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Published online on September 13, 2004, 10.1073/pnas.0405884101
PNAS | September 21, 2004 | vol. 101 | no. 38 | 13885-13890


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

Yoshihiro Oka {dagger}, Akihiro Tsuboi {ddagger}, Tetsuya Taguchi §, Tadashi Osaki {dagger}, Taiichi Kyo ¶, Hiroko Nakajima ||, Olga A. Elisseeva ||, Yusuke Oji ||, Manabu Kawakami {ddagger}, Kazuhiro Ikegame {ddagger}, Naoki Hosen {dagger}, Satoshi Yoshihara {dagger}, Fei Wu {dagger}, Fumihiro Fujiki ||, Masaki Murakami {dagger}, Tomoki Masuda {dagger}, Sumiyuki Nishida {dagger}, Toshiaki Shirakata {dagger}, Shin-ichi Nakatsuka {dagger}{dagger}, Ayako Sasaki ¶, Keiko Udaka {ddagger}{ddagger}, Hiroo Dohy ¶, Katsuyuki Aozasa {dagger}{dagger}, Shinzaburo Noguchi §, Ichiro Kawase {dagger}, and Haruo Sugiyama ||, §§

Departments of {dagger}Molecular Medicine, {ddagger}Cancer Immunotherapy, §Surgical Oncology, ||Functional Diagnostic Science, and {dagger}{dagger}Pathology, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan; Hiroshima Red Cross and Atomic Bomb Survivor Hospital, Hiroshima City, Hiroshima 730-8619, Japan; and {ddagger}{ddagger}Department of Immunology, Kochi Medical School, Nankoku City, Kochi 783-8505, Japan

Communicated by Takashi Sugimura, National Cancer Center, Tokyo, Japan, August 13, 2004 (received for review February 9, 2004)

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.

Abbreviations: CTL, cytotoxic T lymphocyte; AML, acute myelocytic leukemia; MDS, myelodysplastic syndrome; BM, bone marrow; PBMC, peripheral blood mononuclear cell.

§§ To whom correspondence should be addressed. E-mail: sugiyama{at}sahs.med.osaka-u.ac.jp.

© 2004 by The National Academy of Sciences of the USA


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