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A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis
Open accessAbstract
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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“CTLA-4 blockade (alone or in combination with anti-PD-1/PD-L1) produces toxicities in a dose-dependent fashion.22,23”
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Metadata
- Authors
- Johnson, D. B., McDonnell, W. J., Gonzalez-Ericsson, P. I., Al-Rohil, R. N., Mobley, B. C., Salem, J.-E., Wang, D. Y., Sanchez, V., Wang, Y., Chastain, C. A., Barker, K., Liang, Y., Warren, S., Beechem, J. M., Menzies, A. M., Tio, M., Long, G. V., Cohen, J. V., Guidon, A. C., O’Hare, M., Chandra, S., Chowdhary, A., Lebrun-Vignes, B., Goldinger, S. M., Rushing, E. J., Buchbinder, E. I., Mallal, S. A., Shi, C., Xu, Y., Moslehi, J. J., Sanders, M. E., Sosman, J. A., & Balko, J. M.
- Affiliations
- Vanderbilt University (US)
- Duke Medical Center (US)
- Vanderbilt University Medical Center (US)
- Inserm (FR)
- Nanostring Technologies (United States) (US)
- The University of Sydney (AU)
- Melanoma Institute Australia (AU)
- Massachusetts General Hospital (US)
- Northwestern University (US)
- University Hospital Zurich (CH)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Johnson, Douglas B.
- Balko, Justin M.
- ORCID
- 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.
- 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
- 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.
- Venue
- Nature Medicine
- Published
- 2019-07-22
- Volume
- 25
- Issue
- 8
- Pages
- 1243-1250
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6689251
- OpenAlex
- W2964133630
- Cited by
- 176
- References
- 46
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 19 · 2023: 24 · 2022: 32 · 2021: 34 · 2020: 39 · 2019: 1
- FWCI
- 11.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Heart, Lung, and Blood Institute (T32HL069765, R01HL141466, K12HL143956, R01HL155990)
- National Cancer Institute (K23CA204726, R00CA181491, R01CA227481, K12CA090625, P30CA068485, P30CA014236)
- National Institute of Allergy and Infectious Diseases (P30AI110527)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK108352, U24DK059637, R01DK112262)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Clinical Neurology › Autoimmune Neurological Disorders and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- anti-PD-1 therapy, immune-related adverse events, Epstein-Barr virus, memory CD4+ T cells, cytotoxic CD4+ T cells, PD-L1, metastatic melanoma, neuroinflammation, pharmacovigilance
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Encephalitis, Herpesvirus 4, Human, Female, Humans, Immunologic Memory, Lymphocyte Activation, Male, Middle Aged, CD4-Positive T-Lymphocytes, Young Adult, Programmed Cell Death 1 Receptor
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