The
Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of
leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular, and
ovarian cancers and
melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1
vaccines. C57/BL6 (B6) mice were injected with synthetic
peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (
MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1
peptides and antibody responses specific for
WT1 protein. Screening of multiple murine
cancer cell lines identified 2 murine
cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1. Immunization with MHC class I binding
peptides induced WT1
peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1
peptide-immunized animals. WT1
peptide immunization did not show any effect on TRAMP-C
tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of
cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with
leukemia was evaluated for pre-existing antibody responses. Western blot analyses showed WT1-specific
antibodies directed against the N-terminus portion of the
WT1 protein in the sera of 3 of 18 patients with
acute myeloid leukemia (AML). (Blood. 2000;96:1480-1489)