Physicians and cancer researchers in Heidelberg and Mannheim have for the first time carried out a clinical trial to test a cancer vaccine candidate that targets a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene. Results from the first-in-human Phase I study in glioma patients showed that repeated injections of the peptide vaccine were safe, and triggered the anticipated immune response in their tumor tissue.
The researchers are now working towards a Phase II study that will examine whether the IDH1 vaccine leads to better treatment results than standard therapy alone. “Gliomas are diagnosed in around 5,000 people in Germany every year, of which about 1,200 are diffuse gliomas with an IDH1 mutation,” commented study co-director Wolfgang Wick, MD, medical director of the neurological clinic of Heidelberg University Hospital and head of division at German Cancer Research Center (DKFZ). “Up to now, we have usually had only limited success in halting tumor progression in these patients. We believe that the IDH1 vaccine offers the potential for developing a treatment that can suppress these tumors more effectively and on a long-term basis.”
Results from the Phase I study, Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), are reported in Nature, in a paper titled, “A vaccine targeting mutant IDH1 in newly diagnosed glioma.”
Diffuse gliomas are usually incurable brain tumors that spread in the brain and are difficult to remove completely by surgery. Chemotherapy and radiotherapy often only have a limited effect against this type of cancer. In many cases, diffuse gliomas share a common feature, in that among 70% of patients, the tumor cells have the same gene mutation, which results in a single, specific protein building block alteration in the IDH1 enzyme. This creates a novel protein structure, known as a neo-epitope, which can be recognized as foreign by the patient’s immune system.
Tumor vaccines can help the body fight cancer, by alerting the patients’ immune system to these mutated proteins. “Our idea was to support patients’ immune system and to use a vaccine as a targeted way of alerting it to the tumor-specific neo-epitope,” explained study director Michael Platten, MD, medical director of the department of neurology of University Medicine Mannheim and head of division at DKFZ. The IDH1 mutation represents a particularly apt vaccine target candidate, as it is responsible for development of these gliomas, is highly specific to this tumor type, and does not occur in healthy tissue. “That means that a vaccine against the mutated protein allows us to tackle the problem at the root.”
Platten’s team had, several years ago, generated an artificial version of the segment of the IDH1 protein with the characteristic mutation. This mutation-specific peptide vaccine was able to halt the growth of IDH1-mutated cancer cells in mice. “An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumors in syngeneic MHC-humanized mice,” the authors explained.
Encouraged by the preclinical results, Platten and colleagues carried out a Phase I clinical trial to assess the mutation-specific vaccine for the first time in human patients newly diagnosed with an IDH1-mutated glioma (WHO grades III and IV astrocytomas). A total of 33 patients at several different centers in Germany were enrolled in the study, which was supported by the National Center for Tumor Diseases (NCT) Heidelberg and the Neurooncology Working Group (NOA) of the German Cancer Society.
In addition to the standard treatment, the participants received the peptide vaccine, produced by Michael Schmitt, head of cellular immunotherapy, department of hematology, oncology, and rheumatology at Heidelberg University Hospital, and Stefan Stevanovi, professor of molecular immunology at the department of immunology, University of Tübingen. There were three treatment groups, based on the standard-of-care therapy that the patient had received before enrollment into the trial: radiotherapy alone, three rounds of chemotherapy plus temozolomide alone, or combined radiochemotherapy with temozolomide. Treatment consisted of eight vaccinations with IDH1-vac, over the course of 23 weeks.
The researchers were able to evaluate immune response in 30 of the patients. Their analyses showed that 93% of the patients exhibited an immune response that was specific to the vaccine peptide, and did so regardless of the patient’s genetic background—which determines the immune system’s important presentation molecules, the HLA proteins. “IDH1-vac was immunogenic across multiple HLA alleles …” they wrote. The physicians did not observe any serious side effects in any of the patients who were vaccinated.
A large proportion of the vaccinated patients demonstrated pseudoprogression (PsPD), which refers to swelling of the tumor caused by a host of invading immune cells. These patients had a particularly large number of T helper cells in their blood with immune receptors that responded specifically to the vaccine peptide, as single cell sequencing revealed. “Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses … Patients with PsPD had higher maximal levels of peripheral IDH1-vac-induced T cell immune responses than patients who had progressive disease,” the authors wrote. “We were also able to demonstrate that the activated mutation-specific immune cells had invaded the brain tumor tissue,” commented co-author Theresa Bunse, from DKFZ, who coordinated the immunological analyses for the studies.
The three-year survival rate after treatment was 84% in the fully vaccinated patients, and in 63% of patients, tumor growth had not progressed within this period. Among the patients whose immune system showed a specific response to the vaccines, a total of 82% had no tumor progression within the three-year period. “NOA16 met its primary endpoints by demonstrating the safety and immunogenicity of IDH1-vac in patients with newly diagnosed WHO grade 3 and 4 IDH1(R132H)+ astrocytomas without further positive prognostic factors,” the team concluded. “Immunogenicity, irrespective of HLA type, and the high rate of PsPD warrant further clinical investigation of IDH1-vac.”
Platten commented, “We cannot draw any further conclusions about the vaccine efficacy from this early study without a control group.” He further stated, “The safety and immunogenicity of the vaccine were so convincing that we continued to pursue the vaccine concept in a further Phase I study.” In this follow-on study, the researchers are combining the IDH1 vaccine with checkpoint inhibitor immunotherapy. “Checkpoint inhibitors act as an immune boost. We believe there is a good chance that they can activate the immune cells against the gliomas to an even greater extent.” The study is being implemented in cooperation with other centers in Germany and with support from the DKTK.
The researchers are also preparing a Phase II study to investigate whether the IDH1 vaccine leads to better therapeutic results than the standard treatment alone.