The EF1α promoter of cilta-cel drives a highly effective GZMK⁺ transcriptional program.
5 affiliations
- 1Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 2Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
- 3Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
- 4Single Cell Analytics Innovation Lab, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 5Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
Abstract
Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are approved BCMA-directed chimeric antigen receptor (CAR) T cells approved for the treatment of multiple myeloma. Although the higher efficacy of cilta-cel compared to ide-cel may be related to its unique nanobody binding domain, the constructs also differ in their use of EF1α and MND promoters, respectively, to drive CAR expression. To elucidate the basis of cilta-cel's efficacy, we analyzed CAR T cells from 87 patients with multiple myeloma (50 cilta-cel, 37 ide-cel) using flow cytometry and single-cell multi-omics. Cilta-cel showed a 10- fold higher peak expansion and greater persistence, driven by an inflammatory GZMK⁺ T cell subset marked by EOMES expression and motif accessibility, but not exhaustion profile. In myeloma xenograft models, the EF1α promoter in cilta-cel, rather than binding domain, recapitulated increased tumor control, enhanced expansion, and GZMK transcriptional profile compared with the MND promoter (ide-cel). These findings suggest that the efficacy of cilta-cel is linked to an EF1α-driven GZMK⁺ transcriptional trajectory that supports both persistence and effector function.
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BibTeX
@article{herrera2026ef1α,
title = {{The EF1α promoter of cilta-cel drives a highly effective GZMK⁺ transcriptional program.}},
author = {Kevin Herrera and Sneha Mitra and Yuqing Sun and Kimberly Lucero and Kristin A Singh and Kevin Chen and Meril Takizawa and Gunjan L Shah and Sergio Giralt and Jae H Park and Saad Z Usmani and Ronan Chaligne and Elisa de Stanchina and Sham Mailankody and Christina S Leslie and Karlo Perica},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77847-9},
url = {https://europepmc.org/article/MED/42901918},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The EF1α promoter of cilta-cel drives a highly effective GZMK⁺ transcriptional program.
AU - Kevin Herrera
AU - Sneha Mitra
AU - Yuqing Sun
AU - Kimberly Lucero
AU - Kristin A Singh
AU - Kevin Chen
AU - Meril Takizawa
AU - Gunjan L Shah
AU - Sergio Giralt
AU - Jae H Park
AU - Saad Z Usmani
AU - Ronan Chaligne
AU - Elisa de Stanchina
AU - Sham Mailankody
AU - Christina S Leslie
AU - Karlo Perica
PY - 2026
DA - 2026/09/19
JO - Nature communications
DO - 10.1038/s41467-026-77847-9
UR - https://europepmc.org/article/MED/42901918
AB - Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are approved BCMA-directed chimeric antigen receptor (CAR) T cells approved for the treatment of multiple myeloma. Although the higher efficacy of cilta-cel compared to ide-cel may be related to its unique nanobody binding domain, the constructs also differ in their use of EF1α and MND promoters, respectively, to drive CAR expression. To elucidate the basis of cilta-cel's efficacy, we analyzed CAR T cells from 87 patients with multiple myeloma (50 cilta-cel, 37 ide-cel) using flow cytometry and single-cell multi-omics. Cilta-cel showed a 10- fold higher peak expansion and greater persistence, driven by an inflammatory GZMK⁺ T cell subset marked by EOMES expression and motif accessibility, but not exhaustion profile. In myeloma xenograft models, the EF1α promoter in cilta-cel, rather than binding domain, recapitulated increased tumor control, enhanced expansion, and GZMK transcriptional profile compared with the MND promoter (ide-cel). These findings suggest that the efficacy of cilta-cel is linked to an EF1α-driven GZMK⁺ transcriptional trajectory that supports both persistence and effector function.
SN - 2041-1723
ER -