PROJECT SUMMARY The enclosed application presents an approach for effective dendritic cell (DC) genetic antigen delivery to trigger cancer-specific immune reactivity, predicated upon the use of a “hybrid” biomaterial-biological delivery vector featuring a bacterial core within a polymeric coating. Support for the impact of the proposed study includes emerging research demonstrating advances in DC vaccination to prompt sustained immune response outcomes (≥10 years) with improved patient survival in Phase II clinical trials and current open Phase III trials. However, there remain challenges to broad efficacy in that most metastatic patients still do not respond to treatment, thus, presenting an unmet need to improve these immune-based strategies. Compounding this limitation are the standard methods currently utilized for antigen delivery to DCs, with poor immunotherapy outcomes hypothesized to be the result of ineffectual means of antigen delivery that do not consider the cellular-level challenges to DC activation and antigen transport. Systematically dealing with every aspect of DC interaction and antigen delivery, in our view, will have transformative impact on the field of cancer immunotherapy. In response, we propose the application of a biological-biomaterial hybrid vector specifically designed for DC interfacial recognition and antigen delivery. In so doing, we put forth the hypothesis that this technology will address current limitations with DC-based antigen delivery and subsequent immunotherapy effectiveness. The research strategy presents a plan to systematically test this hypothesis through a series of specific aims designed to better assess hybrid vector interaction with and activation of DC (Aim 1); evaluate DC intracellular trafficking of the hybrid vector and final gene delivery effectiveness as a function of vector design (Aim 2); and examine the impact of hybrid vector delivery on DC-mediated T cell activation in vivo (Aim 3). The enclosed project is supported by a well-qualified and complementary team of biological engineers and cancer immunologists capable of positioning the results for translational impact.