Highlights
- Preexisting virus-specific T cells (VSTs) in peripheral blood are a significant predictor of therapeutic success for immune checkpoint inhibitors (ICIs) in progressive multifocal leukoencephalopathy (PML).
- Patients with detectable pretreatment JCV/BKV-specific T cells exhibit an 86% response rate and significantly improved median survival compared to T cell-negative patients.
- The presence of functional antiviral immunity correlates with lower JC viral loads in the cerebrospinal fluid (CSF) and better functional recovery as measured by the modified Rankin Scale (mRS).
- Paradoxically, T cell-negative patients experience a higher frequency and severity of immune-related adverse events (irAEs) following ICI therapy.
Background
Progressive multifocal leukoencephalopathy (PML) is a devastating, often fatal demyelinating disease of the central nervous system. It is caused by the reactivation of the polyomavirus JC (JCV), typically in the setting of profound cellular immune deficiency—such as that seen in HIV/AIDS, hematologic malignancies, or secondary to modern immunomodulatory therapies for multiple sclerosis and autoimmune disorders.
Despite the clear link between immune failure and JCV reactivation, no targeted antiviral therapies have proven effective in clinical trials. The cornerstone of management remains the restoration of host immunity (e.g., antiretroviral therapy for HIV or drug cessation/plasma exchange for natalizumab-associated PML). However, for many patients, immune reconstitution is either impossible or insufficient. Recently, the observation that PD-1 expression is upregulated on JCV-specific T cells in PML patients suggested that immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, might reinvigorate exhausted T cells and promote viral clearance. Early case reports and small cohorts showed promise, but clinical responses have been heterogeneous, highlighting an urgent need for predictive biomarkers to guide patient selection.
Key Content
The Rationale for Checkpoint Inhibition in PML
The pathophysiological basis for using ICIs in PML rests on the ‘exhaustion’ phenotype of antiviral T cells. During chronic or uncontrolled viral replication, T cells express inhibitory receptors like Programmed Cell Death Protein 1 (PD-1). In patients with PML, PD-1 is often overexpressed on CD4+ and CD8+ T cells in both the blood and the CSF. By blocking the PD-1/PD-L1 axis, ICIs are hypothesized to ‘unleash’ the existing pool of JCV-specific T cells, allowing them to proliferate and traffic to the CNS to eliminate virus-infected oligodendrocytes.
Evidence from Multi-Center Cohort Analysis
The recent large-scale retrospective cohort study by Möhn et al. (2026) provides definitive evidence regarding the clinical utility of pretreatment virus-specific T cells (VSTs). In a cohort of 111 patients across 39 centers, the presence of VSTs (detected via ELISpot or flow cytometry) was the single most powerful predictor of ICI efficacy.
- Clinical Response and Survival: Patients who were T cell-positive prior to ICI therapy achieved an 86% response rate. More importantly, their median survival time was not reached during the follow-up period, whereas T cell-negative patients faced a median survival of only 136.5 days (P = .002).
- Viral Dynamics: Therapeutic success correlated strongly with biological markers. T cell-positive patients showed significantly lower JC viral loads in the CSF during follow-up, often reaching undetectable levels (median 0 copies/mL vs. 2500 copies/mL in T-negative patients).
- Functional Outcomes: Beyond survival, the quality of life was preserved in the T cell-positive group, as evidenced by significantly lower (better) scores on the modified Rankin Scale (median mRS 3 vs. 4; P = .009).
The Paradox of Safety and Toxicity
One of the most striking findings of recent research is the distribution of immune-related adverse events (irAEs). Conventionally, one might expect that a more ‘reactive’ immune system (T cell-positive) would be more prone to off-target inflammation. However, the data indicates the opposite: irAEs were most frequent and severe in T cell-negative patients (50% vs. 10%). This suggests that in the absence of a specific antiviral target, ICIs may trigger dysregulated, non-specific immune activation, which is both clinically futile and toxic.
Methodological Evolution in T-Cell Assessment
The shift toward using standardized assays like ELISpot for JCV and BKV (BK virus, which shares significant homology with JCV) has allowed for more precise stratification. Because JCV-specific T cells can be rare in peripheral blood, using BKV-derived peptide pools can increase the sensitivity of detection due to cross-reactivity, providing a broader window into the patient’s latent cellular potential for virus control.
Expert Commentary
Translational Implications
The discovery that preexisting VSTs are required for ICI efficacy shifts the paradigm from ‘priming’ to ‘invigorating.’ It appears that ICIs do not create a de novo immune response against JCV in those who lack it; rather, they serve as a catalyst for an existing, albeit suppressed, T-cell population. For clinicians, this means that a negative VST screen might identify a subpopulation of patients for whom ICI therapy is not only likely to fail but also carries a higher risk of severe neurological or systemic irAEs.
The Role of IRIS
Immune Reconstitution Inflammatory Syndrome (IRIS) remains a double-edged sword in PML. While the study by Möhn et al. showed that T cell-positive patients had fewer ‘traditional’ irAEs, the risk of CNS-IRIS—a potentially fatal inflammatory response to JCV in the brain—must always be monitored. Interestingly, VST-positive patients seem to achieve a more ‘controlled’ immune restoration that favors viral clearance over catastrophic bystander damage.
Limitations and Controversies
As the data is largely retrospective, prospective randomized controlled trials are still needed to establish VST testing as a gold-standard requirement. Furthermore, the ‘unknown’ status of a large portion of the cohort (68/111) suggests that in real-world clinical practice, the timing and availability of specialized immunology lab work remain a significant barrier to implementation.
Conclusion
The use of immune checkpoint inhibitors represents a significant advance in the management of PML, a condition previously regarded as largely untreatable. However, the efficacy of this approach is strictly dependent on the host’s underlying immune architecture. Pretreatment virus-specific T-cell status is a critical biomarker that predicts high response rates, prolonged survival, and a lower risk of toxicity.
Future research should focus on whether ‘priming’ T cell-negative patients—perhaps through vaccination or adoptive T-cell transfer—can convert them into responders before initiating checkpoint blockade. For now, incorporating VST testing into the diagnostic workup of PML is a clinical imperative to optimize the benefit-risk ratio of immunotherapy.
References
- Möhn N, Grote-Levi L, Bonifacius A, et al. Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy. JAMA Neurol. 2026;83(3):280-289. PMID: 41557340.
- Cortese I, Muranski P, Enose-Akahata Y, et al. Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2019;380(17):1597-1605. PMID: 30964783.
- Martin-Blondel G, et al. Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: a new hope? Lancet Infect Dis. 2019;19(9):924-926.
