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Johnson, Douglas B; McDonnell, Wyatt J; Gonzalez-Ericsson, Paula I; Al-Rohil, Rami N; Mobley, Bret C; Salem, Joe-Elie; Wang, Daniel Y; Sanchez, Violeta; Wang, Yu; Chastain, Cody A; Barker, Kristi; Liang, Yan; Warren, Sarah; Beechem, Joseph M; Menzies, Alexander M; Tio, Martin; Long, Georgina V; Cohen, Justine V; Guidon, Amanda C; O'Hare, Méabh; Chandra, Sunandana; Chowdhary, Akansha; Lebrun-Vignes, Bénédicte; Goldinger, Simone M; Rushing, Elisabeth J; Buchbinder, Elizabeth I; Mallal, Simon A; Shi, Chanjuan; Xu, Yaomin; Moslehi, Javid J; Sanders, Melinda E; Sosman, Jeffrey A; Balko, Justin M
Nature Medicine, 08/2019, Volume: 25, Issue: 8Journal Article, Magazine Article
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO GZMB Ki67 ) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
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