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

我们与名古屋大学的吉田博士合作，构建了含有干扰素β基因表达载体的阳离子脂质体。体外和体内研究表明，该材料具有抗黑色素瘤作用，其安全性已被动物实验证实。根据这些数据，我们准备了临床试验的方案和其他形式，并获得了机构伦理委员会和日本厚生福利省委员会的许可。此后，使用该试剂，我们开始了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。其中4例为IV期，1例为III期。转移结节皮损内注射不同剂量的DNA：直径1 cm以上的结节注射10 ug，直径1~2 cm的结节注射30 ug。当存在多个小病灶时，最多可同时治疗3个病灶，但一次治疗的最大总剂量为30微克/体。每周注射3次，共2周。所有患者均接受了6次注射。所有患者均未观察到明显的不良反应。临床反应：混合反应1例，无变化1例，进展性疾病3例。在混合反应的患者中，不仅注射的转移结节完全消失，而且几个未注射的结节也完全消失，但在过程中出现了一些新的转移灶。病理组织学上，退变的皮损内可见黑色素瘤细胞变性，CD8、CD4T细胞密集渗入。

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.