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 1protein (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 + cytotoxicT-cell response requires CD4 + T-cell help. Experimental Design:Three HLA class II peptide epitopes of WT1with high predictive affinities to multiple HLA-DRB1molecules 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.

Analogue peptides for the immunotherapy of human acute myeloid leukemia

“…Similar modifications have led to peptide analogues which are effective at inducing immune responses against a range of tumor types including leukemia and solid tumors [54, [57][58][59]94,95](reviewed in [96]). Despite inherent problems in demonstrating the ability of modified peptides to recognize and kill tumor cells, some heteroclitic epitopes have shown promise in phase I clinical trials [18,71,97].…”

“…Such alterations to the anchor residues can enhance peptide immunogenicity [44] and success of this strategy is dependent on the TCR binding portion of the peptide not being altered significantly by anchor residue substitution. The fact that TCR recognition exhibits a degree of cross reactivity [52] developed a WT1 CD4 + peptide epitope, 122-140, which was mutated through a substitution of residue 126 (arginine to tyrosine) [59]. The group demonstrated that native WT1 epitopes presented on the surface of human cancer cells could be recognized by CD4 + and WT1-specific CTL; which were induced in response to the peptide analogue produced through the mutation of wt peptide.…”

Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia

“…16 Two HLA-A0201 cell lines were used as targets. The WT1-positive, ALL-derived cell line 697 was kindly provided by Hans J. Stauss (University College, London, United Kingdom), and the WT1-negative B-cell lymphoma cell line SKLY-16 was obtained from the ATCC.…”

“…In addition, we developed human leukocyte antigen (HLA) class II peptides that have been shown to induce WT1-specific CD4 ϩ responses in a broad range of HLA-DR.B1 haplotypes. 16 Given the experience with disease status in allogeneic stem cell transplantation and numerous animal models, immune responses are much less probable to be effective in situations of high-volume disease. The chance for the successful application of such a modality may therefore be best when leukemia burden is minimal, so we chose to test the vaccine when patients are in complete remission (CR) but have measurable WT1 transcript.…”

The Role of Immunotherapy in the Treatment of Mesothelioma

“…It is known to be upregulated in epithelioid MM but not in the sarcomatoid subtype and furthermore, its expression does not appear to be of significant prognostic value (Kumar-Singh et al, 1997). However, WT-1 is a relevant immune target in MM (May et al, 2007).…”