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University of Pittsburgh Cancer Institute [K. C., K. N., W. J. S., M. T. L., T. L. W., A. B. D.], Divisions of Basic Research [A. B. D.] and Biological Therapeutics [W. J. S., M. T. L., T. L. W.], and the Departments of Molecular Genetics and Biochemistry [W. J. S., M. T. L.], Otolaryngology [T. L. W.], Pathology [W. J. S., T. L. W., A. B. D.], and Surgery [W. J. S., M. T. L.], School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and the National Cancer Institute, Bethesda, Maryland 20892 [E. A.]
CTLs recognizing the HLA-A2.1-restricted, wild-type sequence p53 epitopes p53149–157 and p53264–272 were generated from CD8-enriched populations of nonadherent peripheral blood lymphocytes (PBLs) obtained from healthy donors. The PBLs were restimulated in vitro with peptide-pulsed granulocyte macrophage colony-stimulating factor- and interleukin (IL)-4-induced autologous dendritic cells in the presence of IL-6 and IL-12 and subsequently cultivated with IL-1
, IL-2, IL-4, IL-6, and IL-7. Bulk anti-p53264–272 CTL populations were generated from PBLs obtained from two of five donors. Both CTL populations were cytotoxic against peptide-pulsed HLA-A2+ target cells, but not against untreated target cells. A CD8+ anti-p53 CTL clone designated p264#2 was isolated from one of the bulk populations. It was found to have an intermediate affinity of approximately 10-9M for the epitope and to mediate cytotoxicity against several human tumor cell lines, including the squamous cell carcinoma of the head and neck cell line SCC-9, which is known to present the wild-type sequence p53264–272 epitope. In addition, CTLs reactive against p53149–157-pulsed targets as well as a HLA-A2+ tumor cell line were cloned from a bulk population of antitumor CTLs obtained from one of the five normal PBLs restimulated with this epitope. The results indicate that CTLs recognizing wild-type sequence epitopes can be generated from precursors present in PBLs obtained from some normal individuals using autologous dendritic cells as antigen-presenting cells and suggest that vaccine strategies targeting these epitopes can lead to antitumor CTL generation, thereby emphasizing the therapeutic potential of p53-based cancer vaccines.
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