A p53 peptide mucosal vaccine induces cellular and humoral immunity and anti-tumor effects in a murine colorectal cancer model

Many patients with metastatic and recurrent colorectal cancer (CRC) have poor outcomes, due in part to resistance to current treatment approaches including immune checkpoint inhibitors, which have activity in only a subset of patients. Missense mutations in the TP53 gene are found in about 65% of CRCs, but no current treatment approach targets mutant TP53 activity. To develop a vaccine approach against CRCs expressing a mutant p53 protein, we used a murine CRC model with conditional expression of a Trp53 codon R270H missense allele, and immunized mice with the experimental vaccine, which combined a synthetic R270H p53 peptide and wild type p53 recombinant protein with a mucosal nanoemulsion (NE) adjuvant to enhance epithelial immune responses. The p53/NE vaccine was administered intranasally to the mice after mutant p53 induction and tumor initiation. Animals vaccinated with the vaccine had markedly increased serum anti-p53 IgG, IgG2a, and IgG2b as compared to mice treated with NE alone or PBS. The vaccination also enhanced antigen-specific Th1 and Th17 cellular immune responses, as shown by increasing production of IFNγ, IL-17a and IL-2. The immunized animals had significantly decreased tumor size/volume, prolonged survival and increased tumor CD8 ⁺ T cell infiltrates. Collectively, we have demonstrated a mucosal vaccine approach against mutated p53 protein in CRC can induce antigen-specific cellular and humoral immunity that is associated with increased tumor CD8 ⁺ T cell infiltrates, reduced tumor volumes and enhanced survival. The findings suggest potential value in pursuing mutated p53 as a vaccine target in CRC.