Subproject for Institution # SP0038706

This proposed research seeks to develop a breakthrough immunotherapeutic agent for the treatment of metastatic castration resistant prostate cancer (mCRPC). Despite recent advances in the development of immunotherapies for cancer, for example antibodies that release anti-tumor immune responses from checkpoint blockade (PD-1, PD-L1, CTLA4), prostate cancer remains a challenge for immunotherapeutic approaches. The FDA-approved cell-based therapy sipuleucel-T improves median overall survival but not median progression-free survival, and yields poor results in patients with increasing burden of the disease. This proposed research, enabled by advances in nanotechnology and immuno-oncology, will address the need for an effective immunotherapy for mCRPC by innovating a nanoparticle cancer vaccine. This cancer vaccine will be developed from spherical nucleic acid technology (SNA), and will consist of a nanostructure formulated with immunostimulatory oligonucleotides and antigens derived from prostate-specific membrane antigen (PSMA). An SNA cancer vaccine is distinguished in its structure from other cancer vaccines, by the polyvalent presentation of immunostimulatory oligonucleotides, and co-functionalization with tumor-associated antigen; these structural features are ideal for interaction with antigen-presenting cells and initiating a potent and PSMA-specific immune response. The multidisciplinary team for this research brings together expertise in chemistry, animal models, tumor immunology, clinical immuno-oncology, animal models, medical oncology and surgery. This research will develop SNA structures and demonstrate their ability to act as therapeutic vaccines for treating prostate cancer, by inducing potent immune responses that target and eliminate prostate cancer cells. The specific aims of the research are 1) Design and Synthesis of SNAs for Stimulating Immune Responses Against PSMA; 2) Evaluation of SNAs for the Ability to Induce Immune Responses Specific to PSMA, Using Human Patient-Derived and Mouse Model Cells; 3) Treatment of Immunocompetent Mouse Models of Prostate Cancer with SNAs. This approach is focused on rapidly identifying and refining SNAs that show promise in potency and anti-PSMA-specific immune responses. A key aspect of this approach will be to demonstrate the immunostimulatory properties of SNAs in patient-derived cells and in an advanced animal model that best mimics the features of the disease; this approach will be taken in order to discover a therapeutic agent that will be ready for rapid translation to clinical trials. The potential impact of this research, through the discovery of an SNA immunotherapeutic that induces anti-PSMA T-cell activity, is an effective treatment for prostate cancer that can be administered by IV, and can be broadly available, made possible by the chemical and modular nature of SNAs that enable the scaleable production of SNAs.