Personalizing Cancer Medicine
The Brain Tumor Program currently runs “personalized” clinical studies based on patients’ gene markers, such as human leukocyte antigen (HLA)-A2, epidermal growth factor receptor (EGFR) variant III and chromosome 1p/19q co-deletion. In addition, the BTP offers a host of molecularly targeted treatment approaches for children whose brain tumors have genomic alterations that make them ideally suited for specific novel-agent trials. These include studies of MEK inhibitors (e.g. AZD6244) for children with BRAF-altered low-grade gliomas and Sonic hedgehog (SHH) inhibitors for children with medulloblastomas that have alterations in the SHH signaling pathway, which are being conducted by the NCI-supported Pediatric Brain Tumor Consortium (in which Pittsburgh is a founding member). Because such alterations are common, they apply to a significant subset of patients with these tumor types.
Each patient is screened for biomarkers that predict the therapeutic benefit of specific agents. Ideally, this would result in the grouping of patients according to which type of therapy would be most effective, with all of the patients benefiting from the respective treatment. In reality though, most conventional molecularly targeted treatment approaches are restricted to the biomarker-positive patient population; patients who are not eligible for the available treatments are neglected. Unfortunately, this is the case for many current clinical trials. Biomarker “positive” patients can be eligible, but ones who are “negative” are simply ineligible. However, new approaches, such as those being pioneered by the BTP Immunotherapy program, attempt to define applicable targets on a patient-by-patient basis.
To develop a truly personalized brain tumor vaccine approach, the Glioma Actively Personalized Vaccine Consortium (GAPVAC) has been formulated by Immatics Inc. and eight European academic centers. Our institution was invited as the only participating site from North America, where Dr. Hideho Okada serves as the Principle Investigator.
Immunotherapeutic approaches incorporating tumor-specific and molecularly defined attributes of the individual patient have not yet been explored. Through the GAPVAC, Dr. Okada and his collaborators will transform the treatment of glioma by developing a novel method for generating a glioma vaccine that is customized to each patient based on the genetic pattern of his or her tumor.
Each patient’s tumor tissue will be analyzed for peptides that are overexpressed or are mutated. To create the vaccine, the overexpressed peptides are selected from a peptide warehouse, while mutated peptides are synthesized de novo (Figure 1).
Next generation exome sequencing and HLA-peptidomics will be integrated to assess each patient’s specific mutated HLA-peptidome. The European Union has funded this research at the 8 sites in Europe but not in the USA; Dr. Okada has already obtained generous funding from Voices Against Brain Cancer, the Musella Foundation for Brain Tumor Research and Information, and Gray Matters Brain Cancer foundation, which will allow us to participate and enroll patients as the only site in North America.