Abstract 3970: Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

Abstract Elimination of cancer cells by effector immune cells represents the culmination of a complex cascade of events, and disruption of any of those events may result in resistance. T cell-engaging therapies, such as T cell bispecific antibodies (TCBs) or chimeric antigen receptors (CARs), are raising extraordinary expectations as future treatments for virtually all cancers. Encouraging these expectations, TCBs and CARs have been recently approved to treat some hematologic malignancies. In contrast, TCBs and CARs against solid tumors tested to date, have failed to show clinical efficacy. This failure prompted intense research and the subsequent identification of mechanisms of primary and acquired resistance. Different strategies are being implemented to overcome these mechanisms of resistance. All these mechanisms impinge on the ability of T cells to reach cancer cells and/or on the inhibition of T cells. However, little is known about putative intrinsic mechanisms of resistance of cancer cells. That is, mechanisms deployed by tumor cells to resist killing by fully active and correctly engaged T cells. Using in vitro and in vivo acquired resistant models to TCBs and CARs directed against HER2, we demonstrate that disruption in interferon-gamma (IFN-g) signaling in cancer cells is a mechanism of intrinsic resistance to killing by fully active, correctly engaged, T lymphocytes. Importantly, we have identified that the kinase JAK2, which transduces the signal initiated by IFN-g, is the component preferably disrupted to acquired resistance across all models used. These results unveil a novel mechanism of resistance to T-cell based therapies, and imply the potential use of JAK2 and IFN-g response as a surrogate biomarker of response to immunotherapies. In addition, they open the avenue for the screening for therapies that can overcome deficient interferon-gamma response or restore JAK2 levels, which are promising potential candidates to increase the benefits of immunotherapies. Citation Format: Alex Martínez-Sabadell, Enrique J. Arenas, Irene Rius Ruiz, Macarena Román Alonso, Marta Escorihuela, Antonio Luque, Carlos Alberto Fajardo, Alena Gros, Christian Klein, Joaquin Arribas. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation [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 3970.