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Peptide Epitopes from the Wilms' Tumor 1 Oncoprotein Stimulate CD4⁺ and CD8⁺ T Cells That Recognize and Kill Human Malignant Mesothelioma Tumor Cells

Authors' Affiliations: ¹ Molecular Pharmacology and Chemistry Program and ² Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: David A. Scheinberg, Molecular Pharmacology and Chemistry Program and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8635; Fax: 212-717-3068; E-mail: d-scheinberg{at}ski.mskcc.org.

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- 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.