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or tumor Ag-derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2-1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely responsible for improved binding. The best CPLs displayed enhanced affinity for MHC, increasing MHC stability and prolonging recognition by Ag-specific T cells and, most importantly, they induced accelerated expansion of antitumor T cell frequencies in vitro and in vivo as compared with the native epitope. Eventually, we were able to construct a toolbox of preferred nonproteogenic residues with which practically any given HLA-A*02 restricted epitope can be readily optimized. These CPLs could improve the therapeutic outcome of vaccination strategies or can be used for ex vivo enrichment and faster expansion of Ag-specific T cells for transfer into patients.","bibjson":{"author":[{"initials":"R","lastname":"Hoppes","name":"Hoppes R"},{"initials":"R","lastname":"Oostvogels","name":"Oostvogels R"},{"initials":"JJ","lastname":"Luimstra","name":"Luimstra JJ"},{"initials":"K","lastname":"Wals","name":"Wals K"},{"initials":"M","lastname":"Toebes","name":"Toebes M"},{"initials":"L","lastname":"Bies","name":"Bies L"},{"initials":"R","lastname":"Ekkebus","name":"Ekkebus R"},{"initials":"P","lastname":"Rijal","name":"Rijal P"},{"initials":"PH","lastname":"Celie","name":"Celie PH"},{"initials":"JH","lastname":"Huang","name":"Huang JH"},{"initials":"ME","lastname":"Emmelot","name":"Emmelot ME"},{"initials":"RM","lastname":"Spaapen","name":"Spaapen RM"},{"initials":"H","lastname":"Lokhorst","name":"Lokhorst H"},{"initials":"TN","lastname":"Schumacher","name":"Schumacher TN"},{"initials":"T","lastname":"Mutis","name":"Mutis T"},{"initials":"B","lastname":"Rodenko","name":"Rodenko B"},{"initials":"H","lastname":"Ovaa","name":"Ovaa H"}],"identifier":[{"id":"10.4049/jimmunol.1400800","type":"doi"},{"id":"25311806","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. 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