T cell persistence and high tumor burden with limited T cell dosing potential, we evaluated ECT204 in rigorous HCC models. In the HepG2 xenograft model, ECT204 T cell exhibited abundant infiltration by immunohistochemistry staining, significantly higher than GPC3-targeting CAR-T. Notably, circulating ECT204 T cells were drastically lower PD-1 expression compared with its CAR-T counterpart. When tested for T cell persistence in HepG2 re-challenge model, ECT204 suppressed re-inoculated tumor 75 days after the initial T-cell dosing. Expansion of ECT204 T cells were detected in peripheral blood after re-challenge, indicating the presence of memory cells that can sustain response. While preclinical studies with high T cell doses are useful for proof-of-concept purposes, they may not reflect clinically feasible doses. Remarkably, ECT204 effectively killed HepG2 cells in vitro at effector:target ratios as low as 1:16 and eliminated tumors in xenografts at a low dose of 0.5 x 106 cells. Overall, these stringent preclinical evaluations support the clinical translation of ECT204. ECT204 is currently in the ARYA-3 Phase 1/2 trial for adults with advanced HCC and is actively enrolling patients in the expansion phase. 1. He, P., et al. “A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma.” Journal of Cancer Research and Clinical Oncology. 149, 7 (2023). 2. Xu, Y., et al. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discovery. 4, 62 (2018). Citation Format: Guangyan Xiong, Hongbing Zhang, Cheng Liu. Preclinical evaluation of GPC3 targeting antibody-TCR T cells in HCC models with tumor rechallenging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB032.