Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy
Year: 2026
Type: article
Study design: Observational Study
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.
Source: JAMA Neurology
Authors: Nora Möhn, Lea Grote-Levi, Agnes Bonifacius, Sabine Tischer-Zimmermann, Sandra Nay, Konstantin Fritz Jendretzky, Mieke Luise Sassmann, Kevin Karacondi, Melanie Zent, Franz Felix Konen, Kurt-Wolfram Sühs, Sven G. Meuth, Marc Pawlitzki, Clemens Warnke, Ilya Ayzenberg, Ruth Schneider, Christoph Helmchen, Norbert Brüggemann, Stephan Klebe, Marcel Hildner, Christian Grefkes, Louisa Nitsch, Petra Hühnchen, Sebastian Böltz, Laura Alt, Hayrettin Tumani, Christoph Kleinschnitz, Refik Pul, Oliver Grauer, David Clifford, Sharmilee Gnanapavan, Rebecca Wicklein, Thomas Perpoint, Martijn Beudel, Arnaud Del Bello, Sebastian Rauer, Heinz Wiendl, Ilijas Jelcic, Jacques Gasnault, Eleonora Cimini, Andrea Antinori, Carmela Pinnetti, Valérie Pourcher, Nicolas Weiss, Nicolas Lambert, Britta Maecker-Kolhoff, Günter U. Höglinger, Sara Zahraeifard, Irene Cortese, Britta Eiz-Vesper, Guillaume Martin-Blondel, Thomas Skripuletz, Immunotherapy for PML Study Group, Laurence De Menibus, Damien Roos-Weil, Juliette Rakotoarison Rakotoarison, Yann Leveneur, Niklas Grassl, Francois Lifermann, Fleur Cohen-Aubart, Douglas Ney, Ronak Kapadia, Yasemin Goreci, Yael Dinur-Schejter, Tzlil Shifman, Oded Shamriz, Joseph Berger, Olivier Lambotte, Asaff Harel, Benjamin Wyplosz, Bodo Grimbacher, Martijn Wijburg, Matthijs Brouwer, Xavier Engalenc, Marion Gaudin, Clemens Kupper, Achille Aouba, Victoria Manda, Xavier Brousse, Mailys Ducours, Pierre Duffau, Jean Christophe Ouallet, Hela Mrabet, Florence Gourdon, Marion Le Maréchal, Raphael Bernard-Valnet, Pierre Delobel, Rebecca Lajaunie, Nassim Kamar, Marine Joly, Emmanuel Treiner, Sebastien Lhomme, Fabrice Bonneville, Carole Ribaute, Jonathan Ciron, Damien Biotti, Xavier Boumaza, Baptiste Bonneau, Agnès Sommet, Béatrice Pignolet
Institutions: University of Bonn, University Hospital Bonn, Medizinische Hochschule Hannover, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Philipps University of Marburg, Universitätsklinikum Gießen und Marburg, St. Josef-Hospital, Ruhr University Bochum, University Hospital Schleswig-Holstein, University of Lübeck, Essen University Hospital, Goethe University Frankfurt, University Hospital Frankfurt, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, University Hospital Ulm, Stiftung Universitätsmedizin Essen, University Hospital Münster, Washington University in St. Louis, Queen Mary University of London, Barts Health NHS Trust, Technical University of Munich, Hospices Civils de Lyon, Amsterdam University Medical Centers, University of Amsterdam, Centre Hospitalier Universitaire de Toulouse, Hôpital Rangueil, University of Freiburg, University Medical Center Freiburg, University of Zurich, University Hospital Zurich, Bicêtre Hospital, Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Sorbonne Université, Pitié-Salpêtrière Hospital, Centre Hospitalier Universitaire de Liège, Centre hospitalier régional de la Citadelle, German Center for Neurodegenerative Diseases, LMU Klinikum, Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, National Institute of Neurological Disorders and Stroke, Centre National de la Recherche Scientifique, Inserm, Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Bristol-Myers Squibb, Alnylam Pharmaceuticals, Washington University in St. Louis, CSL Behring, Queen Mary University of London, Universitätsklinikum Essen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Universiteit van Amsterdam, Albert-Ludwigs-Universität Freiburg, Heinrich-Heine-Universität Düsseldorf, Université de Toulouse, Centre National de la Recherche Scientifique, Deutsches Zentrum für Neurodegenerative Erkrankungen, Medizinischen Hochschule Hannover, Technische Universität München, Humboldt-Universität zu Berlin, Universität Zürich, Centre Hospitalier Universitaire de Toulouse, Fonds Léon Fredericq, Freie Universität Berlin, Universitätsspital Zürich, Assistance publique-Hôpitaux de Paris, Gemeinsame Bundesausschuss, Sorbonne Université, Barts Health NHS Trust, Bundesinstitut für Risikobewertung, National Institute of Neurological Disorders and Stroke
Awards: G2930906758, G3104932707, G3124053119, Young Academy PRACTIS (PRogram of hAnnover medical school for Clinician scienTISts), Progressive multifokale Leukenzephalopathie: Biomarker für eine frühzeitige Diagnose, für die Risikovorhersage unter Immuntherapien sowie für ein Ansprechen auf eine zielgerichtete Therapie
OpenAlex ID: W7124904254