Decade-long persistence of CD19 CAR T cells in B cell lymphomas.

Authors

Luca Paruzzo, Emeline R Chong, Elise A Chong, Zhixuan Zheng, Puneeth Guruprasad, Daniel J Landsburg, Sunita D Nasta, Federico Stella, Ranjani Ramasubramanian, Vitor B de Souza, Mohannad H Alkhatib, Matthew Ho, Antonio Imparato, Gregory M Chen, Don L Siegel, Gabriela Plesa, Anlan Dai, Shane Mackey, Priyamvada Das, Peter Michener, Julie Jadlowsky, Frederic D Bushman, Vrutti Patel, Alberto Carturan, Ellen B Napier, Vanessa E Gonzalez, Danuta Jarocha, Rong Xu, Bruce L Levine, Patrizia Porazzi, Noelle Frey, David L Porter, Jakub Svoboda, Joseph A Fraietta, Carl H June, Stephen J Schuster, Marco Ruella

Published in

Nature medicine. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Chimeric antigen receptor (CAR) T cell therapy induces durable remissions in lymphoid malignancies, yet the extent and biology of long-term CAR T cell persistence in B cell lymphoma remain unclear. Here we report the persistence and characteristics of 4-1BB-costimulated anti-CD19 CAR T cells (CART19) up to 10 years after infusion in 38 patients with non-Hodgkin lymphoma. Beyond year five, the CAR19 transgene was detectable in five of eight long-term responders (7.0-10.1 years), with three patients maintaining B cell aplasia, which is consistent with sustained functional activity. In one patient with a progression-free survival of 10.1 years, CART19 cells comprised 1.2% of circulating T cells 9.3 years after infusion. Long-term persisting CART19 cells exhibited a predominant double-negative (CD4^-CD8^-), effector-memory-like phenotype associated with increased aerobic metabolism and T cell activation programs. Longitudinal profiling revealed a progressive transition from CD8⁺ to double-negative CAR T cells over time. Persisting CART19 shared transcriptional features with long-term CAR T cells described in acute and chronic leukemias. T cell receptor sequencing demonstrated oligoclonal persistence at 9.3 years, with a dominant clone (70% of CART19 cells) already detectable at low frequency (<0.1%) at day 14. Lentiviral integration-site analysis identified a predominant integration within PACS1 without evidence of known drivers of CAR T cell expansion. These findings demonstrate that CART19 cells can persist for more than 10 years in lymphoma and identify phenotypic, transcriptional and clonal features associated with exceptionally long-term persistence. ClinicalTrials.gov registration: NCT02030834.

PMID:
42575986
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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