PML & Immunotherapy: Biomarker Predicts Treatment Success | JAMA Neurology Study

Progressive multifocal leukoencephalopathy (PML) is a rare but severe brain infection that gradually destroys brain tissue, often leading to death within weeks. The infection is triggered by the human polyomavirus 2, also known as the John Cunningham (JC) virus.

A Vulnerable Population

PML primarily affects individuals with weakened immune systems, particularly T-lymphocytes. One treatment approach involves immune checkpoint inhibitors (ICIs), a therapy originally developed for cancer treatment that essentially “re-activates” the immune system. However, ICI therapy isn’t always successful and can have significant side effects.

Predicting Treatment Response

Until recently, it was difficult to determine which patients would benefit from ICI therapy. A team of researchers at the Medizinische Hochschule Hannover (MHH), led by Professor Dr. Thomas Skripuletz, has identified biomarkers that can predict a patient’s response to this immunotherapy. Their findings were published in the journal JAMA Neurology.

Did You Know? Researchers analysed data from 111 PML patients across 39 clinics worldwide between 2021 and 2024.

Improved Outcomes with Biomarker Identification

The study evaluated 111 PML patients from 39 clinics globally who received ICI treatment between 2021 and 2024. Researchers tested a subset of patients for the presence of functional, virus-specific T-cells against the JC virus before treatment began. They then compared the two groups, looking at treatment response, viral load in cerebrospinal fluid, side effects, and survival rates.

“We observed that PML patients with detectable virus-specific T-cells before therapy began experienced significantly higher response rates, better functional outcomes, lower viral loads, and improved survival probabilities during and after ICI treatment,” stated Professor Skripuletz. “They also experienced fewer immune-mediated side effects.”

Alternative Treatment Options at MHH

The MHH offers another treatment option beyond ICI therapy. In 2021, Professor Skripuletz’s team pioneered a method using donated, precisely matched immune cells to halt the virus’s spread. These cells, called allogeneic DIAVIS-T-cells, are derived from healthy individuals who were often infected with the virus but didn’t develop symptoms. They contain T-cells that recognize and attack JC virus-infected cells.

“Before administering virus-specific T-lymphocytes from donors, we always analyse whether patients still have their own virus-directed T-cells in their blood,” explained Professor Skripuletz. Most patients aren’t eligible for checkpoint inhibitors due to the absence of these cells, and therefore benefit from donor T-cell treatment.

Expert Insight: Identifying biomarkers to predict ICI response is a significant step forward, as it allows clinicians to potentially tailor treatment strategies and avoid unnecessary exposure to side effects for patients unlikely to benefit.

Rapid Access to T-Cells

Analysis for virus-specific T-cells is conducted at the alloCELL laboratory at MHH in Hannover. “Thanks to our unique T-cell donor registry, alloCELL, we consistently find a suitable T-cell donor when patients lack their own immune defenses,” emphasized Prof. Dr. Britta Eiz-Vesper, an immunologist at the MHH Institute for Transfusion Medicine and Transplant Engineering and a study co-author.

The alloCELL registry collects data on both tissue characteristics of blood cells and the number of specific T-cells against various viruses. As a leading German manufacturer of virus-specific T-cells, the institute can quickly identify suitable donors and provide T-cell products within days of a request. “We ship these T-cells to centres throughout Germany and internationally,” said Dr. Eiz-Vesper.

The Future of PML Treatment

ICI therapy remains a significant treatment option globally. “Our data provides initial evidence, in a larger cohort, that a blood test for virus-specific T-cells could serve as a biomarker,” Professor Skripuletz noted. This test could identify PML patients who are most likely to respond well to and tolerate checkpoint inhibitors.

“The study underscores the importance of pre-existing antiviral immunity and confirms that JC virus-directed T-cells can guide clinical decisions in this rare but critical neuroinfectious disease.” The goal is to make this testing standard practise before initiating therapy.

Frequently Asked Questions

What is PML?

PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that progressively destroys brain tissue and often leads to death within weeks.

What are immune checkpoint inhibitors?

Immune checkpoint inhibitors (ICIs) are a type of therapy that “re-activates” the immune system, originally developed for cancer treatment, and used as a treatment option for PML.

What did the study at MHH find?

Researchers at MHH found that PML patients with detectable virus-specific T-cells before ICI therapy had better treatment outcomes, lower viral loads, and fewer side effects.

Given the potential for personalized treatment approaches, how might these findings influence the future of managing rare and complex neurological infections?