Abstract 7321: A novel gamma-delta T cell engager platform for cancer immunotherapy

Abstract Bispecific T cell engagers (TCE) bring effector T cells in contact with cancer cells by binding a pan-T cell receptor sequence and a tumor-associated antigen (TAA) simultaneously, thereby initiating activation and killing properties of the T cell. One of the foremost challenges for the clinical use of TCE is tumor heterogeneity, specifically, the limited expression of specific tumor antigens on the cancer cell surface. Gamma-delta (γδ) T cells are unique in that they recognize multiple stress-associated antigens common to most malignancies regardless of origin. This function is independent of MHC restriction, enabling them to target a broad range of tumors. Here, we report initial findings from a novel γδ T cell engager platform (γδ-TCE), specifically two γδ-TCEs targeting hematologic malignancies, CD33-TCE (CD-33, AML) and CD19-TCE (CD19, B_ALL), while also enabling γδ T cells to engage tumor-associated stress ligands with innate surface receptors such as NKG2D, PVR, and others. Preliminary in vitro characterization revealed properties suggestive of pan-δ chain binding, such as competing with isoprenyl pyrophosphate activation of Vδ2+ T cells, yet efficiently driving both activation and expansion of Vδ1+ and Vδ2+ T cell subsets from peripheral blood mononuclear cells (PBMC). Robust expansion of a diverse repertoire of γδ T cells in the tumor environment is critical for continued pressure and a persistent anti-tumor response. Cytotoxicity assays show that both CD33-TCE and CD19-TCE measurably enhanced γδ T cell-mediated lysis of CD33+ AML and CD19+ ALL tumor cells, respectively, in a dose-dependent manner. In co-cultures with tumor cells, γδ-TCE- armored γδ T cells showed markedly increased degranulation and the release of pro-inflammatory cytokines, such as IFN-γ, TNF-α, granzymes, and perforin, further highlighting the activation of γδ T cells into a potent cytotoxic state and amplifying their tumor-eradicating abilities. This novel γδ T cell engager platform represents a promising new approach to cancer immunotherapy, offering an effective strategy for enhancing γδ T cell-mediated tumor cell lysis. Furthermore, the platform’s modular and flexible design suggests applications in treating a broad range of malignancies by combining the innate recognition properties of γδ T cells with the targeting of specific tumor-associated antigens, thus expanding its therapeutic potential. Citation Format: Lei Ding, Sadhak Sengupta, Mariska ter Haak, Kate Rochlin, Yanjie Li, Lawrence S. Lamb. A novel gamma-delta T cell engager platform for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7321.