Personalized cancer vaccines (PCVs) targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing PCVs in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform ("SNP-7/8a") based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles that increased uptake by and activation of antigen-presenting cells that promote T cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n=179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in non-human primates. Altogether, SNP-7/8a is a generalizable approach for co-delivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T cell immunity.

Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a TLR7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8 + T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1 + PD-1 + CD8 + T cells compared to subcutaneous immunization (SNP-SC). Single cell RNA-seq showed that SNP-IV induced stem-like genes ( Tcf7, Slamf6, Xcl1 ) whereas SNP-SC enriched for effector genes ( Gzmb, Klrg1, Cx3cr1) . Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade leading to superior antitumor response compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8 + T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8 + T cells.

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