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

## TL;DR

This study finds that patients with progressive multifocal leukoencephalopathy who have virus-specific T cells before treatment respond better to immune checkpoint inhibitors and live longer.

## Contribution

The study identifies virus-specific T cells as a novel biomarker for predicting treatment outcomes in PML patients receiving immune checkpoint inhibitors.

## Key findings

- Patients with detectable virus-specific T cells had significantly higher response rates and longer survival compared to those without.
- T cell–positive patients had lower JC viral load and fewer severe immune-related adverse events.
- Preexisting antiviral immunity appears to correlate with better clinical outcomes in PML treated with ICIs.

## Abstract

Are pretreatment JC virus- and/or BK virus-specific T cells in the blood associated with the efficacy of immune checkpoint inhibitors (ICIs) in progressive multifocal leukoencephalopathy (PML)?

In this cohort study of 111 patients with PML treated with ICIs, those with detectable virus-specific T cells (n = 21) had significantly higher response rates and longer survival than both T cell–negative patients (n = 22) and those with unknown status (n = 68).

These findings suggest that functional virus-specific T cells, as markers of preexisting antiviral immunity, may be associated with better clinical outcomes and reduced toxicity in patients with PML who are treated with ICIs.

This cohort study evaluates the association between pretreatment JC virus– and BK virus–specific T cells and treatment efficacy in progressive multifocal leukoencephalopathy.

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.

To determine whether pretreatment JCV- and/or BK virus–specific T cells in the blood are associated with treatment efficacy.

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.

Patients received pembrolizumab (n = 81), nivolumab (n = 28), or atezolizumab (n = 2) per availability and prescribing practices at participating centers.

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.

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).

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.