Nearly 50% of oral cavity squamous cell carcinomas (OSCC) contain missense mutations in the p53 gene, making mutant p53 sequence peptides attractive candidates for cellular immunotherapy. The probability is greater, however, that tumors will present wild-type sequence peptides derived from mutant p53 molecules rather that mutant sequence peptides. Targeting wild- type sequence p53 does raise the possibility that such immunotherapy might induce an autoimmune response capable of responding to normal tissues, as well as an antitumor response. In a preclinical studies, however, a vaccine consisting of a wild-type sequence p53 peptide pulsed onto dendritic cells (DC) was shown in mice to be effective in inducing anti- tumor CTL which were not reactive against normal cells, and tumor rejection in the immunization and therapy settings. Recently, two human wild-type sequence peptides, p53 149-157 and p53 264-272, were identified as being naturally presented by tumors using anti-peptide CTL generated in HLA-A2.1-transgenic mice. To guide the clinical development of p53 peptide-based immunotherapy, we propose to generate anti-tumor CTL capable of recognizing these naturally presented epitopes by culturing peripheral blood lymphocytes (PBL) from HLA-A2.1+ individuals with autologous DC pulsed with the p53 peptides. We also propose that DC cultured with wild- type p53 protein will permit identification of additional T-cell-defined p53 epitopes presented by HLA-A2 and other class I HLA molecules, as well as class II molecules, thereby broadening the applicability of p53-based immunotherapy. Following establishment of the culture conditions required for in vitro induction of anti-p53 CTL, we intend to evaluate the generation of anti-p53 CTL from PBL obtained from the OSCC patients, prior to and following participation in clinical trials of p53 gene therapy and IL-12 protein and gene immunotherapy. An inherent part of this research will be to correlate these cellular studies with the anti-p53 humoral responses of these patients.
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