T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

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Publication Details

Journal
Blood
Published
2026-08-24
DOI
https://doi.org/10.1182/blood.2025032274
Primary Topic
CAR-T cell therapy research
Type
article
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article

T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia

Nan‐ping Weng, Don L. Siegel, Carl H. June, Kevin R. Amses et al.
Blood
CAR-T cell therapy research
article

T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia

Nan‐ping Weng, Don L. Siegel, Carl H. June, Kevin R. Amses, Julia Han Noll, Jiang Yuan Li, Jennifer A. Woyach, Adam D. Cohen, Xiao Huang, Marcela V. Maus, Bruce L. Levine, Janna Minehart, Elena Camerini, Alfred L. Garfall, Saar Gill, Luca Paruzzo, Ángel Ramírez-Fernández, Daniel J. Powell, Arnon P. Kater, Humza Hemani, John C. Byrd, Devin Dersh, Stephen J. Schuster, Meixiao Long, Marco Ruella, Noelle V. Frey, Fleur S. Peters, Maya Lavorando, Ankita Jain, Matthew Ho, Robert Bartoszek, Alison W. Loren, Caroline Diorio, David L. Porter, Max A Shestov, Jorg Josef Goronzy, Frederic D Bushman
article en

Abstract

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Blood
National Institutes of Health (US), Mayo Clinic (US), Children's Hospital of Philadelphia (US), Harvard University (US), Hospital of the University of Pennsylvania (US), Ohio Supercomputer Center (US), Massachusetts General Hospital (US), UPMC Hillman Cancer Center (US), National Institute on Aging (US), Amsterdam University Medical Centers (NL), The Ohio State University (US), Drexel University (US), University of Pennsylvania (US), University of Amsterdam (NL)
Openalex Percentile: Top 13%
CAR-T cell therapy research
DOISourceOpenAlex
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