Wilms' tumor 1 peptide–Major Histocompatibility Complex class I complex (WT1-MHC I)

The Wilms' tumor 1 (WT1) peptide–Major Histocompatibility Complex (MHC) class I complex is a therapeutic target consisting of intracellularly processed WT1 fragments presented on the cell surface by HLA molecules (Cheever et al., 2009, Clinical Cancer Research). WT1 is a zinc-finger transcription factor that is highly overexpressed in various leukemias and solid tumors, while its expression in healthy adult tissues is limited to specific sites like the renal podocytes and hematopoietic stem cells (Oka et al., 2004, Blood). This differential expression makes the WT1-MHC complex an attractive target for immunotherapies that aim to bypass the 'undruggable' nature of intracellular proteins. Current therapeutic approaches include peptide vaccines like Galinpepimut-S, which stimulate endogenous T-cell responses, and TCR-mimic antibodies or TCR-engineered T cells that directly bind the pMHC complex (Dao et al., 2013, Science Translational Medicine). These therapies are primarily being evaluated in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), as well as various solid malignancies. However, safety concerns remain regarding potential on-target, off-tumor toxicity in the kidneys and bone marrow, as well as the risk of TCR cross-reactivity with similar self-peptides.

Other names

WT1-HLA complexWT1-pMHCWilms' tumor protein peptide-MHC complexWT1 peptide-HLA-A*02:01 complex

T-cell redirection and activation against cells presenting WT1-derived peptides; induction of peptide-specific cytotoxic T-lymphocyte (CTL) responses (Oka et al., 2004, Blood).