Clinical success
Diffuse glioma is a brain tumor that is almost untreatable, since multiple foci are difficult to remove surgically, and chemotherapy and radiation therapy often have limited effectiveness. In many cases, diffuse gliomas have a common feature: in more than 70% of patients, tumor cells have the same gene mutation. An identical error in DNA leads to the replacement of one specific protein building block in the enzyme isocitrate dehydrogenase 1 (IDH1). This creates a new protein structure (neoepitope) that can be recognized by the patient's immune system as a foreign agent.
A group from the German Cancer Research Center (DKFZ) led by Michael Platten decided to use a vaccine to alert the immune system about a tumor neoepitope. The IDH1 mutation has become the most suitable candidate because it is very specific to gliomas and does not occur in healthy tissues. Moreover, the IDH1 mutation is responsible for the development of these gliomas.
Promising preclinical results
A few years ago, Platten's group created an artificial version of the IDH1 protein segment with a mutation characteristic of glioma. This mutation-specific peptide vaccine was able to stop the growth of IDH1-mutated cancer cells in mice. In 2019, Platten was awarded the German Cancer Prize for this discovery.
Clinical success
Encouraged by the results, Platten and colleagues decided to test a mutation-specific vaccine for the first time in a phase I clinical trial on patients with newly identified IDH1-positive glioma. A total of 33 patients from several centers in Germany were included in the study. In addition to the standard treatment, they received a peptide vaccine; the immune response was evaluated in 30 patients.
The researchers did not observe any serious side effects in any of the vaccinated patients. In 93% of patients, the immune system demonstrated a specific response to the vaccine peptide and reacted regardless of the patient's genetic background.
In a significant part of the vaccinated patients, doctors observed "pseudoprogression" – swelling of the tumor caused by a multitude of invading immune cells. They had a particularly large number of T-helpers in their blood, which specifically reacted to the vaccine peptide. Activated mutation-specific immune cells overcame the blood-brain barrier and penetrated the tumor tissue.
Three-year survival after treatment was 84% in fully vaccinated patients, and 63% of patients had no tumor growth during this period. Among patients whose immune system showed a specific response to the vaccine, a total of 82% had no tumor progression over a three-year period.
Next steps
Without a control group, no further conclusions can be drawn about the effectiveness of the vaccine from this early study. The safety and immunogenicity of the vaccine were so convincing that the authors intend to develop the concept, they plan to study the combination of the IDH1 vaccine with immunotherapy with checkpoint inhibitors. According to the researchers, there is a high probability that checkpoint inhibitors will be able to activate immune cells against glioma to an even greater extent. The study has already begun and is being conducted in collaboration with other cancer centers in Germany.
The group is also preparing a phase II study to compare the effectiveness of the IDH1 vaccine with standard treatment.
Article by M.Platten et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma is published in the journal Nature.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of DKFZ: Vaccination against mutated protein tested in brain tumor patients for the first time.