An optimized peptide vaccine strategy capable of inducing multivalent CD8⁺ T cell responses with potent antitumor...

Therapeutic cancer vaccines are an attractive alternative to conventional therapies for treating malignant tumors, and successful tumor eradication depends primarily on obtaining high numbers of long-lasting tumor-reactive CD8⁺ T cells. Dendritic cell (DC)-based vaccines constitute a promising approach for treating cancer, but in most instances low immune responses and suboptimal therapeutic effects are achieved indicating that further optimization is required. We describe here a novel vaccination strategy with peptide-loaded DCs followed by a mixture of synthetic peptides, polyinosine-polycytidylic acid (poly-IC) and anti-CD40 antibodies (TriVax) for improving the immunogenicity and therapeutic efficacy of DC-based vaccines in a melanoma mouse model. TriVax immunization 7-12 d after priming with antigen-loaded DCs generated large numbers of long-lasting multiple antigen-specific CD8⁺ T cells capable of recognizing tumor cells. These responses were far superior to those generated by homologous immunizations with either TriVax or DCs. CD8⁺ T cells but not CD4⁺ T cells or NK cells mediated the therapeutic efficacy of this heterologous prime-boost strategy. Moreover, combinations of this vaccination regimen with programmed cell death-1 (PD-1) blockade or IL2 anti-IL2 antibody complexes led to complete disease eradication and survival enhancement in melanoma-bearing mice. The overall results suggest that similar strategies would be applicable for the design of effective therapeutic vaccination for treating viral diseases and various cancers, which may circumvent current limitations of cell-based cancer vaccines.