Wilms' tumor (WT1) gene participates in leukemogenesis, is overexpressed in most human leukemias and is detectable in many other human cancers. Because murine and human WT1 are virtually identical, mouse models can answer many of the critical issues for developing WT1 vaccines. Initial experiments identified two mouse cancers that overexpress WT1: TRAMPC - a prostate cancer from mice transgenic for SV40, and BLKSV4O - a fibroblast line transformed by SV40. To test whether vaccines can elicit WT1-specific CTL, B6 mice were immunized with a series of synthetic peptides from the natural sequence of WT1 with motifs for binding to class I MHC molecules. WT1 peptide specific CTL specifically lysed WT1 overexpressing cancer cells. Cold target inhibition confirmed WT1 lysis specificity. The immunized animals showed no clinical signs of autoimmunity. This Phase I grant will address two aims in preparation for clinical trials of WT1 vaccine formulations: l) to determine whether WT1-specific immunity is toxic when the level of CTL immunity is high enough to treat cancer; 2) to identify human WT1 CTL peptides for WT1 peptide-based vaccine formulations. Further experiments will validate that human WT1-specific CTL can specifically lyse human leukemia cells that overexpress WT1.
The proposed studies will lead to a potential vaccine product for therapy of leukemia and other WTI expressing malignancies such as lung, breast and thyroid cancer. Such a vaccine would be marketed both in the U.S. and worldwide.
| Gaiger, A; Carter, L; Greinix, H et al. (2001) WT1-specific serum antibodies in patients with leukemia. Clin Cancer Res 7:761s-765s |
