Abstract A020: Induction of non-canonical CAR T cell states in multiple myeloma patients with durable responses

Abstract Background: T cells engineered to express chimeric antigen receptor (CAR) targeting B-cell maturation antigen (BCMA) have exhibited unprecedented efficacy with >70% response rates in patients with relapsed/refractory multiple myeloma (RRMM). However, most patients ultimately relapse. There are two FDA-approved anti-BCMA CAR T products: ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), the former having significantly more durable responses. The mechanisms that determine the durability of response to CAR T therapy remain unknown. Methods: We longitudinally procured bone marrow and PBMC samples from 20 RRMM patients who received anti-BCMA CAR T therapy, including cilta-cel, ide-cel, and JCARH125. Flow cytometry and single-cell RNAseq were used to investigate the features of CAR T cells that are associated with durable therapeutic responses. Results: At 1-month post infusion, expansion of CAR T cells in bone marrow is positively correlated with progression free survival (PFS) in all MM patients (p=0.009). Cilta-cel CAR T cells are enriched in proliferative and early memory-like phenotypes, while durable responders to ide-cel and JCARH125 exhibited a significantly higher proportion of CAR T cells with CD8+ effector memory-like state. By 6 months, CAR T cells could still be detected by high-throughput flow cytometry in the cilta-cel-treated patients, but CAR T cells were not detectable in most of the patients receiving the other 2 products. Persisting cilta-cel CAR T cells predominantly possessed a non-canonical state with a distinct transcriptional program (Persister CAR T). These Persister CAR T cells expressed high levels of AP1 genes, NF-κB regulators, and effector cytokines, as well as low levels of exhaustion-related genes. Notably, Persister CAR T phenotype is significantly enriched in patients with longer PFS (>12 months). Conclusions: Our data demonstrate that distinct anti-BCMA CAR T cell treatments lead to very different cellular consequences in patients in vivo. Cilta-cel CAR T cell treatment leads to greater expansion and persistence compared to ide-cel and JCARH125. Cilta-cel CAR T cells are more likely to develop a unique Persister CAR T phenotype, which is associated with superior clinical outcomes. These results provide insights into features associated with enhanced durability of response to anti-BCMA CAR T treatment, which could inform future development of more efficacious therapeutic strategies against MM. Citation Format: Kai Wu, Karen Law, Guy Ledergor, Chang Liu, Serena Kwek, Marcel Arias Badia, Zenghua Fan, Vibha Gurunathan, Rachel Wolters, Averey Lea, Matthew Clark, Alexander Cheung, Jeffrey Wolf, Thomas Martin, Justin Eyquem, Lawrence Fong. Induction of non-canonical CAR T cell states in multiple myeloma patients with durable responses [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A020.