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Células T Específicas de Virus y Respuesta a Inhibidores de Puntos de Control en Leucopatía Multifocal Progresiva

Nora Möhn^1,2, Lea Grote-Levi¹, Agnes Bonifacius³

¹Department of Neurology, Hannover Medical School, Hannover, Germany.

|January 20, 2026

Insights

Las células T preexistentes específicas de virus en pacientes con leucoencefalopatía multifocal progresiva (LMP) se correlacionan con mejores resultados cuando se tratan con inhibidores de puntos de control inmunitarios (ICI). Esto sugiere que la inmunidad antiviral es crucial para la terapia ICI eficaz en la LMP.

Área de la Ciencia:

Inmunología
Neurología
Oncología

Sus antecedentes:

La leucoencefalopatía multifocal progresiva (LMP) es una enfermedad desmielinizante grave causada por la reactivación del virus JC (JCV) en personas inmunocomprometidas.
Los inhibidores de los puntos de control inmunitarios (ICI) ofrecen potencial terapéutico para la LMP, pero las respuestas al tratamiento son variables y se necesitan biomarcadores predictivos.

Objetivo del estudio:

Investigar la asociación entre las células T específicas del virus JC (JCV) y/o BK previas al tratamiento y la eficacia del tratamiento con ICI en pacientes con LMP.
Identificar biomarcadores potenciales para predecir la respuesta al tratamiento y los resultados en la LMP.

Principales métodos:

Un estudio de cohorte retrospectivo que involucró a 111 pacientes con LMP tratados con ICI (pembrolizumab, nivolumab o atezolizumab).
Los pacientes se estratificaron según la presencia de células T específicas de virus periféricas (detectadas mediante ELISpot/citometría de flujo) antes del tratamiento.
Se compararon los resultados clínicos, la carga viral y los eventos adversos relacionados con la inmunidad entre los grupos con estado de células T positivo, negativo y desconocido.

Principales resultados:

Los pacientes con células T específicas de virus detectables antes de la terapia con ICI demostraron tasas de respuesta significativamente más altas (86 % frente a 23 % para los negativos para T; P < 0,001).
Los pacientes positivos para T exhibieron una mejor supervivencia (P = 0,002) y mejores resultados funcionales (puntuación de la escala de Rankin modificada, P = 0,009) en comparación con los pacientes negativos para T.
Se observaron cargas virales de JC más bajas en el líquido cefalorraquídeo (P = 0,01) y menos eventos adversos relacionados con la inmunidad (P = 0,02) en pacientes positivos para T.

Conclusiones:

Las células T funcionales preexistentes específicas de virus se asocian con una respuesta clínica mejorada, una supervivencia prolongada y una toxicidad reducida en pacientes con LMP en tratamiento con ICI.
La presencia de inmunidad antiviral antes del tratamiento puede ser un factor crítico para la terapia ICI exitosa en la LMP.
Estos hallazgos resaltan el potencial del monitoreo de células T específicas de virus como biomarcador predictivo para el tratamiento con ICI en la LMP.

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Abstracto

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.

Palabras clave:

células T específicas de virus inhibidores de puntos de control inmunitarios leucoencefalopatía multifocal progresiva inmunidad antiviral biomarcadores respuesta al tratamiento

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