Nora Möhn, Lea Martha 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, C Kleinschnitz, Refik Pul, Oliver M Grauer, David Clifford, Sharmilee Gnanapavan, Rebecca Wicklein, Thomas Perpoint, Martijn Beudel, Arnaud Del Bello, Sebastian Rauer, Heinz Wiendl, Ilijas jelČiĆ, 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, T. Skripuletz, Immunotherapy for PML Study Group, Laurence Hellouin de Menibus, Damien Roos-Weil, Juliette Rakotoarison Rakotoarison, Y. Leveneur, Niklas Grassl, François Lifermann, Fleur Cohen-Aubart, Douglas Ney, Ronak K. Kapadia, Yasemin Göreci, Yael Dinur-Schejter, Tzlil Shifman, Oded Shamriz, Joseph Berger, Olivier Lambotte, Asaff Harel, Benjamin Wyplosz, Bodo Grimbacher, Martijn T. Wijburg, Matthijs Brouwer, Xavier Engalenc, Marion Gaudin, Clemens Küpper, Achille Eric Aouba, Victoria Manda, Xavier Brousse, Mailys Ducours, P. Duffau, Jean Christophe Ouallet, Hela Mrabet, F. Gourdon, Marion Le Maréchal, Raphaël Bernard‐Valnet, Pierre Delobel, R. 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
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.