Targeting KRAS G12V mutation in pancreatic cancer with heterologous peptide vaccination

The incidence of pancreatic cancer related mortality is rising globally - predicted to become the second leading cause of cancer related deaths worldwide. KRAS is an initiating driver mutation in pancreatic ductal adenocarcinoma (PDAC) seen in 90% of cancers. Most KRAS mutations occur at codon 12, of which the single amino acid transitions from glycine to valine (G12V). To target KRAS G12V, we employ a novel heterologous vaccination namely DC-CoAT, consisting of a primary immunization with peptide-pulsed dendritic cells (DC) followed by a composite boost, with agonistic CD40 antibody, peptide antigen, and a TLR3 agonist, referred to as CoAT. With this patented vaccination, we observed the induction of strong immune responses for two lengths of mutated KRAS G12V peptides (9-mer and 10-mer epitopes). Of these, the KRAS G12V10-mer surpassed the immune responses induced by the 9-mer peptide by generation of 50% antigen specific CD8 T cells. Upon challenging our vaccination against tumor models, we observe increased frequencies of immune responses in mice receiving therapy compared to immunized controls. These induced CD8 T cells infiltrated subcutaneous tumors at high percentages and prolonged overall survival in an autochthonous tumor model. Moreover, we found that survival of the vaccinated mice depends upon the strength of the induced immune response. Immunotherapy approaches for targeting PDACs have limited benefits attributed to their immunosuppressive microenvironment but primarily a lack of good targets. In our work, we describe a novel combination of MHC molecule HLA-A11:01 and driver mutation KRAS G12V  for targeting PDACs by means of vaccination.