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 greater than grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE–free survival compared with 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 pretherapy activated naive 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 CA238471, AR077926, CA289978, and CA290302.
Authors
Kavita M. Dhodapkar, Antonio Matera, Alyssa M. Duffy, Azmain Taz, Renee Julia Manalo, Melinda Yushak, Ragini Kudchadkar, David H. Lawson, Madhav V. Dhodapkar
Graphical abstract
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ISSN: 0021-9738 (print), 1558-8238 (online)