Tumor vaccines may also help the body fight cancer. These vaccines alert the patient’s immune system to proteins which can be carrying cancer-typical alterations. Physicians and cancer researchers from Heidelberg and Mannheim have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the primary time. The vaccine mimicked a mutational change in a histone protein typical of this sort of cancer. The vaccine proved to be protected and induced the specified immune responses directed against the brain tumor.

Crucial for the success of cancer vaccinations are protein structures by which the immune cells can recognize the cancer – and which are usually not present (or only to a small extent) on healthy cells. Mutations within the tumor genome often result in protein structures which can be altered in a way typical of cancer.

Diffuse midline gliomas are amongst probably the most aggressive brain tumors. They sometimes occur in children and young adults near the brain stem and are subsequently difficult to access surgically. Chemotherapy or radiation therapy even have limited effectiveness. In this sort of cancer, mutations characteristically occur within the gene encoding histone H3 (H3K27M), a packaging protein of DNA. The mutation gives rise to a novel protein structure – a so-called neoepitope – that might be recognized as foreign by the patient’s immune system.

Such mutations, which occur in similar form in lots of patients, are rare in cancer. They literally lend themselves to the event of tumor vaccines because they occur in all cancer cells, for the reason that mutated histone is causative for the event of midline gliomas. Which means vaccination against the mutated protein gets to the basis of the issue.”

Michael Platten, Director of the Department of Neurology on the University Medical Center Mannheim and Head of Department on the German Cancer Research Center (DKFZ)

The researchers led by Katharina Sahm and Michael Platten synthetically reconstructed the section of the histone H3 protein with the characteristic mutation. Using this peptide, they were in a position to curb the expansion of H3K27M-mutated tumors in a mouse model*. Encouraged by the outcomes, the team decided to check the mutation-specific vaccine produced on the University of Tübingen in patients in a phase I-trial**, which remains to be ongoing.

In parallel, the physicians, along with colleagues from Munich, Berlin, Bonn and Münster, treated eight adult patients with the peptide vaccine in time-limited individual curative trials. These patients, who couldn’t be enrolled within the trial protocol, suffered from diffuse midline gliomas with H3K27M mutation that progressed after standard therapy. Among the affected individuals received therapy with immune checkpoint inhibitors along with tumor vaccination.

No serious unwanted side effects were observed in any of the vaccinated patients. Five of the eight treated patients developed specific immune responses against the mutant protein, which were dominated by CD4 T-helper cells. In considered one of the patients who had shown a robust immune response, the tumor regressed completely and she or he remained tumor-free for 31 months.

The vaccine peptide, which is relatively long at 27 amino acids, worked in patients with different HLA variants. HLA proteins are answerable for the presentation of the mutant peptide on the cell surface and differ from individual to individual depending on their genetic background. Supported by the HI-TRON Mainz – Helmholtz Institute of the DKFZ, the researchers also observed that immune responses decreased over time, so repeated administration of the vaccine could support a sustained effect.

“We cannot make any further statements concerning the efficacy of the vaccination based on these treatments. In any case, the present study has given us beneficial information that can help us to further optimize the event of brain tumor vaccines in the longer term,” explains the study’s senior creator Katharina Sahm, senior physician on the Neurological University Hospital Mannheim and DKFZ researcher. A phase I-trial is currently underway to check the vaccine against the H3K27M mutation in patients with newly diagnosed midline gliomas. Evaluation is predicted to start around 2025.

The project was funded by the Translational Oncology funding program of German Cancer Aid (Deutsche Krebshilfe).

Source:

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Journal reference:

Grassl, N., et al. (2023). A H3K27M-targeted vaccine in adults with diffuse midline glioma. Nature Medicine. doi.org/10.1038/s41591-023-02555-6.