{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:23:37Z","timestamp":1790256217078,"version":"4.1.0"},"reference-count":41,"publisher":"American Society of Hematology","issue":"11","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,6,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chimeric antigen receptor (CAR)\u2013modified T-cell therapies targeting CD19 represent a new treatment option for patients with relapsed\/refractory (R\/R) B-cell malignancies. However, CAR T-cell therapy fails to elicit durable responses in a significant fraction of patients. Limited in\u00a0vivo proliferation and survival of infused CAR T cells are key causes of failure. In a phase 1\/2 clinical trial of CD19 CAR T cells for B-cell malignancies (#NCT01865617), low serum interleukin 15 (IL-15) concentration after CAR T-cell infusion was associated with inferior CAR T-cell kinetics. IL-15 supports T-cell proliferation and survival, and therefore, supplementation with IL-15 may enhance CAR T-cell therapy. However, the clinical use of native IL-15 is challenging because of its unfavorable pharmacokinetic (PK) and toxicity. NKTR-255 is a polymer-conjugated IL-15 that engages the entire IL-15 receptor complex (IL-15R\u03b1\/IL-2R\u03b2\u03b3) and exhibits reduced clearance, providing sustained pharmacodynamic (PD) responses. We investigated the PK and immune cell PDs in nonhuman primates treated with NKTR-255 and found that NKTR-255 enhanced the in\u00a0vivo proliferation of T\u00a0cells and natural killer cells. In\u00a0vitro, NKTR-255 induced dose-dependent proliferation and accumulation of human CD19 CAR T cells, especially at low target cell abundance. In\u00a0vivo studies in lymphoma-bearing immunodeficient mice demonstrated enhanced antitumor efficacy of human CD19 CAR T cells. In contrast to mice treated with CAR T cells alone, those that received CAR T cells and NKTR-255 had markedly higher CAR T-cell counts in the blood and marrow that were sustained after tumor clearance, without evidence of persistent proliferation or ongoing activation\/exhaustion as assessed by Ki-67 and inhibitory receptor\u00a0coexpression. These data support an ongoing phase 1 clinical trial of combined therapy with CD19 CAR T cells and NKTR-255 for R\/R B-cell malignancies.<\/jats:p>","DOI":"10.1182\/bloodadvances.2022008697","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T17:58:02Z","timestamp":1667584682000},"page":"2479-2493","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":25,"title":["A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR T-cell immunotherapy"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7980-3882","authenticated-orcid":false,"given":"Alexandre V.","family":"Hirayama","sequence":"first","affiliation":[{"name":"1Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"2Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"3Department of Medicine, University of Washington, 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