1. Academic Validation
  2. Peptide epitopes from the Wilms' tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells

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

  • Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4547-55. doi: 10.1158/1078-0432.CCR-07-0708.
Rena J May 1 Tao Dao Javier Pinilla-Ibarz Tatyana Korontsvit Victoriya Zakhaleva Rong H Zhang Peter Maslak David A Scheinberg
Affiliations

Affiliation

  • 1 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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-gamma 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.

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