Project Funding Details

Immunotherapies, such as vaccines, may represent attractive approaches in patients with IDH mutant lower grade gliomas (LGG) as the slow growth and relatively intact immunological status of these patients may allow repeated, personalized vaccinations for induction of robust immune responses. While we conducted vaccine trials in LGG patients against non-mutated antigens, we need further refinements of target antigens, such as inclusion of neoantigens derived from somatic gene alterations (e.g. mutations). In regard to immunoregulatory mechanisms, we reported that mutations in IDH cause immunosuppression, which could be reversed by inhibitors against mutant IDH. Integrating these discoveries and the complementary capabilities of our laboratories, our goal is to develop strategies to reverse the local immunosuppression and combine this with vaccines that target multiple neoantigens, thereby preventing recurrence of IDH mutant LGG. Intratumoral heterogeneity of neoantigens is thought to be a major source of immunotherapeutic failures, and most immunotherapies are based on just one random sample of each tumor, assuming it is representative of the whole tumor. We devised an innovative 3-dimensional (3D) sample collection of 10 spatially mapped samples selected to represent maximal anatomy of the tumor. Here we propose to use RNA and exome sequencing of the spatially mapped samples to identify sets of expressed mutations that in aggregate encompass most of the tumor, persist from primary to recurrence, and are predicted to be high quality neoantigens. We will validate the immunogenicity of the predicted neoantigens in the patient-derived peripheral blood mononuclear cells (PBMC). To better understand the local immune response in each tumor region, we will analyze immune cell content and T-cell clonality. Our 3D immuno-genomics approach may provide a novel and more widely applicable paradigm for immunotherapy. Furthermore, we may be able to use our established methods to clone neoantigen-specific T-cell receptor (TCR) to develop TCR-transduced T-cell therapy.