The target antigen determines the mechanism of acquired resistance to T cell-based therapies
Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius Ruiz, Macarena Román Alonso, Pablo Ovejero Romero, Marta Escorihuela, Irene Chicote, Hector G Palmer, Lara Nonell, Mercè Alemany-Chavarria, Christian Klein, Marina Bacac, Joaquín Arribas, Enrique J Arenas, Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius Ruiz, Macarena Román Alonso, Pablo Ovejero Romero, Marta Escorihuela, Irene Chicote, Hector G Palmer, Lara Nonell, Mercè Alemany-Chavarria, Christian Klein, Marina Bacac, Joaquín Arribas, Enrique J Arenas
Abstract
Despite the revolution of immunotherapy in cancer treatment, patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen can be decisive in the success of the clinical response. T cell bispecific antibodies (TCBs) are engineered molecules that include binding sites to the T cell receptor and to a tumor antigen. Using gastric CEA+/HER2+ MKN45 cells and TCBs directed against CEA or HER2, we show that the mechanism of resistance to a TCB is dependent on the tumor antigen. Acquired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels and exhibit a disruption of the interferon-gamma signaling. These results will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.
Trial registration: ClinicalTrials.gov NCT02650713 NCT02324257.
Keywords: 5-AZA; CEA; CP: Cancer; HER2; T cell bispecific antibody; antigen; immunotherapy; interferon-gamma patient-derived xenografts; resistance.
Conflict of interest statement
Declaration of interests M.B. declares employment, stock ownership, and patents with Roche. C.K. declares employment, stock ownership, and patents with Roche. J.A. has received research funds from Roche, Synthon, Menarini, and Molecular Partners, and consultancy honoraria from Menarini.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Source: PubMed