A rare and often fatal brain infection, progressive multifocal leukoencephalopathy (PML), may soon be more effectively treated thanks to recent research identifying biomarkers that predict response to immunotherapy. This discovery offers hope for patients with weakened immune systems who are vulnerable to this devastating condition, and underscores the importance of personalized medicine in tackling complex neurological diseases.
PML is caused by the John Cunningham (JC) virus and progressively destroys brain tissue, often leading to death within weeks. The disease primarily affects individuals with compromised immune systems, particularly those with low levels of T-lymphocytes.
Researchers at the Medical University of Hannover (MHH) in Germany have identified specific biomarkers that can predict whether a patient will respond to immune checkpoint inhibitors (ICIs), a type of cancer therapy that essentially “unleashes” the immune system. The findings, published in a press release from the MHH and detailed in the journal JAMA Neurology, could help doctors tailor treatment plans and improve outcomes.
Improved Response Rates and Longer Survival
The study, conducted between 2021 and 2024, analyzed data from 111 PML patients across 39 clinics worldwide who were treated with ICIs. Researchers examined whether the presence of functional, virus-specific T-cells against the JC virus in the patients’ blood before treatment could predict their response to therapy. They then compared outcomes between groups, looking at factors like disease response, viral load in cerebrospinal fluid, treatment side effects, and survival rates.
“We observed that PML patients with detectable virus-specific T-cells before treatment began experienced significantly higher response rates, better functional outcomes, lower viral loads, and improved survival probabilities during and after ICI therapy,” said Professor Thomas Skripuletz, a senior physician at the Clinic for Neurology with Clinical Neurophysiology at MHH. “Simultaneously, they experienced fewer immune-mediated side effects.”
Targeted, Virus-Specific T-Cells
This discovery is particularly significant because ICI therapy is currently the only treatment option for most clinics worldwide treating PML. However, MHH offers an alternative approach. In 2021, Professor Skripuletz’s team pioneered a method to halt the virus’s spread using donated, precisely matched immune cells.
These allogeneic DIAVIS-T-cells, derived from the blood of healthy individuals who were often infected with the virus without developing symptoms, contain T-cells that recognize and attack JC virus-infected cells.
“Before administering virus-specific T-lymphocytes from donors via infusion, we always analyze whether patients still have their own, virus-directed T-cells detectable in their blood,” Professor Skripuletz explained. Most patients are not eligible for checkpoint inhibitors because these cells are absent—and benefit from treatment with donor T-cells.
Rapid Assistance Through T-Cells
Analysis for the presence of virus-specific T-cells is conducted at the alloCELL laboratory at MHH in Hannover. “Thanks to our unique T-cell donor registry, alloCELL at MHH, we always find a precisely matched T-cell donation when patients lack their own immune defenses,” emphasized Professor Britta Eiz-Vesper, an immunologist at the MHH Institute for Transfusion Medicine and Transplant Engineering and a co-author of the study.
The alloCELL registry collects not only the tissue characteristics of blood cells but also the number of specific T-cells against different viruses. As one of Germany’s leading manufacturers of virus-specific T-cells, the institute can quickly identify suitable donors and make T-cell products available for treatment within days of a request. “We ship the T-cells to centers throughout Germany and abroad,” said Professor Eiz-Vesper.
Blood Test Before ICI Therapy Recommended
Despite the importance of ICI therapy globally, the new research suggests a simple test could improve its effectiveness. “Our data provides initial evidence, in a larger cohort, that a blood test for virus-specific T-cells could be a suitable biomarker,” Professor Skripuletz stated. This test could identify PML patients who are most likely to benefit from and tolerate checkpoint inhibitors.
“The study underscores the central role of pre-existing antiviral immunity and confirms that JC virus-directed T-cells can serve as a guide for clinical decisions in this rare but highly relevant neuroinfectious disease.” The goal is to make this investigation a standard practice before initiating therapy.
Source: Medical University of Hannover
Original Publication: Nora Möhn et al.; Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy; JAMA Neurology, 2026, DOI: 10.1001/jamaneurol.2025.5318
