Midline gliomas show immune response to novel vaccine

brain tumor, illustration
Credit: Alfred Pasica/Science Photo Library/Getty Images

Adult patients with advanced midline glioma have been treated with a peptide vaccine for the first time, according to researchers in Heidelberg and Mannheim, Germany. The vaccine mimicked a mutational change in histone proteins (H3K27M), a marker for this difficult type of brain tumor. The vaccine proved safe and generated promising immune responses.

“We have previously shown that this genetic alteration can be recognized by the immune system, specifically T helper cells, and that a vaccine results in the activation of specific T helper cells and subsequent control of tumors in mice carrying this genetic alteration. It happens,” explains co-senior author Michael Platten. Inside Precision Medicine, Platten is Director of the Department of Neurology at the University Medical Center Mannheim and Head of Department at the German Cancer Research Center (DKFZ).

The team gave information about its work naturopathy, The first author is Niklas Grassi.

Diffuse midline gliomas are one of the most aggressive brain tumors, with a life expectancy of less than a year. They usually occur near the brain stem in children and young adults and are difficult to access surgically. Chemotherapy or radiation therapy also has limited effect.

The mutation in this type of tumor usually occurs in H3K27M, which is a DNA packaging protein. The mutations generate a novel protein structure – a neoepitope, which the patient’s immune system can recognize as foreign. Substitution of lysine 27 to methionine in H3K27M is a mutation that causes an aggressive subtype of diffuse glioma.

“Such mutations, which occur in the same form in many patients, are rare in cancer. They virtually lend themselves to the development of tumor vaccines as they do in all cancer cells, as mutated histones cause the development of midline gliomas. This means that vaccination against the mutated protein gets to the root of the problem,” explains Platten.

The team, led by Platten and Katharina Sahm, senior physician at the Neurological University Hospital Mannheim and DKFZ researchers, artificially recreated the section of the histone H3 protein with the characteristic mutation. Using this peptide, they curbed the growth of H3K27M-mutated tumors in a mouse model. They then tested the mutation-specific vaccine produced at the University of Tübingen on patients in a Phase 1 trial, which is still ongoing.

In parallel, the team treated eight adult patients with the peptide vaccine on a compassionate use basis. These patients had diffuse midline gliomas with H3K27M mutations, which progressed after standard therapy. Some of the affected individuals received treatment with immune checkpoint inhibitors in addition to tumor vaccination.

No serious side effects were observed in any of the vaccinated patients. Five of the eight developed specific immune responses against the mutant protein. These responses were dominated by CD4 T-helper cells. In one patient who showed a strong immune response, the tumor completely regressed and she remained tumor-free for 31 months.

HLA proteins are responsible for the presentation of the mutant peptide on the cell surface and vary from person to person depending on the genetic background of the patient. The researchers report that this vaccine peptide, which is comparatively longer at 27 amino acids, works in patients with different HLA variants.

“…the current study has given us valuable information that will help us further optimize the development of brain tumor vaccines in the future,” explains Sahm.

A Phase I trial is currently underway to test the vaccine against the H3K27M mutation in patients with newly diagnosed midline glioma. The evaluation is expected to begin around 2025.

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