Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression.
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.
Oka
Yoshihiro
Y
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan.
Tsuboi
Akihiro
A
Taguchi
Tetsuya
T
Osaki
Tadashi
T
Kyo
Taiichi
T
Nakajima
Hiroko
H
Elisseeva
Olga A
OA
Oji
Yusuke
Y
Kawakami
Manabu
M
Ikegame
Kazuhiro
K
Hosen
Naoki
N
Yoshihara
Satoshi
S
Wu
Fei
F
Fujiki
Fumihiro
F
Murakami
Masaki
M
Masuda
Tomoki
T
Nishida
Sumiyuki
S
Shirakata
Toshiaki
T
Nakatsuka
Shin-Ichi
S
Sasaki
Ayako
A
Udaka
Keiko
K
Dohy
Hiroo
H
Aozasa
Katsuyuki
K
Noguchi
Shinzaburo
S
Kawase
Ichiro
I
Sugiyama
Haruo
H
D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000633:toxicity*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D016162:Genes, Wilms Tumor; D006801:Humans; D007564:Japan; D007680:Kidney Neoplasms / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*; D009396:Wilms Tumor / Q000276:immunology
D019496:Cancer Vaccines; D010446:Peptide Fragments; D025721:WT1 Proteins