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Clinical Trial
. 2004 Sep 21;101(38):13885-90.
doi: 10.1073/pnas.0405884101. Epub 2004 Sep 13.

Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression

Yoshihiro Oka  1 , Akihiro Tsuboi, Tetsuya Taguchi, Tadashi Osaki, Taiichi Kyo, Hiroko Nakajima, Olga A Elisseeva, Yusuke Oji, Manabu Kawakami, Kazuhiro Ikegame, Naoki Hosen, Satoshi Yoshihara, Fei Wu, Fumihiro Fujiki, Masaki Murakami, Tomoki Masuda, Sumiyuki Nishida, Toshiaki Shirakata, Shin-Ichi Nakatsuka, Ayako Sasaki, Keiko Udaka, Hiroo Dohy, Katsuyuki Aozasa, Shinzaburo Noguchi, Ichiro Kawase, Haruo Sugiyama
Affiliations
Clinical Trial

Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression

Yoshihiro Oka et al. Proc Natl Acad Sci U S A. .

Abstract

The Wilms' tumor gene WT1 is overexpressed in leukemias and various types of solid tumors, and the WT1 protein was demonstrated to be an attractive target antigen for immunotherapy against these malignancies. Here, we report the outcome of a phase I clinical study of WT1 peptide-based immunotherapy for patients with breast or lung cancer, myelodysplastic syndrome, or acute myeloid leukemia. Patients were intradermally injected with an HLA-A*2402-restricted, natural, or modified 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant at 0.3, 1.0, or 3.0 mg per body at 2-week intervals, with toxicity and clinical and immunological responses as the principal endpoints. Twenty-six patients received one or more WT1 vaccinations, and 18 of the 26 patients completed WT1 vaccination protocol with three or more injections of WT1 peptides. Toxicity consisted only of local erythema at the WT1 vaccine injection sites in patients with breast or lung cancer or acute myeloid leukemia with adequate normal hematopoiesis, whereas severe leukocytopenia occurred in patients with myelodysplastic syndrome with abnormal hematopoiesis derived from WT1-expressing, transformed hematopoietic stem cells. Twelve of the 20 patients for whom the efficacy of WT1 vaccination could be assessed showed clinical responses such as reduction in leukemic blast cells or tumor sizes and/or tumor markers. A clear correlation was observed between an increase in the frequencies of WT1-specific cytotoxic T lymphocytes after WT1 vaccination and clinical responses. It was therefore demonstrated that WT1 vaccination could induce WT1-specific cytotoxic T lymphocytes and result in cancer regression without damage to normal tissues.

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Figures

Fig. 1.
Fig. 1.
Tumor regression in patients with breast cancer. (a) Computed tomography of chest before (Left) and after (Right) WT1 vaccination in patient 1. Arrows indicate metastastic tumor masses. (b) Computed tomography of abdomen before (Left) and after (Right) WT1 vaccination in patient 2. Arrows indicate walls of bowel tract. Before WT1 vaccination, the walls were thickened by metastatic tumor cells.
Fig. 2.
Fig. 2.
Reduction in a tumor marker (SCC) in patient 12 with lung cancer. The dotted line indicates an upper limit of normal range.
Fig. 3.
Fig. 3.
Clinical course of patients with de novo AML. Clinical course of patients 20 (a), 23 (b), and 21(c) are shown. WT1 expression levels (solid lines) and percentages of leukemic blast cells in BM (filled columns) are shown. The dotted line indicates the upper limit of normal range in WT1 expression levels. U.D., Undetectable.
See this image and copyright information in PMC

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