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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.
Clin Cancer Res 2007; 13(15 Pt 1):4547-55CC

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.

Authors+Show Affiliations

Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17671141

Citation

May, Rena J., et al. "Peptide Epitopes From the Wilms' Tumor 1 Oncoprotein Stimulate CD4+ and CD8+ T Cells That Recognize and Kill Human Malignant Mesothelioma Tumor Cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 13, no. 15 Pt 1, 2007, pp. 4547-55.
May RJ, Dao T, Pinilla-Ibarz J, et al. 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;13(15 Pt 1):4547-55.
May, R. J., Dao, T., Pinilla-Ibarz, J., Korontsvit, T., Zakhaleva, V., Zhang, R. H., ... Scheinberg, D. A. (2007). Peptide epitopes from the Wilms' tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 13(15 Pt 1), pp. 4547-55.
May RJ, et al. 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. PubMed PMID: 17671141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peptide epitopes from the Wilms' tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells. AU - May,Rena J, AU - Dao,Tao, AU - Pinilla-Ibarz,Javier, AU - Korontsvit,Tatyana, AU - Zakhaleva,Victoriya, AU - Zhang,Rong H, AU - Maslak,Peter, AU - Scheinberg,David A, PY - 2007/8/3/pubmed PY - 2007/10/30/medline PY - 2007/8/3/entrez SP - 4547 EP - 55 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 13 IS - 15 Pt 1 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/17671141/Peptide_epitopes_from_the_Wilms'_tumor_1_oncoprotein_stimulate_CD4+_and_CD8+_T_cells_that_recognize_and_kill_human_malignant_mesothelioma_tumor_cells_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17671141 DB - PRIME DP - Unbound Medicine ER -