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A landmark human trial testing a vaccine that is designed to help the immune system attack brain tumors has shown promising results, and Phase 2 of the trial is now being planned.
According to a Nature In an article published by the researchers leading the trial, the vaccine was safe for all patients and showed the expected immune response to cancerous tissue.
Diffuse gliomas are usually incurable brain tumors that spread throughout the brain and are difficult to completely remove by surgery. Chemotherapy and radiation therapy also usually have a limited effect.
In many cases, diffuse gliomas share a common feature: In more than 70 percent of patients, the tumor cells carry the same genetic mutation. An identical error in the DNA causes a single specific protein building block to be swapped in the IDH1 enzyme. This creates a novel protein structure, known as a neoepitope, that can be recognized as foreign by the patient’s immune system.
“Our idea was to support the immune system of patients and use a vaccine as a specific way to alert them to the specific neoepitope of the tumor,” explained study director Michael Platten, medical director of the Department of Neurology at Mannheim University of Medicine and Head of Division of the German Cancer Research Center (DKFZ).
The IDH1 mutation is a particularly suitable candidate here, as it is highly specific for gliomas and does not occur in healthy tissue. Furthermore, the IDH1 mutation is responsible for the development of these gliomas: “That means that a vaccine against the mutated protein allows us to tackle the problem from the root,” added Platten.
Promising preclinical results
Platten’s team had already generated an artificial version of the IDH1 protein segment with the characteristic mutation several years ago. This mutation-specific peptide vaccine was able to stop the growth of IDH1-mutated cancer cells in mice. In 2019, Platten received the German Cancer Prize for this discovery.
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Encouraged by these results, Platten and a team of doctors decided to test the mutation-specific vaccine for the first time in a phase I study in patients newly diagnosed with an IDH1-mutated glioma.
A total of 33 patients from several different centers in Germany were enrolled in the study. In addition to standard treatment, they received the peptide vaccine produced by the Heidelberg University Hospital and the University of Tübingen. The immune response could be evaluated in 30 patients, according to the study published in Nature.
Doctors did not see serious side effects in any of the patients who were vaccinated. In 93 percent of patients, the immune system showed a specific response to the peptide in the vaccine, regardless of the patient’s genetic background, which determines the important presentation molecules of the immune system, HLA proteins.
In a large proportion of vaccinated patients, doctors observed “pseudo-progression,” inflammation of the tumor caused by a large number of invading immune cells.
These patients had a particularly large number of helper T cells in their blood with immune receptors that specifically responded to the peptide in the vaccine, as revealed by individual cell sequencing.
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“We were also able to show that the activated mutation-specific immune cells had invaded the brain tumor tissue,” reported Theresa Bunse of DKFZ, who coordinated the immunological analyzes for these studies.
The three-year survival rate after treatment was 84 percent in fully vaccinated patients, and tumor growth had not progressed during this period in 63 percent of patients. Among patients whose immune systems showed a specific response to vaccines, a total of 82 percent had no tumor progression within the three-year period.
The concept of a vaccine is pursued
“We cannot draw any further conclusions about the efficacy of the vaccine from this initial study without a control group,” commented Michael Platten. “The safety and immunogenicity of the vaccine were so compelling that we continued the vaccine concept in an additional phase I study.”
In this follow-up study, the researchers are combining the IDH1 vaccine with checkpoint inhibitor immunotherapy. “Checkpoint inhibitors act as an immune booster. We think there is a good chance that they can activate immune cells against gliomas to an even greater extent. “
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The researchers are also preparing a phase II study to examine for the first time whether the IDH1 vaccine leads to better treatment outcomes than standard treatment alone. “Gliomas are diagnosed in around 5,000 people in Germany each year, of which around 1,200 are diffuse gliomas with an IDH1 mutation. So far, we’ve generally had only limited success in stopping tumor progression in these patients. We believe that the IDH1 vaccine offers the potential to develop a treatment that can suppress these tumors more effectively and in the long term, ”commented study co-director Wolfgang Wick, medical director of the Neurological Clinic at Heidelberg University Hospital and Division Chief at DKFZ.
This is promising news indeed, and we will be sure to keep you posted on further developments stemming from these trials.
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