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

Möhn, Nora ; Grote-Levi, Lea; Bonifacius, Agnes; Tischer-Zimmermann, Sabine; Nay, Sandra ; Jendretzky, Konstantin Fritz; Sassmann, Mieke Luise; Karacondi, Kevin; Zent, Melanie; Konen, Franz Felix; Sühs, Kurt-Wolfram; Meuth, Sven G. ; Pawlitzki, Marc ; Warnke, Clemens; Ayzenberg, Ilya; Schneider, Ruth; Helmchen, Christoph; Brüggemann, Norbert ; Klebe, Stephan; Hildner, Marcel; Grefkes, Christian; Nitsch, Louisa; Hühnchen, Petra; Böltz, Sebastian; Alt, Laura; Tumani, Hayrettin ; Kleinschnitz, Christoph ; Pul, Refik; Grauer, Oliver; Clifford, David; Gnanapavan, Sharmilee; Wicklein, Rebecca ; Perpoint, Thomas; Beudel, Martijn; Bello, Arnaud Del; Rauer, Sebastian; Wiendl, Heinz ; Jelcic, Ilijas; Gasnault, Jacques; Cimini, Eleonora; Antinori, Andrea; Pinnetti, Carmela; Pourcher, Valérie; Weiss, Nicolas; Lambert, Nicolas; Maecker-Kolhoff, Britta; Höglinger, Günter U. ; Zahraeifard, Sara; Cortese, Irene; Eiz-Vesper, Britta; Martin-Blondel, Guillaume und Skripuletz, Thomas (2026): Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy. In: JAMA Neurology [Forthcoming]

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2168-6149
• Bemerkung: with the Immunotherapy for PML Study
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 501362249