PROJECT SUMMARY/ABSTRACT: Brain tumors are the number one cause of cancer related deaths in children. Medulloblastoma (MB) is the most common malignant pediatric brain tumor, while brainstem gliomas (BSG) are the most lethal. Though numerous preclinical and clinical studies have demonstrated potential therapeutic benefits for immunotherapy in solid tumors, malignant brain tumors remain universally lethal. In response, our group has pioneered an adoptive cellular therapy platform that relies on the transfer of tumor-reactive T cells and our publications demonstrate that this platform is efficacious against orthotopic high grade gliomas (KR158B, GL261), Group 3 MB (NSC), Sonic hedgehog MB (Ptc), and brainstem glioma (K2). In this proposal, our objective is to increase the specificity and efficacy of adoptive cellular therapy by employing a more targeted approach against embryonal tumors, specifically MB and brainstem gliomas (BSG). Recent elegant studies have identified links between ontogeny and oncology, describing that dysregulation in neural developmental processes lead to childhood CNS tumors, suggesting these cancers arise as a consequence of abnormal developmental processes. This provides great opportunity to leverage developing neural tissue as a source of antigens against MB and BSG. We refer to this genomic intersection between developing tissue and tumors as developmental antigens (DevAg). In this proposal we will identify the DevAgs in both MB and BSG and leverage them for immunological targeting of these tumors. Targeting these developmentally regulated antigens not only negates the requirement for primary tumor resection but also limits potential cross-reactivity with normal gene products. Importantly, this indicates that developing cerebellum do share immunogenic antigens with different subtypes of MB and that multiple subtypes of MB can be targeted by developmental antigens. To our knowledge, our studies are the first to 1. Utilize developing brain antigens to target syngeneic MB and BSG murine models and 2. demonstrate antitumor efficacy using a novel method of targeted enrichment to select for specific antigens. This approach has profound implications in safely and effectively targeting MB and BSG.