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

Möhn N, Grote-Levi L, Bonifacius A, Tischer-Zimmermann S, Nay S, Jendretzky KF, Sassmann ML, Karacondi K, Zent M, Konen FF, Sühs KW, Meuth SG, Pawlitzki M, Warnke C, Ayzenberg I, Schneider R, Helmchen C, Brüggemann N, Klebe S, Hildner M, Grefkes C, Nitsch L, Hühnchen P, Böltz S, Alt L, Tumani H, Kleinschnitz C, Pul R, Grauer O, Clifford D, Gnanapavan S, Wicklein R, Perpoint T, Beudel M, Del Bello A, Rauer S, Wiendl H, Jelcic I, Gasnault J, Cimini E, Antinori A, Pinnetti C, Pourcher V, Weiss N, Lambert N, Maecker-Kolhoff B, Höglinger GU, Zahraeifard S, Cortese I, Eiz-Vesper B, Martin-Blondel G, Skripuletz T (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 83

Journal Issue: 3

DOI: 10.1001/jamaneurol.2025.5318

Abstract

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 <.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.

Authors with CRIS profile

Involved external institutions

National Institute of Neurological Disorders and Stroke (NIH) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Philipps-Universität Marburg Germany (DE) Katholisches Klinikum Bochum (St. Josef- und St. Elisabeth-Hospital gGmbH) Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Universitätsklinikum Essen Germany (DE) Goethe-Universität Frankfurt am Main Germany (DE) Universitätsklinikum Münster Germany (DE) Bicêtre Hospital France (FR) Universitätsklinikum Düsseldorf Germany (DE) Universitätsklinikum Bonn Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Ulm Germany (DE) Washington University in St. Louis United States (USA) (US) Queen Mary University of London United Kingdom (GB) Technische Universität München (TUM) Germany (DE) Hospices Civils de Lyon (CHU) France (FR) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Hôpital Rangueil France (FR) Universitätsklinikum Freiburg Germany (DE) Universitätsspital Zürich (USZ) Switzerland (CH) IRCCS Lazzaro Spallanzani Italy (IT) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Centre hospitalier régional de la Citadelle (CHR de la Citadelle) Belgium (BE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Centre Hospitalier Universitaire (CHU) de Toulouse France (FR)

How to cite

APA:

Möhn, N., Grote-Levi, L., Bonifacius, A., Tischer-Zimmermann, S., Nay, S., Jendretzky, K.F.,... Skripuletz, T. (2026). Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy. JAMA Neurology, 83(3). https://doi.org/10.1001/jamaneurol.2025.5318

MLA:

Möhn, Nora, et al. "Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy." JAMA Neurology 83.3 (2026).

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