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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1480-1489
IMMUNOBIOLOGY
Immunity to WT1 in the animal model and in patients with
acute myeloid leukemia
Alexander Gaiger,
Valerie Reese,
Mary L. Disis, and
Martin A. Cheever
From the Corixa Corporation and the Division of
Oncology, Department of Medicine, University of Washington, Seattle,
WA; and the First Department of Medicine, Division of Hematology,
University of Vienna, Austria.
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).
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