Surface-Presentation of CpG and Protein-Antigen on Pathogen-Like Polymer Particles Generate Strong Prophylactic and Therapeutic Antitumor Protection.

Abstract

Despite significant efforts, development of clinically relevant prophylactic and therapeutic cancer vaccines has proven challenging. Cancer-associated antigens, which are often self-antigens, do not activate innate immune cells sufficiently, underscoring the need for codelivery of appropriate immune-stimulatory adjuvants. Recent research has underscored the need for biomaterial-based carriers for vaccine delivery, not only to target antigens and adjuvants to antigen-presenting cells or to create "depot" like systems but also to avoid acute systemic toxicity of molecular adjuvants that occurs when adjuvants are delivered in their "naked" form. The work presented here focuses on surface-presentation of both antigens and adjuvants on a pathogen-like particle (PLP) platform and understanding how PLP-induced antitumor responses differ when protein antigens and adjuvants, specifically the TLR9 agonist CpG, are delivered on the surface of the same particle (dual-loaded) versus being codelivered on separate particles. Surface-presentation allows easier access of antigens and adjuvants to intracellular targets (e.g., to TLR9 in the phagosomal compartments) and also allows controlled multivalent presentation. Our results show that, surface presentation, as opposed to soluble molecules, was more efficient in activating dendritic cells (DCs) and polarizing them toward generating a stronger cytotoxic T cell response. Signaling and DC polarization between separate and dual-loaded particles were similar, although NF-kB signaling at higher doses was stronger in dual-loaded PLPs. In vivo, dual loaded PLPs performed better than separately loaded PLPs in a prophylactic tumor model of melanoma and were comparable to immunization using incomplete Freud's adjuvant (IFA). In contrast both PLP-based delivery modalities performed similarly in a therapeutic melanoma-vaccine model and significantly outperformed IFA-based vaccination. These results indicate that surface-presentation of antigens and adjuvants on polymer-particles is a promising modality for efficient anticancer vaccines.