Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1) product

The product of the Wilms' tumor gene WT1 is a transcription factor overexpr essed not only in leukemic blast cells of almost all patients with acute my eloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia, but also in various types of solid tumor cells. Thus, it is suggested that the WT1 gene plays an important role in both leukemogenesis and tumorigenesis. Here we tested the potential of WT1 to serve as a target for immunotherapy against leukemia and solid tumors. Four 9-mer WT1 peptides that contain HLA -A2.1-binding anchor motifs were synthesized. Two of them, Db126 and WH187, were determined to bind to HLA-A2.1 molecules in a binding assay using tra nsporter associated with antigen processing-deficient T2 cells, Peripheral blood mononuclear cells from an HLA-A2.1-positive healthy donor were repeat edly sensitized in vitro with T2 cells pulsed with each of these two WT1 pe ptides, and CD8(+) cytotoxic T lymphocytes (CTLs) that specifically lyse WT 1 peptide-pulsed T2 cells in an HLA-A2.1-restricted fashion were induced. T he CTLs also exerted specific lysis against WT1-expressing, HLA-A2.1-positi ve leukemia cells, but not against WT1-expressing, HLA-A2.1-negative leukem ia cells, or WT1-nonexpressing, HLA-A2.1-positive B-lymphoblastoid cells. T hese data provide the first evidence of human CTL responses specific for th e WT1 peptides, and provide a rationale for developing WT1 peptide-based ad optive T-cell therapy and vaccination against leukemia and solid tumors.