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Cancer Immunotherapy Targeting Wilms’ Tumor Gene WT1 Product¹

Yoshihiro Oka^2,*, Keiko Udaka^2,§, Akihiro Tsuboi^*, Olga A. Elisseeva^*, Hiroyasu Ogawa^*, Katsuyuki Aozasa, Tadamitsu Kishimoto^¶ and Haruo Sugiyama^3,

Departments of ^* Molecular Medicine, Pathology, and Clinical Laboratory Science, Osaka University Medical School, Suita, Osaka, Japan; ^§ RESTO, JST, and Department of Biophysics, Kyoto University, Sakyo, Kyoto, Japan; and ^¶ Osaka University, Osaka, Japan

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-2D^b-binding anchor motifs and have a comparatively higher binding affinity for H-2D^b molecules, were tested in mice (C57BL/6, H-2D^b) for in vivo induction of CTLs directed against these WT1 peptides. Only one peptide, Db126, with the highest binding affinity for H-2D^b 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-2D^b-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.