Abstract 3599: Recombinant chimeric antibody-based gamma-delta TCR targeting GPC3 induces potent antitumor response against hepatocellular carcinoma

Abstract Background and Significance: Hepatocellular carcinoma (HCC), a major type of primary liver cancer, is the third leading cause of cancer-related death worldwide. While Glypican-3 (GPC3) is highly upregulated in HCC, it is minimally expressed in normal tissues. The research in our laboratory has been focused on the development of GPC3 as an immunotherapeutic target for liver cancer. Despite many clinical trials, there has not been any approved therapy targeting GPC3 largely due to the combination of antigen heterogeneity, poor tumor penetration, and the inability to induce a durable, potent immune response in the tumor microenvironment (TME). Here, we made a recombinant chimeric antibody-based T cell receptors (named AbTCR) targeting GPC3 and explored its anti-tumor efficacy in xenograft mouse models. Methods: The AbTCR constructs were built by fusing an antigen recognition domain (hYP7 scFv or HN3 VH) specific for GPC3 to the gamma-delta TCR constant region along with a secondary T cell signaling activation motif. The NFAT-tdTomato reporter cell line was established and used to measure the AbTCR-triggered T cell signaling upon stimulation with tumor cells. Anti-tumor efficacy of AbTCR-T cells was determined via luciferase-based cell killing assay as well as multiple HCC xenograft mouse models. Results: The hYP7 GPC3 AbTCR-T cell not only enhances antigen-binding capacity and T cell activity, but also induces infiltration and expansion of T cells in the TME, thereby causing robust liver tumor regression in mice. Conclusion: Our data show that new hYP7-directed GPC3 AbTCR is a promising strategy for treating liver cancer. This work provides a rationale for the use of hYP7 GPC3 AbTCR in clinical studies for treating HCC and other GPC3-positive solid tumors. Citation Format: Dan Li, Tianyuzhou Liang, Zhijian Duan, Hongbing Zhang, Cheng Liu, Mitchell Ho. Recombinant chimeric antibody-based gamma-delta TCR targeting GPC3 induces potent antitumor response against hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3599.