| dc.description.abstract | Immune checkpoint blockade (ICB) has revolutionized cancer treatment and has led to complete and durable responses, but only for a minority of patients. Resistance to ICB can largely be attributed to insufficient number and/or function of anti-tumor CD8+ T cells in the tumor microenvironment. Neoantigen targeted cancer vaccines can activate and expand this T cell repertoire, but historically clinical responses have been poor as immunity against peptide antigens is typically weak. Herein, we describe a nanoparticle vaccine platform that can overcome these barriers in several ways. First, we utilized a scalable method to formulate pH-responsive nanoparticles that are monodisperse, less than 100nm in diameter, and can co-load a variety of peptide neoantigens and adjuvants. Next, the nanocarrier promotes lymphatic drainage, coordinates delivery of antigen and adjuvant(s) into the same antigen presenting cell, and delivers the antigen to the cytosol of the cell which promotes cross-presentation on MHC class I molecules and the downstream CD8+ T cell response. Lastly, we encapsulated synergistic adjuvants, cGAMP and MPLA, into the nanocarrier to induce a more robust innate immune response and increase peptide immunogenicity. We found that the nanovaccine that incorporated both adjuvants synergistically enhanced expression of dendritic cell activation and co-stimulatory markers, pro-inflammatory cytokine secretion, and peptide antigen cross-presentation. Additionally, the nanoparticle platform increased lymphatic drainage and uptake of the peptide neoantigen by immune cells in the lymph node as compared to soluble peptide. Consequently, it enhanced the antigen-specific CD8+ T cell response and delayed tumor growth in several murine tumor models. Finally, it improved efficacy of ICB in a murine colon carcinoma model. Overall, the work in this dissertation provides a proof-of-concept nanovaccine platform that can incorporate synergistic adjuvants to provide a robust anti-tumor CD8+ T cell response and significantly enhance therapeutic efficacy. | |
