PROJECT SUMMARY – Overall Malignant primary brain tumors, like glioblastoma (GBM), are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Moreover, current therapy is incapacitating and limited by non-specific toxicity. Despite hundreds of clinical trials, few agents have been approved for clinical use, and the tumors addressed in this application remain uniformly lethal. The OVERALL GOAL of this PPG is to develop completely new therapies or to improve existing novel therapeutic approaches through a better understanding of the immunobiology of patient's response to both the tumor and the therapy to achieve prolonged survival in patients with GBM without concomitant toxicity. Within this overall goal, we have focused on eliminating the key barriers that have thus far restricted successful immunotherapy against brain tumors. In the three proposed clinical trials, we will focus on enhancing immunotherapy through more potent platforms, through reducing immunosuppression, through modulating the tumor microenvironment, and through understanding the immune-mediated mechanisms activated by the different platforms. Importantly, this PPG leverages an extraordinary group of senior scientists with a long history of collaboration and successful translational research to accomplish these goals. Project 1, led by John Sampson, will conduct a Phase 2 trial based on his recently published pilot trial demonstrating that preconditioning the vaccine site with tetanus/diphtheria (Td) recall antigens prior to tumor-targeted DC vaccination against Cytomegalovirus (CMV) antigens shown to be re-activated within the tumor dramatically extended OS in patients with GBM. This Phase 2 trial will validate these pilot findings in a larger group of patients. Furthermore, this trial will also incorporate a novel, fully human, clinically approved anti-CD27 mAb that simultaneously reduces immunosuppression and potentiates vaccination through concomitant regulatory T cell depletion and CD27 costimulation. Project 2, led by Michael Gunn, evaluates a completely novel and extraordinarily potent cellular vaccine strategy and examines if monocyte vaccination in humans is safe and will result in robust anti-tumor antigen-specific T cell responses. Project 3, led by Darell Bigner, will conduct a Phase 2 clinical trial based on the promising Phase 1 work with a recombinant oncolytic poliovirus, to elucidate mechanisms by which this therapy generates an anti-tumor immune response, and to examine the synergistic therapeutic combination with the chemotherapeutic lomustine. These projects will be supported by an Administrative Core, as well as three shared resource cores to provide Biostatistics and Bioinformatics resources (Core 1), Clinical Trials and Imaging infrastructure (Core 2), and Correlative Studies and Immune Monitoring expertise (Core 3). While the individual therapies proposed are diverse, our cent...