WT1 as a novel target antigen for cancer immunotherapy.
Wild-type Wilms' tumor gene WT1 is expressed at high levels not only in most of acute myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in various types of solid tumors including lung cancer. We tested the ability of the gene product (WT1) to serve as a target antigen for tumor  specific immunotherapy both in human in vitro system and mouse in vivo system. In the latter, we can evaluate the efficacy and the side effects of WT1 vaccination in vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1 binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups also have succeeded in generating CTLs which specifically lyse WT1-expressing leukemia cells, and which do not inhibit colony-formation of normal hematopoietic cells that express WT1 at physiological levels. In the mouse in vivo system, immunization of C57BL/6 mice with one WT1 peptide with relatively high binding affinity for H-2D(b) molecules, which contain H-2D(b) binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing tumor cells in an H-2D(b)-restricted manner. Furthermore, mice immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA vaccination) rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to WT1-expressing normal organs by the induced CTLs. The WT1 protein has been identified as a novel tumor antigen and recent investigations provide a rationale for developing WT1-based adoptive T cell therapy and vaccination against various kinds of malignant neoplasms.
Deapartment of Molecular Medicine, Osaka University Medical School, 2-2, Yamada-oka, Suita City, Osaka 565-0871, Japan. yoshi@imed3.med.osaka-u.ac.jp
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Oka
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Tsuboi
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Elisseeva
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Udaka
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Sugiyama
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D025721:WT1 Proteins / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D025721:WT1 Proteins