Development of Spherical Nucleic Acids for Prostate Cancer Immunotherapy

Abstract

Although the strategy of therapeutic vaccination for the treatment of prostate cancer has advanced to and is available in the clinic (Sipuleucel-T), the efficacy of such therapy remains limited. Here, we develop Immunostimulatory Spherical Nucleic Acid (IS-SNA) nanostructures comprised of CpG oligonucleotides as adjuvant and prostate cancer peptide antigens, and evaluate their antitumor efficacy in syngeneic mouse models of prostate cancer. IS-SNAs with the specific structural feature of presenting both antigen and adjuvant CpG on the surface (hybridized model (HM) SNAs) induce stronger cytotoxic T lymphocyte (CTL) mediated antigen-specific killing of target cells than that for IS-SNAs with CpG on the surface and antigen encapsulated within the core (encapsulated model (EM) SNAs). Mechanistically, HM SNAs increase the co-delivery of CpG and antigen to dendritic cells over that for EM SNAs or admixtures of linear CpG and peptide, thereby improving cross-priming of antitumor CD8 + T cells. As a result, vaccination with HM SNAs leads to more effective antitumor immune responses in two prostate cancer models. These data demonstrate the importance of the structural positioning of peptide antigens together with adjuvants within IS-SNAs to the efficacy of IS-SNA-based cancer immunotherapy.

Spherical Nucleic Acid Vaccine Structure Markedly Influences Adaptive Immune Responses of Clinically Utilized Prostate Cancer Targets

“…Previous work using model or syngeneic antigens has demonstrated that vaccine structure can influence the codelivery of adjuvant and antigen components, the intracellular trafficking and cross-presentation of antigens, and the kinetics of antigen processing signals. [44,48] However, herein, this work capitalizes on the translational promise of rational vaccinology by utilizing targets that allow for vaccine structure to be benchmarked and validated against clinical formulations. For these studies, we selected a SNA architecture that optimizes the efficacy of the three parameters: codelivery, trafficking, and kinetics.…”

“…This was done through disulfide bond formation through a cysteine on the peptide's N-terminus and a 3ʹ-thiol functionalized to the CpG complement using previously published methods. [48] The peptides incorporated in the SNA, PSMA 711-719 or TARP 29-37-9V (Table S2, Supporting Information), come from two different PCa-upregulated proteins and were selected to illustrate the translatability of this platform across antigen selection. In particular, the TARP 29-37-9V mutated epitope-enhanced peptide was selected due to its improved immunogenicity and cytolytic capability.…”

“…Indeed, they have been shown to elicit robust immune responses in mice, as well as in an ongoing Phase 1b/2 clinical trial. [44,[48][49][50] SNAs are comprised of highly oriented and densely packed oligodeoxynucleotides radially arranged around a nanoparticle core. SNAs are internalized by cells more rapidly and to greater extents than linear structures, and they do not require toxic ancillary transfection reagents.…”

“…Using this approach, vaccine structure has been shown to have a tremendous impact on the resulting efficacy and potency of the induced immune response. [44,48,49,[56][57][58] The consideration of structure in vaccine design postulates that previously unsuccessful clinical trials may not have failed due to the selected target, but rather because the vaccine did not deliver the components in a structure that elevated their immunogenicity. The ability to enhance vaccine efficacy through structure provides the field with an opportunity to analyze previously unsuccessful clinical candidates and reformulate them as potent vaccines.…”

Gene Regulation Using Spherical Nucleic Acids to Treat Skin Disorders

“…A similar SNA technology, "sticky-flares", uses longer antisense sequences that allow the fluorophore to remain bound to the transcript, enabling the tracking of mRNA movement in the cell and changes in gene expression in real time [40]. Rapidly proliferating cancer cells with high telomerase activity can be identified using SNA oligos functionalized with telomerase primers, while immune cells can be conditioned to target cancer cells by loading SNAs with cancer cell lysates or antigens [41][42][43]. Antibodies can be conjugated to the DNA or absorbed onto the SNA for cell-specific targeting [44].…”