Progressive multifocal leukoencephalopathy (PML) is a rare but very serious brain disease. It is caused by the reactivation of the widespread JC virus when the immune system is severely weakened. There is currently no targeted antiviral therapy available, which is why new treatment approaches are urgently needed. In recent years, so-called immune checkpoint inhibitors have been increasingly used; these “unlock” the immune system and reactivate the body’s own immune cells. Researchers at the University Hospital Bonn, the University of Bonn, and Hannover Medical School (MHH) have investigated why not all people with PML benefit equally from this therapy. The results were recently published in the journal JAMA Neurology.
PML is a rare but very serious infectious disease of the brain. It is caused by the JC virus, also known as human polyomavirus-2. Many people carry this virus without experiencing any symptoms. It becomes dangerous when the immune system is severely weakened, for example due to HIV infection, certain types of cancer, or immunosuppressive therapies. In such cases, the virus can reactivate and migrate into the central nervous system, where it causes what is known as demyelinating inflammation. This means that the “insulating layer” of the nerves is lost, ultimately leading to neurological deficits such as paralysis, speech disorders, or visual disturbances. The symptoms of PML are diverse and often progress rapidly.
Immune checkpoint inhibitors release the immune system’s “brakes”
There is currently no specific antiviral treatment, and the overall mortality rate for this disease is very high. The prognosis depends largely on whether the body’s immune defenses can be successfully restored. “In recent years, so-called immune checkpoint inhibitors have been used increasingly. These are drugs that are primarily approved for various types of cancer and are intended to ‘release the brakes’ on the immune system and reactivate the body’s own immune cells. However, not all PML patients benefit equally from this therapy, and until now it was unclear why,” explains Dr. Nora Möhn from the Department of Neuroimmunology and Neuromuscular Diseases at the UKB, who also conducts research at the University of Bonn, describing her motivation.
Existing antiviral defense mechanisms determine treatment success
In an international study involving over 100 PML patients, Möhn, together with Dr. Lea Grote-Levi and Prof. Dr. Thomas Skripuletz from the MHH, was able to show that existing antiviral defense mechanisms are crucial before treatment begins. Patients in whom virus-specific T cells against the JC virus were detectable in the blood prior to treatment with immune checkpoint inhibitors responded significantly better to immunotherapy. They survived longer, had more favorable neurological outcomes, and were less likely to develop severe side effects. In contrast, for patients without such virus-specific immune cells, the benefit of the therapy was significantly lower, while side effects occurred more frequently.
“The results suggest that immune checkpoint inhibitors are not equally effective in all PML patients, but are particularly helpful when a certain ‘residual function’ of the immune system is still present. A blood test could help in the future to better assess who will benefit from this therapy and who may be better suited for other treatment strategies,” says Möhn. “The study thus represents an important step toward more personalized and safer treatment of this life-threatening viral disease.”
Publication:
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. doi:10.1001/jamaneurol.2025.5318
Contact:
University Hospital Bonn
Center of Neurology
PD Dr. Nora Möhn
Tel.: +49 (0)228 287-31431
nora.moehn@ukbonn.de
