Journal article
T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia
Blood
24 Aug 2026
PMID: 42636161
Abstract
•Senescence-associated features, distinct from exhaustion alone, identify CLL CAR T-cell products with poor expansion and inferior clinical outcome.•Ibrutinib attenuates senescence-associated features and improves CAR T-cell functional reserve.
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.
Metrics
1 Record Views
Details
- Title
- T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia
- Creators
- Julia Han Noll - University of PennsylvaniaDevin Dersh - University of PennsylvaniaJiang Yuan Li - National Institute on AgingHumza Hemani - National Institute on AgingMaya Lavorando - University of PennsylvaniaRobert Bartoszek - University of PennsylvaniaKevin R. Amses - University of PennsylvaniaAnkita Jain - University of PennsylvaniaJanna Minehart - University of PennsylvaniaMatthew Ho - University of PennsylvaniaÁngel Ramírez-Fernández - University of PennsylvaniaLuca Paruzzo - University of PennsylvaniaMaksim Shestov - University of PennsylvaniaElena Camerini - Amsterdam University Medical CentersFleur S. Peters - Amsterdam University Medical CentersXiao Huang - Drexel UniversityAlison W. Loren - University of PennsylvaniaJennifer A. Woyach - The Ohio State UniversityJörg J. Goronzy - Mayo ClinicArnon P. Kater - Amsterdam University Medical CentersMarco Ruella - University of PennsylvaniaJohn C. Byrd - UPMC Hillman Cancer CenterDaniel J. Powell - University of PennsylvaniaSaar I. Gill - University of PennsylvaniaDavid L. Porter - University of PennsylvaniaStephen J. Schuster - UPMC Hillman Cancer CenterFrederic D. Bushman - University of PennsylvaniaDonald L. Siegel - University of PennsylvaniaBruce L. Levine - University of PennsylvaniaCarl H. June - University of PennsylvaniaNoelle V. Frey - Hospital of the University of PennsylvaniaAdam D. Cohen - University of PennsylvaniaAlfred L. Garfall - University of PennsylvaniaMeixiao Long - Ohio Supercomputer CenterMarcela V. Maus - Harvard UniversityNan-Ping Weng - National Institute on AgingCaroline J. Diorio - Children's Hospital of PhiladelphiaJoseph A. Fraietta - University of Pennsylvania
- Publication Details
- Blood
- Publisher
- American Society of Hematology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; School of Biomedical Engineering and Science
- Other Identifier
- 991022203452304721