An immunogenic WT1-derived peptide that induces T cell response in the context of HLA-A*02:01 and HLA-A*24:02 molecules

Abstract

The Wilms' tumor oncogene protein (WT1) is a highly validated tumor antigen for immunotherapy. WT1-targeted immunotherapy has been extensively explored in multiple human trials in various cancers. However, clinical investigations using WT1 epitopes have generally focused on two peptides, HLA-restricted to HLA-A*02:01 or HLA-A*24:02. The goal of this study was to identify new epitopes derived from WT1, to expand the potential use of WT1 as a target of immunotherapy. Using computer-based MHC-binding algorithms and validation of the T cell responses specific for the identified peptides, we found that a recently identified HLA-A*24:02-binding epitope (239-247), NQMNLGATL (NQM), was also a strong CD8 T cell epitope for HLA-A*02:01 molecule. A peptide second position Q240L substitution (NLM) or Q240Y substitution (NYM), further enhanced the T cell responses in both HLA-A*02:01 positive and HLA-A*24:02 positive healthy donors. Importantly, T cells stimulated with the new analog peptides displayed heteroclitic cross-reactivity with the native NQM sequence and were able to kill HLA-matched WT1-positive tumor cell lines and primary leukemia blasts. In addition, longer native and heteroclitic HLA-DR.B1-binding peptides, comprising the nine amino acid NQM or NLM sequences, could induce T cell response that recognized the CD8 epitope NQM, suggesting the processing and the presentation by HLA-A*02:01 molecules of the CD8 T cell epitope embedded within it. Our studies suggest that the analog peptides NLM and NYM could be potential candidates for future immunotherapy targeting WT1 positive cancers in the context of HLA-A*02:01 and A*24:02 positive populations.

A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial

“…Our study suggested that HSP70 and GPC3 are immunogenic eligible candidate proteins for peptide vaccination therapy, and peptides derived from these proteins can be administered and induce peptide-specific CTLs for patients with various GI cancers and the three common types of HLA alleles. It has been difficult to apply previous vaccination therapies to larger populations, considering that almost all peptides used previously are restricted to one HLA allele [4,5,31]. In contrast, our vaccination therapy used novel peptides which can bind to multi-HLA types including HLA-A*24:02, 02:01, and 02:06.…”

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

“…As an example, in idiopathic myelofibrosis (IM) [53], and in PMF [54][55][56] it emerged from the analyses that the WT1 gene is highly modulated. A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A * 24:02 has been identified [57].…”

Sensitive and quantitative detection of MHC-I displayed neoepitopes using a semi-automated workflow and TOMAHAQ mass spectrometry

“…In addition to enrichment, we sought to apply automation to the peptide isolation and desalting step, and successfully incorporated additional on-cartridge modifications where reduction-alkylation, TMT tagging, and/or oxidation steps could be applied. A number of clinically relevant MHC-I displayed neoepitopes are known to contain cysteine and/or methionine residues (37,38), so chemical treatments that maximize the detection of such peptides are desired. We found, in contrast with work from others (19), that TMT tagging decreased the number of neoepitopes detected in our synthetic mixture, however this could be due to the much simpler or hydrophilic mixture with which we were working.…”