Product-Intrinsic NF-κB-Driven Transcriptional Programs Connote Durability of CAR-T Response in Multiple Myeloma
Abstract
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.
Article Details
Authors (30)
Jerald D Noble
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Barbara C Peixoto
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Meghan A Menges
Moffitt Cancer Center, Tampa, Florida, United States
Julieta Abraham-Miranda
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Constanza Savid-Frontera
Moffitt Cancer Center, Tampa, Florida, United States
William Sawyer
Vasu D Sorathia
1. Department of Clinical Science, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
Luis A. Cuadrado Delgado
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Salvatore A Corallo
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Julia Christine Llanos
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Emily C Merritt
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Gabriel De Avila
H Lee Moffitt Cancer Center, Tampa, Florida, United States
Omar Alexis Castaneda-Puglianini
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Hien D Liu
H.Lee Moffitt Cancer Center, Tampa, Florida, United States
Melissa Alsina
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Taiga Nishihori
Moffitt Cancer Center, Tampa, Florida, United States
Kenneth H Shain
Moffitt Cancer Center, Tampa, Florida, United States
Ariosto S Siqueira Silva
H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Rachid C Baz
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Brandon J Blue
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Ariel F Grajales-Cruz
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Doris K Hansen
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
John L Cleveland
Moffitt Cancer Center & Research Institute, Tampa, Florida, United States
Fabiana Perna
Moffitt Cancer Center, Tampa, Florida, United States
Conor C Lynch
H.Lee Moffitt Cancer Center, Tampa, Florida, United States
Jennifer M Binning
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Reginald M Atkins
Moffitt Cancer Center, Tampa, Florida, United States
Xiaofei Song
Molecular Synthesis Center, Key Laboratory of Marine Drugs of Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotherapeutics, School of Medicine and Pharmacy
Frederick L. Locke
Ciara L Freeman
H. Lee Moffitt Cancer Center, Tampa, Florida, United States