Immunity to WT1 in the animal model and in patients with acute myeloid leukemia

The Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpre ssed in most types of leukemia in humans. WT1 is also detectable in many ty pes of lung, thyroid, breast, testicular and ovarian cancers and melanoma i n humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse mode ls might lead to resolution of many of the critical issues for developing W T1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from t he natural sequence of WT1 containing motifs for binding to major histocomp atibility (MHC) class II molecules. Immunization induced helper T-cell resp onses specific for the immunizing WT1 peptides and antibody responses speci fic for WT1 protein. Screening of multiple murine cancer cell lines identif ied 2 murine cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1 . Immunization with MHC class I binding peptides induced WT1 peptide-specif ic cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40 . WT1 specificity of lysis was confirmed by cold target inhibition. No toxi city was noted by histopathologic evaluation in the WT1 peptide-immunized a nimals. WT1 peptide immunization did not show any effect on TRAMP-C tumor g rowth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-sp ecific antibody, demonstrating that WT1 can be immunogenic in the context o f cancer cells. To evaluate whether WT1 might be similarly immunogenic in h umans, serum from patients with leukemia was evaluated for preexisting anti body responses, Western blot analyses showed WT1-specific antibodies direct ed 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) (C) 2000 by The American Society of Hematology.