Enhancing Antigen Delivery Using Spherical Nucleic Acidsfor Optimal Prostate Cancer Immunotherapy

Abstract

Abstract Prostate cancer ranks as the second leading cause of cancer-related death in the United States in men. For patients with metastatic or recurrent disease, cancer vaccines remain an attractive treatment approach while therapeutic efficacy is rather limited. Here, we developed Spherical Nucleic Acid nanostructures (SNAs) to deliver adjuvant CpG and prostate cancer peptide antigens to potentiate antitumor responses. We show that SNAs that differ in the positioning of the antigen within the nanostructure lead to differences in the quality of immune responses generated by vaccination with SNAs. SNAs conjugated with both antigen and adjuvant CpG on the surface (HM SNAs)induce stronger cytotoxic T lymphocyte (CTL) mediated antigen-specific killing of target cells than that for SNAs with CpG on the surface and antigen encapsulated within the core (EM SNAs). Mechanistically, HM SNAs increase co-delivery of CpG and antigen, thereby promoting dendritic cells-mediated cross-priming compared to EM SNAs, or admix of free peptide and linear CpG. Furthermore, vaccination with HM SNAs led to significantly inhibits tumor growth in two syngeneic mouse models of prostate cancer. These data suggest that the positioning of peptide antigens within SNA structures can be exploited to enhance the therapeutic performance of SNAs, representing a novel approach to vaccine design for cancer immunotherapy and potentially other diseases that can be addressed through modulating the immune system.