A nanoparticle vaccine that targets neoantigen peptides to lymphoid tissues elicits robust antitumor T cell responses

Cancer vaccines using synthetic long peptides (SLP) targeting tumor antigens have been tested in the clinic but outcomes have been unimpressive, potentially because these peptides elicit predominantly CD4+ T cell responses. The authors hypothesized that enhanced delivery of peptide antigens to, and uptake in, secondary lymphoid tissues should elicit more robust CD8+ and CD4+ T cell responses and improve anti-tumor responses. They designed SLP-containing cationic lipoplexes (SLP-Lpx) that improve delivery of peptides to myeloid cells in the spleen and lymphatics. Using KRAS G12D mutations as neoantigens, vaccination of mice with naked synthetic peptides plus CpG primarily stimulated CD4+ T cells with limited tumor growth inhibition, whereas SLP-Lpx stimulated both CD4+ and CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner. Combining SLP-Lpx with a checkpoint inhibitor led to profound growth suppression of established tumors. Preferential targeting of neoantigen-derived peptides to the spleen via lipoplexes elicits potent CD4+ and CD8+ T cell responses that inhibit tumor growth.