Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression
Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression
复制标题
DOI：
10.1073/pnas.0405884101
复制
发表时间：
2004-09-21
影响因子：
11.1
通讯作者：
Sugiyama, H
中科院分区：
文献类型：
--
作者：
Oka, Y;Tsuboi, A;Sugiyama, H
Wilms肿瘤基因WT 1在白血病和各种类型的实体瘤中过表达，并且WT 1蛋白被证明是针对这些恶性肿瘤的免疫治疗的有吸引力的靶抗原。在这里，我们报告了一项基于WT 1肽的免疫治疗乳腺癌或肺癌、骨髓增生异常综合征或急性髓性白血病患者的I期临床研究的结果。患者皮内注射HLA-A*2402限制性的，天然的，或修饰的9聚体WT 1肽与Montanide ISA 51佐剂乳化，以0.3，1.0，或3.0毫克/身体，在2周的时间间隔，与毒性和临床和免疫反应作为主要终点。26名患者接受了一次或多次WT 1疫苗接种，26名患者中有18名完成了WT 1疫苗接种方案，注射了三次或更多次WT 1肽。毒性仅包括在具有足够正常造血的乳腺癌或肺癌或急性髓性白血病患者中WT 1疫苗注射部位的局部红斑，而严重白细胞减少症发生在具有源自表达WT 1的转化造血干细胞的异常造血的骨髓增生异常综合征患者中。在20例可评估WT 1疫苗接种疗效的患者中，有12例显示出临床应答，如白血病母细胞或肿瘤大小和/或肿瘤标志物减少。在WT 1疫苗接种后WT 1特异性细胞毒性T淋巴细胞的频率增加与临床应答之间观察到明显的相关性。因此，证明了WT 1疫苗接种可以诱导WT 1特异性细胞毒性T淋巴细胞，并导致癌症消退而不损害正常组织。
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.