Mentor Name: Thomas De Raedt

Pediatric high and low grade gliomas are cancers that arises in the brain and spinal cord. They are characterized by poor prognosis of advanced disease and disproportionally contribute to childhood cancer morbidity and mortality. Thus, it is imperative to discover more effective and safer therapies for glioma patients. Immunotherapies with chimeric antigen receptor (CAR) T cells have emerged as a promising treatment in several cancers. However, CAR T cells face several challenges in glioma, such as identifying tumor-specific antigens and circumventing the high levels of immunosuppression in the tumor microenvironment. Over the last three years, we have worked closely with the Maris Lab to identify pediatric glioma-specific peptides presented on human leukocyte antigens (HLA) that can be targeted with peptide centric CARs (PC CARs). Through an immunopeptidomics campaign on 17 pediatric high-grade gliomas and 16 pediatric low-grade gliomas, we identified a large number >15 potential PC CAR targets. Now we will now prioritize these peptides for PC-CAR development and preclinical assessment of specificity and potency in pediatric glial cancer models. Our ultimate goal is to engineer potent and safe peptide-centric (PC) CARs that target these HLA presented peptides. Top candidates will be validated as PC-CAR T cell therapeutic targets, and through discovery of scFv binders, PC-CAR T cells directed toward these novel glioma immunotherapy targets will be engineered and then tested for efficacy and safety. Importantly, these therapies also have the capacity for even broader impact: these candidate antigens have been discovered in other pediatric solid cancers such as neuroblastoma. Development of these PC-CARs hold the potential to provide novel therapies that cover the majority of the pediatric glioma populations.