Novel adjuvant therapies for head and neck cancer (HNC) are urgently needed, since the survival from this disease has not improved significantly in over 30 years. Recent advances in the development of antitumor vaccines have created an opportunity for evaluation of such vaccines in patients with SCCHN. In general, many shared human tumor antigens are derived from proteins overexpressed in tumors relative to normal cells. Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers, but mutant p53-based immunotherapy would require 'custom made' vaccines for use in relatively few patients. Since most mutations of p53, however, are associated with accumulation or 'over expression' of mutant p53 in the tumor cytosol, the protein is readily accessible to degradation into peptides for immune recognition. Thus, a vaccine targeting wt p53 peptides derived not from the specific mutations but from normal epitopes in the altered p53 molecules appears to be a more attractive approach to developing broadly applicable p53-based cancer vaccines. Based on our preliminary results, we propose a phase I clinical trial of a DC-based multi-epitope wt p53 vaccine that contains two HLA-A*0201 (HLA-A2.1)-restricted Tcell- defined p53 peptides plus either a wt p53 or nonspecific helper peptide. This project also includes extensive ex vivo immunological analyses of the SCCHN patients' responses to immunization as well as tumor characterization to determine whether the tumor is capable of presenting the targeted wt p53 epitopes. Preclinical work developing another wt p53 T helper peptide, with broader HLA binding will also be performed. Results from the in vitro analyses and immunologic responses to the phase I vaccine trial will be combined to facilitate the continued development of p53-based immunotherapy for SCCHN, enabling the design of a future phase II wt p53-based vaccine trial.
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