Cancer Immunotherapy Targeting Wilms’ Tumor Gene WT1 Product

Abstract

The Wilms’ tumor gene WT1 is expressed at high levels not only in acute myelocytic and lymphocytic leukemia and in chronic myelocytic leukemia but also in various types of solid tumors including lung cancers. To determine whether the WT1 protein can serve as a target Ag for tumor-specific immunity, three 9-mer WT1 peptides (Db126, Db221, and Db235), which contain H-2Db-binding anchor motifs and have a comparatively higher binding affinity for H-2Db molecules, were tested in mice (C57BL/6, H-2Db) for in vivo induction of CTLs directed against these WT1 peptides. Only one peptide, Db126, with the highest binding affinity for H-2Db molecules induced vigorous CTL responses. The CTLs specifically lysed not only Db126-pulsed target cells dependently upon Db126 concentrations but also WT1-expressing tumor cells in an H-2Db-restricted manner. The sensitizing activity to the Db126-specific CTLs was recovered from the cell extract of WT1-expressing tumor cells targeted by the CTLs in the same retention time as that needed for the synthetic Db126 peptide in RP-HPLC, indicating that the Db126-specific CTLs recognize the Db126 peptide to kill WT1-expressing target cells. Furthermore, mice immunized with the Db126 peptide rejected challenges by WT1-expressing tumor cells and survived for a long time with no signs of autoaggression by the CTLs. Thus, the WT1 protein was identified as a novel tumor Ag. Immunotherapy targeting the WT1 protein should find clinical application for various types of human cancers.

Role of the WT1 tumor suppressor in murine hematopoiesis

“…3,[29][30][31][32][33][34][35][36][37] The clinical use of anti-WT1 cytotoxic T-lymphocytes (CTLs) for preferential destruction of WT1-expressing malignant cells in leukemia is under evaluation. [38][39][40][41] A number of lines of evidence suggest that WT1 may play a role in regulating hematopoiesis. In the human hematopoietic system, WT1 appears to be normally expressed in bone marrow CD34 ϩ cells.…”

Transcription factors and translocations in lymphoid and myeloid leukemia

“…Elevated expression of the wild-type WT1 gene has been identified in almost all leukemic cells, independent of the type of disease. 11,24 In leukemic cells, the WT1 gene has been shown to function as an oncogene. 11,[25][26][27] The WT1 wild-type expression level in cells shows an inverse correlation between WT1 expression levels and prognosis.…”

“…11,24 In leukemic cells, the WT1 gene has been shown to function as an oncogene. 11,[25][26][27] The WT1 wild-type expression level in cells shows an inverse correlation between WT1 expression levels and prognosis. 24 There is an increased WT1 expression at relapse compared with that at diagnosis in cases of acute leukemia, 11 as well as growth inhibition of leukemic cells which occurs with WT1 antisense oligomers.…”

“…11 The WT1 gene product acts as a regulator of gene expression depending on how it combines with other regulatory proteins in different cell types. 11 It contains a proline-rich amino terminus which functions as a transcriptional repressor 12 and four contiguous cys 2 -his 2 zinc fingers at the carboxy end, which bind DNA in vitro. 13,14 It is mapped to chromosome 11p13 and is encoded by 10 exons.…”

“…11,[25][26][27] The WT1 wild-type expression level in cells shows an inverse correlation between WT1 expression levels and prognosis. 24 There is an increased WT1 expression at relapse compared with that at diagnosis in cases of acute leukemia, 11 as well as growth inhibition of leukemic cells which occurs with WT1 antisense oligomers. 25 Furthermore, in the 32D cl3 myeloid progenitor cell line and in normal myeloid progenitor cells, a block in differentiation and an induction of proliferation in response to G-CSF was seen.…”