Cancer immunotherapy targeting Wilms' tumor gene WT1 product.
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.
Oka
Y
Y
Department of Molecular Medicine, Osaka University Medical School, Suita, Osaka, Japan.
Udaka
K
K
Tsuboi
A
A
Elisseeva
O A
OA
Ogawa
H
H
Aozasa
K
K
Kishimoto
T
T
Sugiyama
H
H
D000818:Animals; D002474:Cell-Free System / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018390:Gene Targeting / Q000379:methods*; D016162:Genes, Wilms Tumor / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D010446:Peptide Fragments; D014157:Transcription Factors; D025721:WT1 Proteins