Abstract 3517: A bispecific pan-γδT cell engager with IL-15 fusion that activates both δ1 and δ2 types of γδT cells for the treatment of acute myeloid leukemia

Abstract Background: Bispecific T cell engagers redirecting pan CD3+ T cells for tumor immunotherapy have demonstrated clinical promise in treating mainly hematologic cancers but are often accompanied with severe toxicity due to cytokine storms. An alternative approach involves engaging innate-like γδ T cells instead which possess inherent antitumor activity but are less prone to toxicity. Unfortunately, most γδ T cell-based therapeutics reported so far exhibit suboptimal clinical efficacy due to subtype-specific engagement, limited quantity, and poor durability of γδ T cells in cancer therapy. Methods and Results: We characterized a pan γδ T cell receptor antibody capable of binding and activating γδ T cell receptors from both δ1 γδ T cells (mainly resident in mucosal tissues and tumors) and δ2 γδ T cells (predominantly found in blood circulation). When paired with an antibody targeting the acute myeloid leukemia (AML) associated target CD123, this bispecific pan γδ T cell engager, TAVO317A, mediated tumor cell dependent activation and degranulation of both δ1 and δ2 γδ T cells and redirected them to potently kill antigen-specific hematologic cancer cells. To enhance the durability of bispecific pan γδ T cell engagers in tumor therapy, we engineered an attenuated IL-15 along with the IL-15 receptor α sushi domain as a fusion component on the CD123 bispecific pan γδ T cell engager. The addition of the IL-15 domain further boosted the ability of the engager to promote the activation and proliferation of γδ T cells. In humanized AML cell xenograft models, the CD123 bispecific pan γδ T cell engager effectively recruited γδ T cells to control AML tumor growth. Moreover, the CD123 engager with IL-15 fusion exhibited even better efficacies in tumor cell elimination and sustained γδ T cell activity without requiring IL-2 supplementation. Conclusions: By recruiting both δ1 and δ2 γδ T cells, our bispecific pan γδ T cell engager can mobilize more γδ T cells that may otherwise be of limited quantity for tumor therapy. In addition, the engineered IL-15 domain for immune modulation can facilitate enhanced durability of γδ T cells in tumor cytotoxicity. Our novel proprietary bispecific pan γδ T cell engager platform has the potential to serve as a potent and efficacious alternative to CD3-based therapy by offering enhanced liquid and solid tumor immunotherapy with a better safety profile. Citation Format: Mingcan Yu, Peng Chen, Ying Jin, Fulai Zhou, Honglei Bi, Mark Chiu, Di Zhang. A bispecific pan-γδT cell engager with IL-15 fusion that activates both δ1 and δ2 types of γδT cells for the treatment of acute myeloid leukemia [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 3517.