Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy.
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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, Del Bello Arnaud, 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, Skripuletz Thomas, Immunotherapy for PML Study Group
Аннотация
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.