Abstract 2044: The target antigen determines the mechanism of acquired resistance to T cell based therapies

Abstract Introduction: Immunotherapy has revolutionized the way many cancers are treated. Despite its success, cancer patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen is important and can be decisive in the success of the clinical response, particularly when resistance emerge. T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. It is assumed that, as all TCBs have the same mechanism of action, mechanisms of resistance are independent of the tumor antigen. Objective: This study was designed to identify the mechanisms that trigger the resistance against HER2 and CEACAM5 T cell bispecific antibodies. We assessed TCB sensitivity using in vitro and in vivo assays combining human cell lines or patient-derived models with human lymphocytes. Material and Methods: Using gastric CEA+/HER2+ MKN45 cells as a model and TCBs directed against CEA or HER2, here we show for the first time that the mechanism of resistance to a T cell-based therapy is dependent on the tumor antigen. Results: Acquired resistant models to a high-affinity CEA-targeted TCB exhibit a reduction of CEA antigen levels due to epigenetic transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels as HER2 downregulation led to an impairment of proliferation. Furthermore, using this latter model, we identified that disruption of interferon- gamma signaling confers resistance to killing by active T lymphocytes. Conclusions: Our results unveil different mechanisms of acquired resistance to TCBs depending on the selected antigen, which will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances. Citation Format: Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius, Marta Escorihuela, Antonio Luque, Irene Chicote, Hector García Palmer, Marina Bacac, Joaquin Arribas, Enrique Javier Arenas Lahuerta. The target antigen determines the mechanism of acquired resistance to T cell based therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2044.