T Cells Predict Immunotherapy Success in Brain Infection PML

New Biomarker Offers Hope for Improved Immunotherapy in Deadly Brain Infection

A rare and often fatal brain infection, progressive multifocal leukoencephalopathy (PML), may become more treatable thanks to a newly identified biomarker that predicts response to immunotherapy. Researchers at Hannover Medical School (MHH) in Germany have discovered that the presence of virus-specific T cells before treatment significantly correlates with positive outcomes in patients receiving immune checkpoint inhibitors (ICIs).

PML is caused by the John Cunningham (JC) virus and primarily affects individuals with weakened immune systems. The infection progressively destroys brain tissue, often leading to death within weeks. While ICIs, a type of therapy originally developed for cancer, can “switch the immune system back on” to fight the virus, their effectiveness has been unpredictable – until now.

The study, published in JAMA Neurology, evaluated data from 111 PML patients treated with ICIs at 39 clinical departments worldwide between 2021 and 2024. Researchers found that patients with detectable functional, virus-specific T cells prior to starting ICI therapy experienced significantly higher response rates, better functional progression, lower viral loads during the course of treatment and a better probability of survival during and after ICI treatment, according to Professor Dr. Thomas Skripuletz, senior physician at the Clinical Department of Neurology with Clinical Neurophysiology at MHH.

Importantly, these patients also experienced fewer immune-related side effects. This finding is crucial because ICIs, while potentially life-saving, can sometimes trigger harmful immune responses in other parts of the body.

Alternative Therapy Utilizing Donor T Cells

While ICIs represent one treatment pathway, MHH has also pioneered an innovative approach using donor T cells. This therapy, developed by Professor Dr. Britta Eiz-Vesper and Professor Dr. Skripuletz’s team, involves infusing patients with T cells from healthy donors who have been exposed to the JC virus but haven’t developed PML. These donor T cells are specifically equipped to recognize and destroy JC virus-infected cells.

The success of this donor T cell therapy hinges on the patient’s existing immune status. Before we administer virus-specific T lymphocytes from donors via infusion, we always analyze whether the patient’s own T cells that are directed against the virus can still be detected in the blood of the sick person, explains Professor Skripuletz. Patients lacking their own virus-specific T cells are generally better candidates for the donor T cell therapy.

The MHH’s alloCELL donor registry plays a vital role in this process. This unique registry not only catalogs tissue characteristics but also the number of specific T cells against various viruses, enabling researchers to quickly identify and provide precisely matched T cell donations when a patient’s own immune cells are insufficient. The institute is a leading manufacturer of virus-specific T cells in Germany, ensuring rapid availability for treatment.

The Future of PML Treatment: A Blood Test for Targeted Therapy

Despite the success of donor T cell therapy in certain cases, ICIs remain a crucial treatment option globally. The MHH study suggests that a simple blood test to detect virus-specific T cells could become a standard practice before initiating ICI therapy. This test could help clinicians identify patients most likely to benefit from ICIs and minimize unnecessary treatment and potential side effects in those who are unlikely to respond.

Professor Skripuletz emphasizes that our data provide evidence that a blood test for virus-specific T cells could be suitable as a biomarker. The goal is to integrate this examination into the standard protocol for PML patients before starting treatment.

This research highlights the critical role of pre-existing antiviral immunity in fighting PML and underscores the potential of T cells as a guide for clinical decision-making in this rare but devastating neurological disease. The findings offer a significant step forward in improving outcomes for individuals battling this challenging infection.