Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein Journal Article

Authors: Pinilla-Ibarz, J.; May, R. J.; Korontsvit, T.; Gomez, M.; Kappel, B.; Zakhaleva, V.; Zhang, R. H.; Scheinberg, D. A.
Article 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.
Keywords: child; oncoprotein; human cell; t lymphocyte; t-lymphocytes; reverse transcription polymerase chain reaction; amino acid substitution; protein binding; cancer cell culture; cytotoxicity; in vitro study; cell line, tumor; chronic myeloid leukemia; prediction; rna; lymphocyte activation; immune tolerance; hla matching; amino acid sequence; gamma interferon; cancer vaccine; cancer vaccines; quantitative analysis; molecular recognition; immunogenicity; peptide fragments; cytotoxic t lymphocyte; wt1 protein; cross reaction; enzyme linked immunospot assay; major histocompatibility complex; hla-a antigens; leukemia cell line; major histocompatibility antigen class 1; antigens, cd8; peptide derivative; epitopes; wt1 proteins; rna isolation; interferon type ii; leukemia, myeloid, chronic; chromium 51
Journal Title: Leukemia
Volume: 20
Issue: 11
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2006-11-01
Start Page: 2025
End Page: 2033
Language: English
DOI: 10.1038/sj.leu.2404380
PUBMED: 16990779
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 26" - "Export Date: 4 June 2012" - "CODEN: LEUKE" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Rena J May
    9 May
  2. Marta Gomez
    11 Gomez
  3. Rong Hua Zhang
    18 Zhang
  4. Barry J Kappel
    28 Kappel
  5. Javier Pinilla
    30 Pinilla