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

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.

SUBMITTER: Johnson DB

PROVIDER: S-EPMC6689251 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Johnson Douglas B DB McDonnell Wyatt J WJ Gonzalez-Ericsson Paula I PI Al-Rohil Rami N RN Mobley Bret C BC Salem Joe-Elie JE Wang Daniel Y DY Sanchez Violeta V Wang Yu Y Chastain Cody A CA Barker Kristi K Liang Yan Y Warren Sarah S Beechem Joseph M JM Menzies Alexander M AM Tio Martin M Long Georgina V GV Cohen Justine V JV Guidon Amanda C AC O'Hare Méabh M Chandra Sunandana S Chowdhary Akansha A Lebrun-Vignes Bénédicte B Goldinger Simone M SM Rushing Elisabeth J EJ Buchbinder Elizabeth I EI Mallal Simon A SA Shi Chanjuan C Xu Yaomin Y Moslehi Javid J JJ Sanders Melinda E ME Sosman Jeffrey A JA Balko Justin M JM

Nature medicine 20190722 8

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 ...[more]

PMID: 31332390

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Project description:BackgroundImmune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can trigger immune-related encephalitis. We report one of the largest case series of patients with immune-related encephalitis and review of the literature.MethodsRetrospective series of patients with immune-related encephalitis and literature review.ResultsFourteen patients with cancer treated with ICI (50% combination therapy) developed immune-related encephalitis. Diagnostic testing revealed cerebral spinal fluid (CSF) lymphocytic pleocytosis (85%) and elevated protein (69%), abnormal brain magnetic resonance imaging(MRI) (33%) or brain FDG-PET (25%), electroencephalogram (EEG) abnormalities (30%), and autoantibodies (31%). Encephalitis treatment included: corticosteroids (86%), intravenous immunoglobulin (IVIg) (36%), plasmapheresis (7%), and rituximab (29%). There were no deaths and 12 patients had significant recovery, although long-term complications were observed. All patients discontinued ICI. Longitudinal follow-up demonstrated anti-cancer response to ICI at 3 months (85%) and 6 months post-ICI initiation (77%). A literature review identified 132 patients with immune-related encephalitis. Most were treated with PD-1 inhibitors (18% combination). Common abnormalities included elevated CSF protein (84%) or pleocytosis (77%), abnormal brain MRI (65%), or autoantibodies (47%). Nearly all were treated with corticosteroids, many required additional therapy with IVIg (26%) or rituximab (12%). Most patients had clinical improvement (81%) but a minority (10%) had a clinical relapse after completing corticosteroid taper. ICIs were resumed in 7 patients (5%), with relapse in 3.Conclusions and relevanceImmune-related encephalitis is treatable and improves with corticosteroids in most cases but may require additional immunosuppression. Re-emergence of encephalitis is rare and does not typically result in adverse outcomes, and this should be considered in neurological immune-related adverse event management guidelines.

Project description:Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary leukemias. The advent of immune checkpoint blockade (ICB) has dramatically changed our understanding of cancer biology and has altered the standards of care for patients. However, the impact of ICB on hematopoietic myeloid clonal expansion remains to be determined. We studied if exposure to ICB therapy affects hematopoietic clonal architecture and if their evolution contributed to altered hematopoiesis. Blood samples from patients with melanoma and NSCLC (n = 142) demonstrated a high prevalence of CH. Serial samples (or post ICB exposure samples; n = 25) were evaluated in melanoma and NSCLC patients. Error-corrected sequencing of a targeted panel of genes recurrently mutated in CH was performed on peripheral blood genomic DNA. In serial sample analysis, we observed that mutations in DNMT3A and TET2 increased in size with longer ICB exposures in the melanoma cohort. We also noted that patients with larger size DNMT3A mutations with further post ICB clone size expansion had longer durations of ICB exposure. All serial samples in this cohort showed a statistically significant change in VAF from baseline. In the serial sample analysis of NSCLC patients, we observed similar epigenetic expansion, although not statistically significant. Our study generates a hypothesis for two important questions: (a) Can DNMT3A or TET2 CH serve as predictors of a response to ICB therapy and serve as a novel biomarker of response to ICB therapy? (b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes).

Project description:Predicting the outcome of immunotherapy is essential for efficient treatment. The recent clinical success of immunotherapy is increasingly changing the paradigm of cancer treatment. Accordingly, the development of immune-based agents is accelerating and the number of agents in the global immuno-oncology pipeline has grown 60-70% over the past year. However, despite remarkable clinical efficacy in some patients, only few achieve a lasting clinical response. Treatment failure can be attributed to poorly immunogenic tumors that do not attract tumor infiltrating lymphocytes (TILs). Therefore, we developed positron emission tomography (PET) radiotracers for non-invasive detection of CD4+ and CD8a+ TILs in syngeneic mouse tumor models for preclinical studies. Methods: Seven syngeneic mouse tumor models (B16F10, P815, CT26, MC38, Renca, 4T1, Sa1N) were quantified for CD4+ and CD8a+ TILs using flow cytometry and immunohistochemistry (IHC), as well as for tumor growth response to Sym021, a humanized PD-1 antibody cross-reactive with mouse PD-1. Radiotracers were generated from F(ab)'2 fragments of rat-anti-mouse CD4 and CD8a antibodies conjugated to the p-SCN-Bn-Desferrioxamine (SCN-Bn-DFO) chelator and radiolabeled with Zirconium-89 (89Zr-DFO-CD4/89Zr-DFO-CD8a). Tracers were optimized for in vivo PET/CT imaging in CT26 tumor-bearing mice and specificity was evaluated by depletion studies and isotype control imaging. 89Zr-DFO-CD4 and 89Zr-DFO-CD8a PET/CT imaging was conducted in the panel of syngeneic mouse models prior to immunotherapy with Sym021. Results: Syngeneic tumor models were characterized as "hot" or "cold" according to number of TILs determined by flow cytometry and IHC. 89Zr-DFO-CD4 and 89Zr-DFO-CD8a were successfully generated with a radiochemical purity >99% and immunoreactivity >85%. The optimal imaging time-point was 24 hours post-injection of ~1 MBq tracer with 30 µg non-labeled co-dose. Reduced tumor and spleen uptake of 89Zr-DFO-CD8a was observed in CD8a+ depleted mice and the uptake was comparable with that of isotype control (89Zr-DFO-IgG2b) confirming specificity. PET imaging in syngeneic tumor models revealed a varying maximum tumor-to-heart ratio of 89Zr-DFO-CD4 and 89Zr-DFO-CD8a across tumor types and in-between subjects that correlated with individual response to Sym021 at day 10 relative to start of therapy (p=0.0002 and p=0.0354, respectively). The maximum 89Zr-DFO-CD4 tumor-to-heart ratio could be used to stratify mice according to Sym021 therapy response and overall survival was improved in mice with a 89Zr-DFO-CD4 ratio >9 (p=0.0018). Conclusion: We developed 89Zr-DFO-CD4 and 89Zr-DFO-CD8a PET radiotracers for specific detection and whole-body assessment of CD4+ and CD8a+ status. These radiotracers can be used to phenotype preclinical syngeneic mouse tumor models and to predict response to an immune checkpoint inhibitor. We foresee development of such non-invasive in vivo biomarkers for prediction and evaluation of clinical efficacy of immunotherapeutic agents, such as Sym021.

Dataset Information

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

Publications

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

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Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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