Peptide-based polymer Toll-Like Receptor 7/8 agonist nanoparticles increase the breadth of anti-tumor CD8 T cell immunity

Abstract

Abstract Targeting tumor specific neoantigens through personalized therapeutic vaccination is a promising approach to induce T cell immunity against a variety of tumors. Current vaccine formulations induce CD8 T cell responses against a limited subset of pre-selected neoantigens. We developed a novel vaccine platform to enhance the breadth and magnitude of CD8 T cell responses by chemically coupling synthetic neoantigen peptides to a synthetic polymer containing a toll-like receptor-7/8 agonist that self-assembles into nanoparticles (termed SPP-7/8a). To test the efficiency of the SPP-7/8a platform for inducing antigenic breadth, 173 transcribed non-synonymous single nucleotide variants were identified in a mouse melanoma tumor line (SB-3123). Mice were vaccinated twice with a random set of 96 SB-3123 neoantigens with SPP-7/8a. The binding affinity was predicted for each neoantigen using the Immune Epitope Database and Analysis Resource (IEDB.org) Consensus algorithm, which ranged from the 0.15 to 3.05 percentile. Overall, CD8 T cell responses were detectable at frequencies ranging from 0.1% to 16% of total CD8 T cells against 10 of the 96 neoantigens (~10%). However, by stratifying the 96 neoantigens according to high affinity binders (Consensus < 0.5), 7/14 (50%) induced CD8 T cell responses. These data show that the SPP-7/8a platform efficiently induces CD8 T cell using peptides that have high binding affinity. Ongoing studies will determine whether the increased breadth of CD8 responses following SPP-7/8a vaccination confers protection against established tumors.