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MHH researchers have found biomarkers that predict which patients will benefit from treatment with checkpoint inhibitors.
Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection. It gradually destroys brain tissue and often leads to death within a few weeks. It is triggered by human polyomavirus 2, also known as John Cunningham (JC) virus. PML primarily affects people with weakened immune cells, especially T lymphocytes. One treatment option is the use of immune checkpoint inhibitors (ICI). This therapy, which is well known in cancer medicine, reactivates the immune system, so to speak. However, the treatment is not always successful and can also have serious side effects. It is not yet possible to predict which patients will benefit from ICI therapy and which will not. An interdisciplinary team at Hannover Medical School (MHH) led by Prof. Dr Thomas Skripuletz, senior physician at the Department of Neurology with Clinical Neurophysiology, has now found biomarkers that can predict response to immunotherapy. The results of the study have been published in the journal ‘JAMA Neurology’.
Higher response rates, longer survival
In their study, the researchers evaluated 111 PML patients from 39 clinics worldwide who were treated with ICI between 2021 and 2024. Before starting therapy, they were able to test the blood of some of the patients to determine whether or not functional, virus-specific T cells against the JC virus were present. They then examined both groups and compared, among other things, how the patients responded to ICI therapy, how much virus could be detected in the cerebrospinal fluid, what side effects the treatment had, and how long the survival time was. ‘We observed that PML patients with detectable virus-specific T cells before the start of therapy had significantly higher response rates, better functional outcomes, lower viral loads during the course of treatment, and a better probability of survival during and after ICI treatment,’ emphasizes Professor Skripuletz. ‘At the same time, they experienced fewer immune-mediated side effects.’
Perfectly matched T cells thanks to the alloCELL donor registry
This result is of great significance, as ICI therapy is the only treatment option for PML in most clinics worldwide. However, there is another treatment option at MHH. In 2021, Professor Skripuletz's team found a groundbreaking way to stop the spread of the virus with the help of donated, perfectly matched immune cells. These directly isolated, so-called allogeneic DIAVIS T cells come from the blood of healthy people who were often infected with the virus without developing any symptoms of the disease. They have T cells that recognize JC virus-infected cells as foreign and trigger an immune response. ‘Before we administer virus-specific T lymphocytes from donors via infusion, we always analyze whether the patient's own T cells directed against the virus are still detectable in the blood,’ says Professor Skripuletz. However, most patients are not eligible for checkpoint inhibitors because these cells are missing – in this case, they benefit from treatment with donor T cells.
The alloCELL laboratory at the MHH in Hanover analyzes the presence of virus-specific T cells. ‘Thanks to our unique T-cell donor registry alloCELL at the MHH, we always find a perfect T-cell donation when no own defense cells can be detected,’ emphasizes Prof. Dr Britta Eiz-Vesper, immunologist at the MHH Institute for Transfusion Medicine and Transplant Engineering and 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. Because the institute is also one of Germany's leading producers of virus-specific T cells, suitable donors can be found quickly and the T cell products made available for treatment within a few days of the request. ‘We send the T cells to all kinds of centers in Germany and also abroad,’ says the immunologist.
Blood test recommended before ICI therapy
Nevertheless, ICI therapy plays an important role worldwide. ‘Our data provide the first evidence in a larger cohort that a blood test for virus-specific T cells could be suitable as a biomarker,’ Professor Skripuletz notes. This test can identify PML patients in whom checkpoint inhibitors are particularly likely to be effective and better tolerated. ‘The study underscores the central role of pre-existing antiviral immunity and confirms that T cells targeting the JC virus can serve as a guide for clinical decisions in this rare but highly relevant neuroinfectious disease.’ The goal is to make this test standard practice before starting therapy.
SERVICE:
Further information is available from Prof. Dr. Thomas Skripuletz, skripuletz.thomas@mh-hannover.de.
The original paper ‘Virus-Specific T Cells and Response to Checkpoint Inhibitors in Progressive Multifocal Leukoencephalopathy’ can be found here: https://jamanetwork.com/journals/jamaneurology/fullarticle/2843887
Prof. Dr Britta Eiz-Vesper and Prof. Dr Thomas Skripuletz analyze the results of a test that reveals ...
Copyright: Karin Kaiser/MHH.
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