Carcinoembryonic antigen (CEA) is a common tumor-associated antigen. Several T-cell specific epitopes have been identified within the terminal repeat domains of CEA, suggesting that CEA may be a target for vaccine development. These epitopes have been identified by computer based predictions of consensus binding motifs to human HLA molecules. However, there is currently no evidence that these """"""""predicted"""""""" epitopes are actually relevant to in vivo priming of T-cell responses. These peptides usually exhibit high binding affinity to MHC, while presentation of lower affinity epitopes may be more relevant for initiating T-cell responses by self-antigens. Dr. Howard Kaufman has extensive postdoctoral training in the development of CEA-specific vaccines. His appointment at the Albert Einstein provides him with an extraordinary center of excellence in immunology. He is a member of the comprehensive cancer center and has been provided with lab space, protected research time, access to core facilities, and membership in the interdisciplinary Immuno-Oncology program. Dr. Stan Nathenson is a senior faculty member and a recognized expert in MHC structure and antigen presentation. Dr.Nathenson has agreed to collaborate with Dr. Kaufman on a project to identify more biologically relevant CEA epitopes. This will be accomplished using a biochemical immunoaffinity method for selecting specific peptides as developed by Dr. Nathenson. Since techniques for generating large numbers of antigen-presenting cells from humans is not practical, a murine model will be utilized. A human HLA-A2 transgenic mouse will be used to establish a stable dendritic cell population, which can be vaccinated with CEA and subjected to peptide elution after antigen presentation. Bulk T- cells derived from these mice will be used to identify specific peptides. The peptides will be sequenced and characterized for affinity binding and recognition by human T-cells. This project will identify novel CEA epitopes that may have more biological relevance for tumor vaccine development. The murine system may also have broader application in the isolation of epitopes from other antigens and by other HLA molecules. Dr. Kaufman will benefit in learning the experimental procedures developed by Dr. Nathenson as they pertain to peptide purification. Ultimately, this will strengthen his long-term goals of establishing a basic tumor immunology laboratory dedicated to tumor vaccine development.
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