Peptide epitopes from the Wilms' tumor 1 oncoprotein stimulate CD4 + and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells Journal Article

  

Authors:	May, R. J.; Dao, T.; Pinilla-Ibarz, J.; Korontsvit, T.; Zakhaleva, V.; Zhang, R. H.; Maslak, P.; Scheinberg, D. A.
Article Title:	Peptide epitopes from the Wilms' tumor 1 oncoprotein stimulate CD4 + and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells
Abstract:	Purpose: Wilms' tumor 1 protein (WT1), a transcription factor overexpressed in malignant mesothelioma, leukemias, and other solid tumors, is an ideal target for immunotherapy. WT1 class I peptide epitopes that were identified and shown to stimulate CD8+ T cells are being tested as vaccine candidates in several clinical trials. The induction and maintenance of a robust memory CD8+ cytotoxic T-cell response requires CD4+ T-cell help. Experimental Design: Three HLA class II peptide epitopes of WT1 with high predictive affinities to multiple HLA-DRB1 molecules were identified using the SYFPEITHI algorithm. Due to the highly polymorphic nature of the HLA class II alleles, such reactivity is critical in the development of a broadly useful therapeutic. One of the WT1 CD4+ peptide epitopes, 122-140, comprises a previously identified CD8+ peptide epitope (126-134). By mutating residue 126 from an arginine to a tyrosine, we embedded a synthetic immunogenic analogue CD8+ epitope (126-134) inside the longer peptide (122-140). This analogue was previously designed to improve immunogenicity and induce a potent CD8+ response. Results: WT1 peptides 328-349 and 423-441 are able to stimulate a peptide-specific CD4+ response that can recognize WT1+ tumor cells in multiple HLA-DRB1 settings as determined by IFN-γ enzyme-linked immunospot assays. The mutated WT1 peptide epitope 122-140 is able to induce CD4+ and cytotoxic CD8 + WT1-specific T-cell responses that can recognize the native WT1 epitopes on the surface of human WT1+ cancer cells. Cross-priming experiments showed that antigen-presenting cells pulsed with either mesothelioma or leukemia tumor lysates can process and present each of the CD4+ peptides identified. Conclusions: These studies provide the rationale for using the WT1 CD4+ peptides in conjunction with CD8+ peptide epitopes to vaccinate patients with WT1-expressing cancers. © 2007 American Association for Cancer Research.
Keywords:	controlled study; leukemia; human cell; mutant protein; binding affinity; cd8+ t lymphocyte; cell proliferation; cd8-positive t-lymphocytes; t-lymphocytes; amino acid substitution; tumor cells, cultured; dendritic cells; amino acid sequence; gamma interferon; algorithm; reverse transcriptase polymerase chain reaction; hla antigen class 2; hla dr antigen; cd4+ t lymphocyte; cd4-positive t-lymphocytes; hla-dr antigens; peptide fragments; epitope; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; malignant mesothelioma; mesothelioma; wt1 protein; enzyme linked immunospot assay; antigen presenting cell; t lymphocyte activation; immunization; memory t lymphocyte; immunopharmacology; epitopes; wt1 proteins; interferon type ii; chromium
Journal Title:	Clinical Cancer Research
Volume:	13
Issue:	15
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2007-08-01
Start Page:	4547
End Page:	4555
Language:	English
DOI:	10.1158/1078-0432.ccr-07-0708
PUBMED:	17671141
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-34547660192&partnerID=40&md5=47ea61abd541df19fd1ba397e5f9e933
Notes:	--- - "Cited By (since 1996): 20" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"

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