A wild-type sequence p53 peptide presented by HLA-A24 induces cytotoxic T lymphocytes that recognize squamous cell carcinomas of the head and neck

Evidence has accumulated indicating that HLA-A2-restricted CTLs specific fo r human wild-type sequence p53 epitopes lyse tumor cells expressing mutant p53, To explore the possibility that wild-type sequence p53 peptides could also be used in vaccines for patients expressing HLA-A24 antigen, another f requent HLA class I allele, we investigated the induction of RLA-A24-restri cted p53-specific CTLs from the peripheral blood lymphocytes of normal dono rs. Of six p53-derived peptides possessing an HLA-A24 binding moth, the p53 peptide 125-134 (p53(125-134)) was found to have a high binding capacity a nd induced peptide-specific CTLs from peripheral blood mononuclear cells, u sing peptide-pulsed autologous dendritic cells and subsequent cultivation w ith cytokines interleukin 2 and interleukin 7, Bulk CTL populations lysed p eptide-pulsed HLA-A24(+) targets as well as HLA-A24(+) squamous cell carcin oma of the head and neck (SCCHN) cell lines, However, IFN-gamma pretreatmen t of HLA-A24(+) SCCHN cell lines was necessary for lysis, suggesting that a ligand density higher than that normally expressed by tumor cells is requi red for these CTLs to mediate lysis, Moreover, a cloned CTL, designated TH# 99, isolated from the bulk population by limiting dilution, lysed HLA-A24() SCCHN targets more efficiently than the bulk CTL population, Lysis was in hibited by anti-HLA class I monoclonal antibody but not by anti-HLA-DR mono clonal antibody. These results indicate that HLA-A24-restricted CTLs recogn izing the wild-type sequence p53(125-134) can be generated using autologous dendritic cells from precursors present in peripheral blood lymphocytes ob tained from normal HLA-A24(+) donors. This finding suggests that vaccine st rategies targeting wild-type sequence p53 epitopes can be extended to a wid er range of cancer patients.