Identification of a Clinically Efficacious CAR T Cell Subset in Diffuse Large B Cell Lymphoma by Dynamic Multidimensional Single-Cell Profiling

Authors

Ali Rezvan
Gabrielle Romain
Mohsen Fathi
Darren Heeke
Melisa Martinez-Paniagua
Xingyue An
Irfan N Bandey
Melisa J Montalvo
Jay R T Adolacion
Arash Saeedi
Fatemeh Sadeghi
Kristen Fousek
Nahum Puebla-Osorio
Laurence J N Cooper
Chantale Bernatchez
Harjeet Singh
Nabil Ahmed
Mike Mattie
Adrian Bot
Sattva Neelapu
Navin Varadarajan

Publication Date

7-1-2024

Journal

Nature Cancer

DOI

10.1038/s43018-024-00768-3

PMID

38750245

PMCID

PMC12345446

PubMedCentral® Posted Date

8-13-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8+ T cells (CD8-fit T cells). CD8-fit T cells are capable of migration and serial killing and harbor balanced mitochondrial and lysosomal volumes. Using independent datasets, we validate that CD8-fit T cells (1) are present premanufacture and are associated with clinical responses in individuals treated with axicabtagene ciloleucel, (2) longitudinally persist in individuals after treatment with CAR T cells and (3) are tumor migrating cytolytic cells capable of intratumoral expansion in solid tumors. Our results demonstrate the power of multimodal integration of single-cell functional assessments for the discovery and application of CD8-fit T cells as a T cell subset with optimal fitness in cell therapy.

Keywords

Humans, Lymphoma, Large B-Cell, Diffuse, Single-Cell Analysis, Immunotherapy, Adoptive, CD8-Positive T-Lymphocytes, Receptors, Chimeric Antigen, T-Lymphocyte Subsets, Biological Products

Comments

This article has been corrected. See Nat Cancer. 2024 May 22.

Published Open-Access

yes

Recommended Citation

Rezvan, Ali; Romain, Gabrielle; Fathi, Mohsen; et al., "Identification of a Clinically Efficacious CAR T Cell Subset in Diffuse Large B Cell Lymphoma by Dynamic Multidimensional Single-Cell Profiling" (2024). Faculty, Staff and Student Publications. 4895.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4895