胸苷激酶基因治疗脑胶质瘤25例报告

Gene therapy for brain glioma with RT-HSV thymidinekinase(TK) gene and gancidovir system

目的 报告25例脑胶质细胞瘤用含单纯疱疹病毒胸苷激酶基因的逆转录病毒载体生产细胞（pLTKcSN/VPC）注入和羟甲基无环鸟苷（GCV）全身给药治疗脑胶质瘤2～5年随访观察（失访1例）的结果,并拟申请Ⅱ期临床试验。方法 选择大脑半球侧脑室外区确诊为脑胶质瘤的病例,在直视或显微镜下行全切除或大部分切除术,残腔周围脑组织内每隔1cm、深1.5cm用微量注射泵注入预制的基因工程细胞,10～14d后开始每天2次静脉内滴入GCV5mg·kg-1·12h-1,共14d,术后4～5周按常规给予化疗药物氯乙环已亚硝脲（CCNU）和（或）表鬼臼毒噻吩糖苷（VM26）。同时,与我院以往病情相近的经常规治疗的30例恶性胶质瘤（间变型29例,多形性胶质母细胞瘤1例）的生存率相比较。结果25例均安全渡过围手术期。在22个月以前,基因治疗组的情况均优于手术加化疗（ACCNU和VM26）的常规治疗组。基因组的中位生存时间为（470±93.17）d,12个月的生存率为0.6,18个月为0.35;常规治疗组的中位生存时间为（395±93.15）d,12个月的生存率为0.5,18个月为0.33。1例间变型少突胶质瘤患者至今已正常生活60.3个月;1例间变型星形细胞瘤患者已正常生活25个月,尚未见再发征象;另有1例多形性胶质母细胞瘤在2年时MRI才见有肿瘤扩增（47.9个月后失访）;

Objective To evaluate the safety and efficacy of gene therapy for glioma, Herpes simplex virus-thymidinekinase/gancielovir (HSV-TK/GCV) gene therapy was performed in 25 cases with glioma during phase I clinical trial. The results of 2-5 years' follow-up provided the evidence of feasibility for phase Ⅱ clinical trial. Methods Sixteen cases with anaplastic gliomas, 5 cases with multiforme glioblastomas and 4 cases with astrocytomas outside the lateral ventricle were involved in this program. Total or extensive excisions of the tumors were performed and the vector producer cells were inoculated around the residual spaces. Ten to fourteen days after the operation, GCV5mg·kg-1·12 h-1 was intravenously injected into the patients, twice a day for 2 weeks. Follow-up was conducted for 2-5 years. The control group consisted of 30 cases with similar comparable gliomas treated with ordinary operation as well as chemical and radiation therapy. Results All cases were safe in perioperative period. During the follow-up period of 2-5 years, the median survival of the genie group was (470±93.17) days and that of the control group was (395±93. 15) days. The 1-year survival rate of the genie group was 0.6 while that of the control group was 0.5. The 18-month survival rate of the genie group was 0.5, and that of the control group was 0.33. Two malignant cases had survived for 23 and 56 months, living a normal life; Four cases with astrocytomas had been alive since the operation for 3-5 years. Conclusion Experience from the 2-5 years' follow-up has proved that gene therapy is more effective than ordinary methods.