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Generation of Cytotoxic T Lymphocytes against Native and Altered Peptides of Human Leukocyte Antigen-A*0201 Restricted Epitopes from the Human Epithelial Cell Adhesion Molecule¹

Department of Adult Oncology, Dana Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 02114 Boston, Massachusetts [A. T., M. W., J. L. S., R. H. V., S. H., A. M. K., J. G. G.], and Division of Oncology, University Hospital, 8044 Zurich, Switzerland [A. T., R. A. S.]

A growing number of human tumor antigens have been described that can be recognized by CTLs in a MHC class I restricted fashion. The epithelial cell adhesion molecule (Ep-CAM) is expressed in a variety of human tumors and has attracted attention as a therapeutic target for monoclonal antibody serotherapy. We have identified immunogenic peptides derived from Ep-CAM, that bind to human leukocyte antigen-A*0201 and elicit strong peptide-specific human CTL responses, demonstrating that there is an effective T-cell repertoire against these Ep-CAM-derived peptides that can be recruited. Alterations to these peptides were made to increase their binding affinity to MHC class I molecules. The use of such "heteroclitic" peptides allowed generation of cytotoxic T cells that demonstrated increased killing of target cells pulsed not only with the heteroclitic but also with the native peptide. Most important, CTL cell lines that are generated against these peptides specifically lyse epithelial tumor cells expressing Ep-CAM but not normal hematopoietic or bronchial epithelial cells.

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