Abstract 869: Distinct expansion, phenotype, function, and toxicity of cilta-cel vs. ide-cel CAR T cells in the real world

Abstract Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are approved chimeric antigen receptor T cell (CAR T) therapies for multiple myeloma. Unfortunately, most patients receiving these treatments will experience toxicities and/or relapse highlighting the need for optimizing CAR T strategies. We performed the first in-depth, comparative and prospective biomonitoring of patients (N=39) receiving cilta-cel or ide-cel in the real-world setting. Cilta-cel response rates were higher, although not statistically significant, and atypical neurotoxicities/infections were more frequent in the cilta-cel group. Peak circulating CAR T counts were significantly higher in cilta-cel patients, driven by a pronounced CD4+ CAR T expansion, and correlated with depth of clinical response. The pronounced expansion of cilta-cel CAR T was associated with higher CAR expression and overexpression of CD27. The cilta-cel CAR T expansion was followed by a CAR-specific switch from proliferation-associated genes to genes/surface markers associated with effector/memory (EM) function. The comparably longer persistence of cilta-cell CAR T was associated with increased resistance to exhaustion and increased IL-7R expression; in vitro data showed persistent and antigen-independent activation and higher metabolic activity of cilta-cel vs. ide-cel CAR T. Among cilta-cel-treated patients experiencing atypical neurotoxicities, central nervous system (CNS)-infiltrating, effector-type cilta-cel CAR T presented a distinct inflammatory phenotypic/cytokine-expression profile. This first report of in-depth, comparative patient biomonitoring following real-world cilta-cel or ide-cel therapy highlights intrinsic biological differences between these BCMA-targeting CAR T products, potentially explaining differences in clinical activity and toxicity. Our findings may guide the optimization of cellular immunotherapy strategies in myeloma patients. Citation Format: Djordje Atanackovic, Tim Luetkens, Dina Schneider, Peirong Hu, Xu Wang, Amol C. Shetty, Luke Tallon, Imari Patel, Rohan Singh, Etse Gebru, Rediet Mulatu, Destiny Omili, Daniel Yamoah, Xiaoxuan Fan, Aerielle Matsangos, Patricia Lesho, Kenneth A. Dietze, Ariel A. Fromowitz, Kim Hankey, Saurabh Dahiya, Jean A. Yared, Nancy M. Hardy, Rima Koka, Michael E. Kallen, Ashraf Badros, Aaron P. Rapoport, Mehmet Kocoglu. Distinct expansion, phenotype, function, and toxicity of cilta-cel vs. ide-cel CAR T cells in the real world [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 869.