title: Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein.
abstract: Wilms tumor protein 1 (WT1) is a transcription factor overexpressed in several types of leukemia and solid tumors. For this reason, WT1 is an attractive target for immunotherapy. Four peptide nonamers from WT1 have been identified by others to generate a WT1-specific cytotoxic response in the context of human leukocyte antigen (HLA)-A0201 and A2402. However, as WT1 is a self-antigen, breaking tolerance is a potential obstacle to vaccination. Here, we use a strategy to circumvent tolerance by designing synthetic immunogenic analog peptides that could crossreact to the native peptides (a heteroclitic response). A number of synthetic peptides derived from nonamer sequences of the WT1 protein were designed in which single amino-acid substitutions were introduced at HLA-A0201 major histocompatibility complex (MHC)-binding positions. Several of new peptides could stabilize MHC class I A0201 molecules better than native sequences. Some analogs were also able to elicit WT1-specific T-cell recognition and cytotoxic T-cell lymphocytes more effectively than native sequences. Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pinilla-Ibarz
authors.forename: R J
authors.initials: RJ
authors.lastname: May
authors.forename: T
authors.initials: T
authors.lastname: Korontsvit
authors.forename: M
authors.initials: M
authors.lastname: Gomez
authors.forename: B
authors.initials: B
authors.lastname: Kappel
authors.forename: V
authors.initials: V
authors.lastname: Zakhaleva
authors.forename: R H
authors.initials: RH
authors.lastname: Zhang
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000595:Amino Acid Sequence; D016827:CD8 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; D019496:Cancer Vaccines; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D025721:WT1 Proteins; D007371:Interferon-gamma