{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:07:06Z","timestamp":1790644026153,"version":"4.1.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["CA238471"],"award-info":[{"award-number":["CA238471"]}]},{"name":"NIH","award":["AR077926"],"award-info":[{"award-number":["AR077926"]}]},{"name":"NIH","award":["CA289978"],"award-info":[{"award-number":["CA289978"]}]},{"name":"NIH","award":["CA290302"],"award-info":[{"award-number":["CA290302"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Background: Combined checkpoint blockade (CCB) of programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4) is highly active in melanoma but limited by significant morbidity from immune-related adverse events (irAEs). Effective strategies to prevent CCB-mediated irAEs are lacking. Methods: Patients with advanced melanoma were randomly assigned to receive standard of care ipilimumab and nivolumab alone (Arm-A: ipi\/nivo, n=7) or with one cycle of rituximab (Arm-B; ipi\/nivo+rituximab, n=7). Results: Patients receiving ipi\/nivo+rituximab experienced lower rates of &gt; grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE-free survival compared to those in ipi\/nivo arm (2-year G3-irAE-free survival 86% versus 29% (p=0.01), without adverse impact on tumor regression or survival. G3 hypersensitivity reactions to rituximab (43% in Arm-B) prompted trial closure. Rituximab depleted pre-therapy activated na\u00efve B cells linked to autoimmunity and enhanced CCB-mediated induction of myeloid inflammation and CXCL13+ICOS+ CD4 T cells. Conclusion: B-cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk. Trial Registration: ClinicalTrials.gov NCT03719131 Funding: NIH<\/jats:p>","DOI":"10.1172\/jci205606","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:00:43Z","timestamp":1787673643000},"source":"Crossref","is-referenced-by-count":1,"title":["B-cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma"],"prefix":"10.1172","author":[{"given":"Kavita M.","family":"Dhodapkar","sequence":"first","affiliation":[{"name":"Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Matera","sequence":"additional","affiliation":[{"name":"Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2848-8661","authenticated-orcid":true,"given":"Alyssa M.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University, Atlanta, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azmain","family":"Taz","sequence":"additional","affiliation":[{"name":"Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee Julia","family":"Manalo","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University, Atlanta, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Yushak","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University, Atlanta, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragini","family":"Kuchadkar","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University, Atlanta, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Lawson","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University, Atlanta, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhav V.","family":"Dhodapkar","sequence":"additional","affiliation":[{"name":"Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,8,25]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/205606\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:00:45Z","timestamp":1787673645000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/205606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":0,"alternative-id":["10.1172\/JCI205606"],"URL":"https:\/\/doi.org\/10.1172\/jci205606","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}