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

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 toprevent CCB-mediated irAEs are lacking. 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). 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. 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. B-cell depletion favorably modulates CCB-mediated immune activation and reduces irAE risk.