GENE THERAPY USING HSV TK GENE WITH ADMINISTRATION OF GANCICLOVIR IN ADULTS

使用 HSV TK 基因并给予成人更昔洛韦的基因治疗

• 批准号: 6116802
• 负责人: ROBERT G GROSSMAN
• 金额: $ 3.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116802
• 关键词: brain neoplasms; chemosensitizing agent; clinical research; clinical trial phase I; combination cancer therapy; computed axial tomography; drug administration rate /duration; drug screening /evaluation; ganciclovir; gene therapy; herpes simplex virus 2; human subject; magnetic resonance imaging; recombinant DNA; thymidine kinase; transfection /expression vector

There are 15,000 new cases of primary brain tumors with 11,000 deaths annually in the United States, and brain tumors are the second leading cause of cancer death in children and young adults. Even with aggressive surgical and radiation therapies many patients with brain tumors have survival times of only 9 to 10 months. Hence, the prognosis for this disease is bleak and compels investigation of new therapeutic avenues. Direct introduction of therapeutic genes into tumor cells may provide an effective treatment of brain tumors. One strategy is to confer drug sensitivity to tumor cells by inserting a recombinant gene into them. This gene is from the common Herpes virus and it codes for the enzyme thymidine kinase (HSV-tk) enzyme. Thymidine kinase converts the anti- viral drug ganciclovir into a form that is toxic to rapidly dividing cells such as tumor cells. Non-dividing are not harmed. This approach is especially suitable for the treatment of brain tumors since the normal brain tissue is made up largely of non-dividing cells. Several techniques have been used to introduce therapeutic genes to tumors. Of these, virus-mediated transfer is currently the most efficient method and the most efficient virus is the genetically engineered adenovirus. We have demonstrated using two animal models that adenovirus-mediated transfer of the HSV-tk gene and ganciclovir treatment resulted in ablation of the tumors and significant increases in life spans. This phase I study is designed to study the safety and efficacy of gene therapy for patients with brain tumors. Patients with malignant brain tumors refractory to all potentially curative therapy will be treated with intra-tumor injections of replication-defective adenovirus vector delivering the Herpes Simplex Virus thymidine kinase gene. Initial tests will use a low dose of virus. Ganciclovir will then be administered intravenously at 10 mg/kg/day for 14 days. Only one course of therapy will be administered. Each patient will be carefully monitored for one month for adverse effects. Five patients will be tested with this low dose before another group of patients are treated with a higher dose and monitored closely for 1 month. This will be repeated until the target dose is reached or significant toxicity is detected. Effectiveness will be monitored by MRI and/or CT scans and by comparing survival times to the historical survival times for patients with recurrent brain tumors. The primary objective of this initial study is to determine whether the treatment is associated with significant toxicity.

新增1.5万例原发性脑肿瘤患者，其中1.1万人死亡 每年在美国，脑瘤是第二大 儿童和年轻人死于癌症的原因。即使是在 许多脑部疾病患者的积极手术和放射治疗 肿瘤的存活期只有9到10个月。因此，预后 对于这种疾病是黯淡的，并迫使研究新的治疗方法 林荫道。将治疗性基因直接导入肿瘤细胞可能会提供 脑瘤的有效治疗方法。一种策略是将药物 通过在肿瘤细胞中插入重组基因来实现对肿瘤细胞的敏感性。 这个基因来自常见的疱疹病毒，它编码这种酶。 胸苷激酶(HSV-tk)酶。胸腺嘧啶核苷激酶将抗- 病毒药物更昔洛韦的形式是有毒的，以迅速分裂 细胞，如肿瘤细胞。不分青红皂白不会受到伤害。这种方法 尤其适用于脑肿瘤的治疗，因为 正常的脑组织主要由未分裂的细胞组成。几个 技术已经被用来将治疗性基因引入肿瘤。的 这些，病毒介导的转移是目前最有效的方法 而最有效的病毒是遗传工程化腺病毒。 我们已经使用了两种腺病毒介导的动物模型 HSV-tk基因转移和更昔洛韦治疗导致 肿瘤的消融和寿命的显著延长。 这项第一阶段的研究旨在研究基因的安全性和有效性。 脑肿瘤患者的治疗。恶性脑疾病患者的临床分析 对所有潜在治疗方法都无效的肿瘤将被治疗 瘤内注射复制缺陷型腺病毒载体 传递单纯疱疹病毒胸苷激酶基因。首字母 测试将使用低剂量的病毒。更昔洛韦届时将被 静脉注射10 mg/kg/d，连续14天。只有一道菜 将会进行治疗。每个病人都会小心翼翼地 监测一个月的不良反应。五个病人将会是 在另一组患者接受治疗之前用这种低剂量进行测试 剂量较大，严密监测1个月。这将是 重复使用，直到达到目标剂量或出现显著毒性 检测到。有效性将通过核磁共振和/或CT扫描进行监测， 通过将生存时间与历史生存时间进行比较 复发性脑瘤患者。这样做的主要目标是 初步研究是确定这种治疗是否与 毒性很大。