ABSTRACT – Overall Building on the Duke Brain Tumor Program's longstanding focus on development, refinement, and testing of immunotherapies to treat low-grade gliomas and glioblastoma (GBM), this renewal of the Duke SPORE in Brain Cancer continues work to develop new or improve existing therapies to improve the life of patients with primary malignant brain tumors. To achieve this goal, the Program provides the infrastructure, oversight, and resources to conduct innovative translational research relevant to these treatments (Aim 1). Innovative research proposed includes: 1) studies of potent neoantigen and Cytomegalovirus vaccines in the context of regulatory T cell depletion using a novel approach targeting CD27 to overcome both host immunosuppression and antigenic heterogeneity endemic to GBM (Project 1); 2) studies employing a novel therapeutic strategy to reverse the recently discovered phenomenon of T cell sequestration in patients with GBM and overcome the limitations imposed on immunotherapy by longstanding lymphopenia in this population (Project 2); and 3) studies examining the mechanisms and efficacy of a novel cellular tumor vaccine strategy that uses antigen- loaded monocytes and an endogenous antigen transfer pathway to stimulate potent anti-tumor T cell responses (Project 3). To support this work, the SPORE ensures the availability of expertise through three Shared Resource Cores, all continued from the current award: a Biostatistics and Bioinformatics Core (Core 1), Clinical Trial Operations Core (Core 2), and a Biorepository, Pathology, and Immune Monitoring Core (Core 3) (Aim 2). Research central to the theme of the SPORE is further enhanced by the Program's commitment to seeding developmental research and implementing approaches to grow the research community through its Developmental Research and Career Enhancement Programs (Aim 3). Finally, the Duke SPORE in Brain Cancer continues to participate in and lead inter-SPORE activities to enhance collective impact (Aim 4). Contributions include continuing leadership of an active inter-SPORE collaboration in Immune Monitoring that is working to establish common standards and to harmonize assays, and proposed contributions to the NCI's new Functional Data Commons effort. Taken together, the Duke Brain SPORE is ideally positioned to address and overcome limitations in existing malignant brain tumor therapies and enhance collective research environment to advance shared research community goals.