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.
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We thank Hans Stauss for providing some of the cell lines used in this paper. This work was supported by NIH PO1 23766, RO1 55349, F32-CA119479A, The Doris Duke Charitable Foundation, The Lymphoma Foundation, The William and Alice Goodwin Commonwealth Foundation for Cancer Research. JPI was an ASCO Young Investigator 03-04 and DAS is a Doris Duke Distinguished Clinical Scientist.
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Pinilla-Ibarz, J., May, R., Korontsvit, T. et al. Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein. Leukemia 20, 2025–2033 (2006). https://doi.org/10.1038/sj.leu.2404380
- WT1 peptides
- cancer vaccine
- peptide epitope
- cytolytic T cells
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