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Combinatorial Peptide Libraries as an Alternative Approach to the Identification of Ligands for Tumor-reactive Cytolytic T Lymphocytes¹

Torrey Pines Institute for Molecular Studies and Mixture Sciences, Inc., San Diego, California 92121 [C. P., R. A. H.]; Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital, 1011 Lausanne, Switzerland [V. R-G., V. D., J-C. C., P. R., D. V.]; Multidisciplinary Oncology Center, University Hospital, 1005 Lausanne, Switzerland [P. G.]; and Molecular Statistics and Bioinformatic Section, Biometric Research Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [R. S., Y. Z.]

The recent identification of molecularly defined human tumor antigens recognized by autologous CTLs has opened new opportunities for the development of antigen-specific cancer vaccines. Despite extensive work, however, the number of CTL-defined tumor antigens that are suitable targets for generic vaccination of cancer patients is still limited, mostly because of the painstaking and lengthy nature of the procedures currently used for their identification. A novel approach is based on the combined use of combinatorial peptide libraries in positional scanning format (positional scanning synthetic combinatorial peptide libraries, PS-SCLs) and tumor-reactive CTL clones. To validate this approach, we herein analyzed in detail the recognition of PS-SCLs by Melan-A-specific CTL clones. Our results indicate that, at least for some clones, most of the amino acids composing the native antigenic peptide can be identified through the use of PS-SCLs. Interestingly, this analysis also allowed the identification of peptide analogues with increased antigenic activity as well as agonist peptides containing multiple amino-acid substitutions. In addition, biometrical analysis of the data generated by PS-SCL screening allowed the identification of the native ligand in a public database. Overall, these data demonstrate the successful use of PS-SCLs for the identification and optimization of tumor-associated CTL epitopes.

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