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Clinical Research and Public HealthIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI205606

B-cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma

Kavita M. Dhodapkar,1 Antonio Matera,1 Alyssa M. Duffy,2 Azmain Taz,1 Renee Julia Manalo,2 Melinda Yushak,2 Ragini Kuchadkar,2 David H. Lawson,2 and Madhav V. Dhodapkar1

1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

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1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

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1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

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1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

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1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

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1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

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1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

Find articles by Kuchadkar, R. in: PubMed | Google Scholar

1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

Find articles by Lawson, D. in: PubMed | Google Scholar

1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, United States of America

2Winship Cancer Institute, Emory University, Atlanta, United States of America

Find articles by Dhodapkar, M. in: PubMed | Google Scholar

Published August 25, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI205606.
Copyright © 2026, Dhodapkar et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 25, 2026 - Version history
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Abstract

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 > 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 naïve 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

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  • Version 1 (August 25, 2026): In-Press Preview
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