(391d) Polyanhydride Nanoparticles Activate Dendritic Cells and Enhance CD8+ T Cell Memory Response Leading to Delayed Tumor Progression

In addition to conventional chemotherapy and checkpoint inhibitor therapy, effective immunotherapies are required for eliminating malignancies. Cytotoxic T cell responses are critical for providing protection against tumors. There is a need for new vaccine regimens that can activate antigen presenting cells (APCs) leading to the induction of effective cell-mediated immunity. Currently approved vaccine adjuvants such as alum, oil-in-water emulsions or the widely studied TLR adjuvants have not been proven successful in this context. In addition, innate immune stimulating adjuvant-associated inflammation and the production of innate immune effector molecules such as nitric oxide (NO) have been shown to impair CD8+ T cell effector and memory functions and APC activation. Particularly, dendritic cells (DCs) have been reported to have altered metabolism, decreased survival and impaired co-stimulatory upregulation in the presence of excess NO. Therefore, adjuvants capable of generating a large number of memory CD8+ T cell populations in a single dose without inducing an overt inflammatory response can prove to be beneficial.

Polyanhydride nanoparticle-based vaccines consisting of 1,6-bis(p-carboxyphenoxy) hexane (CPH), and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctante (CPTEG) can provide a unique alternative to existing cancer vaccines. These nanoparticles are easily phagocytosed by DCs and provide upregulation of co-stimulatory molecules. They also persist in the local tissues providing a controlled release of their encapsulated payload. In this study, the ability of these nanoparticles to activate DCs and induce an effective memory CD8+ T cell response was demonstrated using an antigen-specific tumor challenge model where protection is restricted to only CD8+ T cell-mediated responses. Nanoparticles, most notably, activated CD8α+ DCs, which are important for cross-priming, without the secretion of large amounts of pro-inflammatory cytokines and chemokines such as TNF, CXCL9, and CXCL10. Nanoparticles did not drive metabolic changes in DCs or induce production of NO. Immunization with a single dose of nanoparticles encapsulating low doses of a model tumor antigen, ovalbumin, induced a protective CD8+ T cell memory response, decreased tumor progression, and increased time on study. The induction of memory responses was also found to be more efficacious in mice immunized with nanoparticles than animals immunized with the TLR9 agonist, CpG, which supports our hypothesis that the effects of differentially inflammatory adjuvants can alter vaccine efficacy.

Collectively, these results suggest that polyanhydride-based nanovaccine platform represents an effective prophylactic approach towards generating antigen-specific CD8+ T cell memory and preventing tumor progression without being overtly inflammatory, which is commonly associated with other adjuvants.