Since mutant p53 gene products are often over expressed in tumors, enhanced class I MHC-presentation of p53-derived peptides from wild type sequence portions of these molecules might also occur. The recent finding that human tumors present p53-derived wild type sequence peptides derived from over expressed mutated p53 confirms the potential of p53 peptide-based immunotherapy, which also raises the possibility that such therapy might induce undesirable """"""""anti-self"""""""" responses, as well. While there is a noticeable lack of comparable naturally processed murine CTL-defined tumor peptides to guide the design and development of clinical protocols, a murine p53 wild type sequence peptide p53 232-240 (residues 232-240) was identified as an H-2kd binding peptide, and a dendritic cell-based vaccine developed in the applicant's laboratory. Immunization of mice with this vaccine induced anti-tumor CTL, and tumor rejection in immunization and therapy settings (Mayordomo et al. J. Exp. Med. 1996 in press), in the absence of any apparent undesirable side effects. The applicant proposes to further investigate the biological characteristics and therapeutic potential of the p53232-240 peptide immunization, particularly in regard to the nature of anti-tumor CTL induced. The applicant proposes a series of experiments aimed at optimizing the efficacy of this vaccine in inducing anti-tumor immune responses, while avoiding the induction of undesired """"""""anti-self"""""""" responses. In addition, as a preclinical model for studying the impact a cancer vaccine might have on tumor development, the applicant proposes to investigate the effects that p53232-240 peptide-based immunization has on chemical carcinogenesis in mice.
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