{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:28:59Z","timestamp":1787678939864,"version":"build-2784847793"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>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\u207bCD28\u207b and KLRG1\u207a CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-na\u00efve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-\u03b2-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.<\/jats:p>","DOI":"10.1182\/blood.2025032274","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:00:16Z","timestamp":1787590816000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia"],"prefix":"10.1182","author":[{"given":"Julia Han","family":"Noll","sequence":"first","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-4192","authenticated-orcid":false,"given":"Devin","family":"Dersh","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang Yuan","family":"Li","sequence":"additional","affiliation":[{"name":"National Institute of Aging, Baltimore, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1766-683X","authenticated-orcid":false,"given":"Humza","family":"Hemani","sequence":"additional","affiliation":[{"name":"National Institute of Aging, Baltimore, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Lavorando","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Bartoszek","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4470-104X","authenticated-orcid":false,"given":"Kevin R","family":"Amses","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1216-7890","authenticated-orcid":false,"given":"Ankita","family":"Jain","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8053-690X","authenticated-orcid":false,"given":"Janna","family":"Minehart","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Ho","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-6878","authenticated-orcid":false,"given":"Angel","family":"Ramirez-Fernandez","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-0194","authenticated-orcid":false,"given":"Luca","family":"Paruzzo","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max A","family":"Shestov","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9885-456X","authenticated-orcid":false,"given":"Elena","family":"Camerini","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0509-315X","authenticated-orcid":false,"given":"Fleur S","family":"Peters","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands, Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7733-9094","authenticated-orcid":false,"given":"Xiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Drexel University, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison W.","family":"Loren","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3403-9144","authenticated-orcid":false,"given":"Jennifer A.","family":"Woyach","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorg Josef","family":"Goronzy","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Rochester, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3190-1891","authenticated-orcid":false,"given":"Arnon P","family":"Kater","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4301-5811","authenticated-orcid":false,"given":"Marco","family":"Ruella","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8778-1000","authenticated-orcid":false,"given":"John C","family":"Byrd","sequence":"additional","affiliation":[{"name":"UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Daniel J.","family":"Powell","sequence":"additional","affiliation":[{"name":"University Of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saar I.","family":"Gill","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Porter","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3376-8978","authenticated-orcid":false,"given":"Stephen J.","family":"Schuster","sequence":"additional","affiliation":[{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic D","family":"Bushman","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2098-2251","authenticated-orcid":false,"given":"Donald L.","family":"Siegel","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6971-8465","authenticated-orcid":false,"given":"Bruce L.","family":"Levine","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-3557","authenticated-orcid":false,"given":"Carl H.","family":"June","sequence":"additional","affiliation":[{"name":"University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3688-9836","authenticated-orcid":false,"given":"Noelle V","family":"Frey","sequence":"additional","affiliation":[{"name":"Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-3843","authenticated-orcid":false,"given":"Adam D.","family":"Cohen","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-5748","authenticated-orcid":false,"given":"Alfred L","family":"Garfall","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-5612","authenticated-orcid":false,"given":"Meixiao","family":"Long","sequence":"additional","affiliation":[{"name":"osumc, columbus, Ohio, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7578-0393","authenticated-orcid":false,"given":"Marcela V.","family":"Maus","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8175-8953","authenticated-orcid":false,"given":"Nan-Ping","family":"Weng","sequence":"additional","affiliation":[{"name":"National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Diorio","sequence":"additional","affiliation":[{"name":"The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3066-7378","authenticated-orcid":false,"given":"Joseph A.","family":"Fraietta","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,8,24]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2025032274\/2541116\/blood.2025032274.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2025032274\/2541116\/blood.2025032274.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:15:38Z","timestamp":1787678138000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2025032274\/570470\/T-cell-immunosenescence-limits-CD19-CAR-T-cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2025032274","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]},"article-number":"blood.2025032274"}}