A depleção de células B melhora o índice terapêutico de bloqueio combinado em pacientes com melanoma avançado

Resumo original em inglês

O que aconteceu

BACKGROUNDCombined 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.METHODSPatients 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).RESULTSPatients 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.CONCLUSIONB cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk.TRIAL REGISTRATIONClinicalTrials.gov NCT03719131.FUNDINGNIH CA238471, AR077926, CA289978, and CA290302.

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