JC virus is a common virus and in most cases non-immunosuppressed make an immune response to the virus and keep it in check. However if you are immunosuppressed there is a risk that the virus escapes control and PML develops. There has been some benefit if you take the brakes off immune control and block checkpoint control you can sometimes deal with the virus to limit the damage of PML.
Here they looked at people who were JC virus positive meaning they had a T cell immune response to the virus before getting a checkpoint inhibitor and those with the response before seemed to be able to do better. So it sort of says that people who have seen the virus do better. So maybe a solution would be to vaccinate people against JC virus. I am not aware that this available. Maybe it will be one day
Möhn N, Grote-Levi L, Bonifacius A, Tischer-Zimmermann S, Nay S, Jendretzky KF, Sassmann ML, Karacondi K, Zent M, Konen FF, Sühs KW, Meuth SG, Pawlitzki M, Warnke C, Ayzenberg I, Schneider R, Helmchen C, Brüggemann N, Klebe S, Hildner M, Grefkes C, Nitsch L, Hühnchen P, Böltz S, Alt L, Tumani H, Kleinschnitz C, Pul R, Grauer O, Clifford D, Gnanapavan S, Wicklein R, Perpoint T, Beudel M, Del Bello A, Rauer S, Wiendl H, Jelcic I, Gasnault J, Cimini E, Antinori A, Pinnetti C, Pourcher V, Weiss N, Lambert N, Maecker-Kolhoff B, Höglinger GU, Zahraeifard S, Cortese I, Eiz-Vesper B, Martin-Blondel G, Skripuletz T; Immunotherapy for PML Study Group. Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy. JAMA Neurol. 2026 Jan 20. doi: 10.1001/jamaneurol.2025.5318.
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.
Source: multiple-sclerosis-research.org