Phase I/IIa clinical trial of gene therapy for advanced melanoma using cationic liposomes containing interferon beta gene

使用含有干扰素β基因的阳离子脂质体治疗晚期黑色素瘤的I/IIa期临床试验

基本信息

批准号：
15390340
负责人：
SAIDA Toshiaki
金额：
$ 8.96万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

We constructed cationic liposomes containing interferon beta gene expression plasmid in collaboration with Dr. Yoshida at Nagoya University. In vitro and in vivo studies revealed anti-melanoma effects of this material and its safety was confirmed by animal experiments. Based on these data, we prepared the protocol and other forms for the clinical trial and got permission from the institutional ethical committee and from the committee of the Ministry of Health and Welfare of Japan. Thereafter, Using this reagent, we started a phase I/IIa clinical trial of interferon beta gene therapy for patients with advanced melanoma. A total of 5 patients were treated with this therapy : 4 patients in stage IV and one patient in stage III. The following doses of DNA were injected into metastatic nodular skin lesions : 10 ug for nodules up to 1 cm in diameter and 30 ug for 1 to 2 cm in diameter. Up to 3 lesions were simultaneously treated when multiple small lesions were present, but maximum total dose at one treatment was 30 ug/body. The injections were performed 3 times a week for 2 weeks. All the patients received a total 6 times injection. No significant adverse effects were observed in any patients. The clinical response was as follows : mixed response in one patient, no change in one patient and progressive disease in 3 patients. In the patient who showed mixed response, not only the injected metastatic nodule but also several non-injected nodules disappeared completely, however, a few new metastatic lesions appeared during the course. Histopathologically, in the regressed lesions, degeneration of melanoma cells was observed along with dense infiltrate of CD8 and CD4 T cells within the lesions.

我们在与名古屋大学的吉田博士合作时构建了含有干扰素β基因表达质粒的阳离子脂质体。体外和体内研究揭示了该材料的抗黑色素瘤作用及其安全性通过动物实验证实。基于这些数据，我们为临床试验准备了协议和其他形式，并获得了机构道德委员会的许可以及日本卫生和福利部委员会的许可。此后，使用该试剂，我们开始针对晚期黑色素瘤患者的干扰素β基因治疗的I/IIA期临床试验。总共使用此疗法治疗了5例患者：IV期中的4例患者，一名患者在第三阶段。将以下剂量的DNA注入转移性结节性皮肤病变：直径高达1 cm的结节10 ug，直径为1至2厘米的30 ug。当存在多个小病变时，同时治疗了多达3个病变，但一种治疗时的最大总剂量为30 ug/身体。注射每周3次，持续2周。所有患者的注射量总计6次。任何患者均未观察到明显的不良反应。临床反应如下：一名患者的混合反应，一名患者没有变化和3例患者进行性疾病。在表现出不同反应的患者中，不仅注射的转移结节，而且几个未注射的结节也完全消失了，但是，在课程中，出现了一些新的转移性病变。从组织病理学上讲，在回归病变中，观察到黑色素瘤细胞的变性以及病变中CD8和CD4 T细胞的致密浸润。