The genetic instability of cancers leads to mutations in protein coding DNA that can give rise to mutant peptides, referred to as neoantigens. Peptide-based neoantigens combined with immunostimulatory molecules (i.e. Adjuvants) offer a personalized vaccine approach for eliciting cancer-specific T cells that can mediate tumor clearance. However, the broad range of peptide neoantigen properties (e.g., solubility, charge, length, etc.) presents challenges for ensuring formulation consistency and reliable priming of T cell immunity. To address these challenges, we developed a standardized approach for delivering peptide neoantigens in self-assembling nanoparticles that co-deliver Toll-like receptor-7/8 agonists (TLR-7/8a). Our approach was to append peptide neoantigens with a tag sequence that binds to a complementary tag on particle-forming polymer TLR-7/8a conjugates, which together undergo particle formation under controlled conditions. Through systematic optimization of the tags and polymer physical and chemical properties, we show that reliable nanoparticle assembly and priming of T cell immunity can be achieved for peptide neoantigens representing the extremes of peptide neoantigen charge and hydrophobicity. To assess generalizability, we evaluated the hydrodynamic behavior and <i>in vivo</i> immune responses of over 100 peptides-based neoantigens from four mouse tumor models using our approach. We show that peptides co-delivered with TLR-7/8a in nanoparticles optimized for size and charge permit an ~ 20-40-fold increase in the magnitude of CD8 T cell responses against several peptide-based neoantigens that were previously reported to be non-immunogenic. Studies to understand the <i>in vivo</i> mechanism for improved T cell immunogenicity showed that the self-assembling nanoparticle carriers of peptides and TLR-7/8a improved antigen durability and uptake by dendritic cells, as well as enhanced the magnitude and persistence of cytokines (i.e., IL-12, Type I Interferons) in lymph nodes draining the sites of immunization. Altogether, our data show how a chemically defined adjuvant delivery platform can maximize the breadth and potency of T cell immunity with peptide neoantigens.

Synthetic polymers delivering peptide neoantigens and TLR-7/8 agonists as personalized cancer vaccines

253rd National Meeting (2017)

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