PMID- 16990779
OWN - NLM
STAT- MEDLINE
DCOM- 20061205
LR  - 20201226
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 20
IP  - 11
DP  - 2006 Nov
TI  - Improved human T-cell responses against synthetic HLA-0201 analog peptides 
      derived from the WT1 oncoprotein.
PG  - 2025-33
AB  - 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.
FAU - Pinilla-Ibarz, J
AU  - Pinilla-Ibarz J
AD  - Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer 
      Center, New York, NY 10021, USA.
FAU - May, R J
AU  - May RJ
FAU - Korontsvit, T
AU  - Korontsvit T
FAU - Gomez, M
AU  - Gomez M
FAU - Kappel, B
AU  - Kappel B
FAU - Zakhaleva, V
AU  - Zakhaleva V
FAU - Zhang, R H
AU  - Zhang RH
FAU - Scheinberg, D A
AU  - Scheinberg DA
LA  - eng
GR  - F32-CA119479A/CA/NCI NIH HHS/United States
GR  - P01 23766/PHS HHS/United States
GR  - R01 55349/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060831
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (CD8 Antigens)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Epitopes)
RN  - 0 (HLA-A Antigens)
RN  - 0 (HLA-A*02:01 antigen)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Peptide Fragments)
RN  - 0 (WT1 Proteins)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Amino Acid Sequence
MH  - CD8 Antigens/immunology
MH  - Cancer Vaccines/*immunology
MH  - Cell Line, Tumor
MH  - Epitopes/immunology
MH  - HLA-A Antigens/*immunology/metabolism
MH  - HLA-A2 Antigen
MH  - Humans
MH  - Immune Tolerance/immunology
MH  - Interferon-gamma/metabolism
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology/*therapy
MH  - Peptide Fragments/chemical synthesis/*immunology/metabolism
MH  - Protein Binding/immunology
MH  - T-Lymphocytes/cytology/*immunology/metabolism
MH  - WT1 Proteins/*genetics/metabolism
EDAT- 2006/09/23 09:00
MHDA- 2006/12/09 09:00
CRDT- 2006/09/23 09:00
PHST- 2006/09/23 09:00 [pubmed]
PHST- 2006/12/09 09:00 [medline]
PHST- 2006/09/23 09:00 [entrez]
AID - 2404380 [pii]
AID - 10.1038/sj.leu.2404380 [doi]
PST - ppublish
SO  - Leukemia. 2006 Nov;20(11):2025-33. doi: 10.1038/sj.leu.2404380. Epub 2006 Aug 31.