Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy

Importance Progressive multifocal leukoencephalopathy (PML) is a life-threatening demyelinating disease caused by reactivation of the JC virus (JCV) in immunocompromised patients. While immune checkpoint inhibitors (ICIs) show therapeutic potential, responses vary and predictive biomarkers are lacking. Objective To determine whether pretreatment JCV- and/or BK virus–specific T cells in the blood are associated with treatment efficacy. Design, Setting, and Participants This retrospective cohort study included 111 patients with PML who were treated with ICIs stratified by peripheral virus-specific T cell presence (ELISpot/flow cytometry) between August 2021 and May 2024, with a median (IQR) follow-up of 7 (1-13) months. Of 112 patients with definite PML across 39 centers, 1 patient refused participation; 111 patients were included. Exposure Patients received pembrolizumab (n = 81), nivolumab (n = 28), or atezolizumab (n = 2) per availability and prescribing practices at participating centers. Main Outcome and Measures Clinical outcomes, diagnostic parameters, and immune-related adverse events were compared; association of virus-specific T-cell responses with survival was analyzed using the Kaplan-Meier method. Results The study cohort consisted of 111 patients (median IQR age, 61 50-70 years; 74 male 66.6%). Twenty-one patients had detectable virus-specific T cells prior to therapy, 22 were T cell–negative and 68 had an unknown T-cell status. T cell–positive patients showed significantly higher response rates and improved survival compared to both T cell–negative patients (18/21 86% vs 5/22 23%; P lt; .001; median survival time, none 95% CI, undefined vs 136.5 days 95% CI, 19 to ∞; P = .002) and those with unknown T-cell status (18/21 86% vs 29/68 43%; P = .001; median survival time, none vs 162 days 95% CI, 66 to ∞; P = .004). They achieved better functional outcomes (median IQR modified Rankin Scale score, 3 2-4 vs 4 3-6; P = .009) and lower JC viral load in cerebrospinal fluid (median IQR, 0 copies/mL 0-502.5 vs 2500 copies/mL 0-6900; P = .01) during follow-up compared to T cell–negative patients. Immune-related adverse events were most frequent in T cell–negative patients (10/20 50%), including the most severe events, and least frequent in T cell–positive patients (2/20 10%) ( P = .02). Conclusions and Relevance Preexisting functional virus-specific T cells were associated with better clinical response, longer survival, and lower toxicity in PML. These findings suggest the likely importance of preexisting antiviral immunity for successful ICI therapy.