Cyclin B-1 As a Tumor-specific Antigen in Oral Carcinoma

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DESCRIPTION: The goal of this Program Project Grant (PPG) is continue development of novel vaccination strategies for human oral squamous cell carcinoma (OSCC) initiated 4 years ago. The current competitive renewal application is based on considerable progress in all aspects of the vaccine development process, including new antigen discovery, generation of helper and cytotoxic T cell responses to wild-type sequence (wt) p53 epitopes, determination of the frequency of tumor epitope-specific T cells in the peripheral circulation of patients with OSCC, and insights into cytokine-mediated protection of immune effector cells as well as mechanisms responsible for the sensitivity of T cells to apoptosis in the tumor environment. A clinical trial of a vaccine composed of autologous dendritic cells (DC) and apoptotic tumor cells (ATC) in patients with advanced OSCC is still in progress. Building on the knowledge gained in the last four years, we now plan to expand translational aspects of the Program and to bring the candidate vaccine epitopes to a pilot clinical trial. Research necessary to accomplish this goal will include pre-clinical evaluation of the candidate helper and cytotoxic epitopes individually and together for immunogenicity, using T cells obtained from normal donors and patients with OSCC; studies of overexpression of epitope-containing proteins in the tumor; determination of the frequency of the epitope-specific T cells, using tetramers and ELISPOT, in the circulation of OSCC patients and the ability of these T cells to respond to the natural and /or synthetic antigenic epitopes presented on autologous DC. To increase efficacy of potential vaccines, mechanisms of tumor-cell resistance to immune cells will be evaluated and strategies developed to overcome or diminish this resistance. Taking advantage of our discovery that aberrant expression in OSCC of cyclin B1 protein is p53 dependent, a pre-clinical model in p53 knockout mice, which spontaneously develop tumors, will be used to study protective as well as therapeutic effects of cyclin B1-based vaccines. This will allow us to evaluate cyclin B1 and its peptides as prophylactic vaccines. Therapeutic goals include a pilot vaccination trial for patients with OSCC to be treated later in the program with the optimized T-cell defined antigen(s). The ongoing DC/ATC trial and p53-based vaccination trials at NCI will provide specimens for testing of immune responses to the vaccine. Three projects and two cores (Tissue Procurement/DC Laboratory and Clinical Support/Biostatistics) comprise the Program. This Program Project has a long-term objective of improving survival of OSCC patients through novel vaccination strategies.