%0 Journal Article
%T A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis.
%A Johnson DB
%A McDonnell WJ
%A Gonzalez-Ericsson PI
%A Al-Rohil RN
%A Mobley BC
%A Salem JE
%A Wang DY
%A Sanchez V
%A Wang Y
%A Chastain CA
%A Barker K
%A Liang Y
%A Warren S
%A Beechem JM
%A Menzies AM
%A Tio M
%A Long GV
%A Cohen JV
%A Guidon AC
%A O'Hare M
%A Chandra S
%A Chowdhary A
%A Lebrun-Vignes B
%A Goldinger SM
%A Rushing EJ
%A Buchbinder EI
%A Mallal SA
%A Shi C
%A Xu Y
%A Moslehi JJ
%A Sanders ME
%A Sosman JA
%A Balko JM
%J Nat Med
%V 25
%N 8
%D 08 2019
%M 31332390
%F 87.241
%R 10.1038/s41591-019-0523-2
%X 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.