Joint press release of the German Cancer Research Center (DKFZ), Mannheim University Medical Center, Heidelberg University Hospital and the National Center for Tumor Diseases (NCT) Heidelberg.

Tumor vaccinations can support the body in its fight against cancer. Mutations in the tumor genome often lead to proteins that are altered in a way that is typical of cancer. A vaccine can alert the patient’s immune system to such mutated proteins. Physicians and cancer researchers from Heidelberg and Mannheim have now tested a mutation-specific vaccine against malignant brain tumors in a clinical trial for the first time. The vaccination proved to be safe and triggered the desired immune responses in the tumor tissue, as the team now reports in the journal Nature.

Diffuse gliomas are usually incurable brain tumors that spread throughout the brain and are difficult to remove completely by surgery. Chemotherapy or radiation therapy are also often only effective to a limited extent. In many cases, diffuse gliomas have one particular feature in common: In more than 70 percent of cases, the tumor cells carry a matching gene mutation. An identical spelling mistake in the genetic material that results in a single, specific protein building block being exchanged in the IDH1* enzyme. This results in a novel protein structure – a so-called neoepitope – that can be recognized as foreign by the patient’s immune system.

“Our idea was to support the patients’ immune defenses and target the tumor-specific neoepitope with a vaccine”, says clinical trial leader Michael Platten, director of the Department of Neurology at the University Medical Center Mannheim and Department Head at the German Cancer Research Center. The IDH1 mutation is particularly suitable for this purpose: It occurs highly specifically in gliomas and does not occur in healthy tissues. In addition, the mutated IDH1 is causative for the development of gliomas: “This means that with a vaccine against the mutated protein, we are getting to the root of the problem“, explains Michael Platten, a neurologist.

Several years ago, his team had already synthesized the section of the IDH1 protein with the characteristic mutation. This mutation-specific peptide vaccine was able to stop the growth of IDH1-mutated cancer cells in mice. In 2019, Michael Platten was awarded, among other things, the German Cancer Prize for this discovery.

Encouraged by these results, the physicians around Michael Platten decided to test the mutation-specific vaccine for the first time in a phase 1 trial** in patients, who had been newly diagnosed with an IDH1-mutated glioma (WHO grade 3 and 4 astrocytomas). The study, supported by the National Center for Tumor Diseases (NCT) Heidelberg and the Neuro-oncology Working Group of the German Cancer Society (NOA), enrolled a total of 33 patients in several centers in Germany. In addition to standard therapy, they received the peptide vaccine, prepared by Michael Schmitt, Head of Cell and Immunotherapy, Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, and Stefan Stevanovic of the Institute of Immunology, University of Tübingen. Immune responses could be evaluated in 30 patients.

The doctors did not observe any serious side effects in any of the vaccinated patients. In 93 percent of the patients, the immune system reacted specifically against the vaccine peptide. This was true regardless of the patient’s genetic background, which determines the important presentation molecules of the immune system, the HLA proteins.

In a large proportion of the vaccinated patients, the doctors observed a so-called “pseudoprogression”, a swelling of the tumor caused by an invasion of immigrating immune cells. These patients had particularly large numbers of T-helper cells in their blood, whose immune receptors responded specifically to the vaccine peptide, as revealed by single-cell sequencing. “We were also able to demonstrate that the activated mutation-specific immune cells migrated into the brain tumor tissue”, reports Theresa Bunse, DKFZ, who coordinated the immunological analyses for these studies.

84 percent of those fully vaccinated were still alive three years after treatment, and in 63 percent tumor growth did not progress further within this period. Among the patients whose immune system had responded specifically to the vaccine, as many as 82 percent lived for three years without tumor progression.

“We cannot make any further statements about the efficacy of the vaccine in this early study without a control group”, explains Michael Platten. “The safety and immunogenicity of the vaccine were so convincing that we continued the vaccination concept in another phase 1 trial.” In this follow-up study, physicians combine the IDH1 vaccine with an immunotherapy called a checkpoint inhibitor. “Checkpoint inhibitors act as immune boosters. We think there’s a good chance they’ll activate immune cells more distinctly against gliomas.” This study is being conducted in collaboration with other centers in Germany and with support from the German Consortium for Translational Cancer Research (DKTK).

The physicians are also preparing a phase II study that will allow them to test for the first time whether the IDH1 vaccine leads to better treatment results than standard therapy alone. “Every year, about 5000 people in Germany are diagnosed with glioma, about 1200 of which are diffuse gliomas with an IDH1 mutation. So far, we can usually only halt the tumors in these patients to a limited extent. We see opportunities to develop a treatment with the IDH1 vaccine that will repress these tumors more effectively and in the long term”, says co-study leader Wolfgang Wick, Head of the Department of Neurology at the Heidelberg University Hospital, and also Head of the Department at the German Cancer Research Center.

* Isocitrate dehydrogenase 1
** Neuro-oncology Working Group of the German Cancer Society (NOA) trial 16, ClinicalTrials.gov Identifier NCT02454634.

Michael Platten, Lukas Bunse, Antje Wick, Theresa Bunse, Lucian Le Cornet, Inga Harting, Felix Sahm, Khwab Sanghvi, Chin Leng Tan, Isabel Poschke, Edward Green, Sune Justesen, Geoffrey A. Behrens, Michael Breckwoldt, Angelika Freitag, Lisa-Marie Rother, Anita Schmitt, Oliver Schnell, Jörg Hense, Martin Misch, Dietmar Krex, Stefan Stevanovic, Ghazaleh Tabatabai, Joachim P. Steinbach, Martin Bendszus, Andreas von Deimling, Michael Schmitt, and Wolfgang Wick: A vaccine targeting mutant IDH1 in newly diagnosed glioma
Nature 2021, DOI: