{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:42:38Z","timestamp":1792107758211,"version":"4.4.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"11","funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung and Blood Institute","doi-asserted-by":"crossref","award":["HL006070"],"award-info":[{"award-number":["HL006070"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Investigator-Initiated Studies Program of Merck Sharp & Dohme LLC"},{"name":"Merck Sharp & Dohme LLC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Immune checkpoint blockade has been shown to restore anti-tumor T-cell function and elicit durable responses in select solid and hematopoietic malignancies. However, single-agent anti-programmed death 1 (PD-1) antibodies proved less efficacious in patients with chronic lymphocytic leukemia (CLL). In patients with high-risk or relapsed\/refractory CLL, we conducted a phase 2 study testing the combination of lead-in ibrutinib and up to 2 cycles of fludarabine, followed by continuous therapy with ibrutinib and 17 cycles of pembrolizumab administered every 3\u2009weeks. A total of 15 patients were enrolled. In 10 patients evaluable for response, we observed 1 complete response and 9 partial responses. There was no discernible benefit of the combination beyond what is expected from ibrutinib monotherapy. However, 3\u2009weeks after the first dose of pembrolizumab, we detected CD8 T-cell proliferation in a subset of patients, whom we called \u201cimmune responders.\u201d In the responders, CD27-expressing CD8 T cells were relatively increased over immune nonresponders. Paired single-cell RNA and TCR sequencing revealed clonal expansion of activated GZMK+ CD8 effector memory and terminally differentiated effector cells. After 6\u2009months of pembrolizumab treatment, the proportion of activated and proliferating CD8 T cells returned to baseline levels. Similarly, most novel clonotypes identified after 1 cycle of pembrolizumab decreased in frequency on long-term treatment. In summary, pembrolizumab did not improve the clinical response over ibrutinib monotherapy but transiently activated distinct clonotypes of CD8 T cells in a subset of CLL patients.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf182","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T01:18:28Z","timestamp":1755047908000},"page":"2881-2893","source":"Crossref","is-referenced-by-count":3,"title":["Activation and exhaustion of CD8 T cells in patients with chronic lymphocytic leukemia treated with ibrutinib and pembrolizumab"],"prefix":"10.1093","volume":"214","author":[{"given":"Rui","family":"Mu","sequence":"first","affiliation":[{"name":"Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M","family":"Hornick","sequence":"additional","affiliation":[{"name":"Integrated 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