A case report of clonal EBV-like memory CD4 + T cell activation in fatal checkpoint inhibitor-induced encephalitis

Douglas B Johnson1,2, Wyatt J McDonnell3,4,5,6,7, Paula I Gonzalez-Ericsson8, Rami N Al-Rohil5,9, Bret C Mobley5, Joe-Elie Salem3,10, Daniel Y Wang3, Violeta Sanchez5, Yu Wang11, Cody A Chastain3, Kristi Barker12, Yan Liang12, Sarah Warren12, Joseph M Beechem12, Alexander M Menzies13,14,15,16, Martin Tio13, Georgina V Long13,14,15,16, Justine V Cohen17, Amanda C Guidon17, Méabh O'Hare17, Sunandana Chandra18, Akansha Chowdhary18, Bénédicte Lebrun-Vignes10, Simone M Goldinger19, Elisabeth J Rushing20, Elizabeth I Buchbinder21, Simon A Mallal3,4,5,6,22, Chanjuan Shi5, Yaomin Xu11, Javid J Moslehi3, Melinda E Sanders5, Jeffrey A Sosman23, Justin M Balko24,25,26,27

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. douglas.b.johnson@vumc.org.
  2. Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA. douglas.b.johnson@vumc.org.
  3. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  4. Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.
  5. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  6. Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN, USA.
  7. Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  8. Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
  9. Department of Pathology and Dermatology, Duke University Medical Center, Durham, NC, USA.
  10. Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.
  11. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
  12. NanoString Technologies, Seattle, WA, USA.
  13. Melanoma Institute Australia, Sydney, Australia.
  14. The University of Sydney, Sydney, New South Wales, Australia.
  15. Royal North Shore Hospital, Sydney, New South Wales, Australia.
  16. Mater Hospital, Sydney, New South Wales, Australia.
  17. Massachusetts General Hospital, Boston, MA, USA.
  18. Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
  19. Department of Dermatology, University Hospital, Zurich, Switzerland.
  20. Institute of Neuropathology, University Hospital, Zurich, Switzerland.
  21. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  22. Institute for Immunology and Infectious Diseases, Perth, Australia.
  23. Northwestern Feinberg School of Medicine, Chicago, IL, USA.
  24. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. justin.balko@vumc.org.
  25. Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA. justin.balko@vumc.org.
  26. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. justin.balko@vumc.org.
  27. Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA. justin.balko@vumc.org.

Abstract

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.

Presented By Justin Balko

Medicine, Immunology & MicrobiologyNicholas Liao2019-08