Product-Intrinsic NF-κB-Driven Transcriptional Programs Connote Durability of CAR-T Response in Multiple Myeloma

Idecabtagene vicleucel (ide-cel) induces deep responses in relapsed/refractory multiple myeloma (RRMM), yet more than half of patients relapse within one year. The intrinsic features of CAR-T products that distinguish durable from non-durable responders are poorly defined, particularly at single-cell resolution, and defining drivers of durable response is critical to guide patient counseling and to inform strategies for optimizing CAR-T manufacturing and efficacy. To address this need, 40 ide-cel infusion products (184,398 cells) were profiled using single-cell RNA sequencing. These analyses revealed that a transcriptional program in CD4 CAR-T cells that led to durable responses is characterized by NF-κB signaling, pro-survival circuits, tonic/chemokine signaling, and elevated CAR transgene expression. These features were associated with prolonged progression-free and overall survival irrespective of baseline clinical characteristics. Further, analysis of paired apheresis and tumor microenvironment samples showed that elevated NF-κB activity is an intrinsic hallmark of T-cell fitness that is characterized by a central memory phenotype and the lack of checkpoint receptorligand expression, and that these features were manifest in marrow-derived and peripheral blood T cells prior to CAR-T manufacturing. Finally, validating functional relevance, pharmacologic inhibition of NF-κB abrogated CAR-T cytotoxicity and cytokine production in vitro. Our results support that NFKB in the ide-cel product marks a signaling axis impacting CAR-T function and NFKB activity represents a global marker of T cell fitness present prior to CAR-T manufacture.