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: 6306268
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6306268
• 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.

原发性脑肿瘤新增病例 15,000 例，死亡 11,000 例 每年在美国，脑肿瘤是第二大癌症 儿童和年轻人癌症死亡的原因。 即使与 积极的手术和放射治疗许多脑部患者 肿瘤的存活时间只有9至10个月。 因此，预测 因为这种疾病的前景黯淡，迫使人们研究新的治疗方法 途径。 将治疗基因直接引入肿瘤细胞可能会提供 有效治疗脑肿瘤。 一种策略是给予药物 通过将重组基因插入肿瘤细胞中来提高肿瘤细胞的敏感性。 该基因来自常见的疱疹病毒，编码酶 胸苷激酶 (HSV-tk) 酶。 胸苷激酶将抗 将病毒药物更昔洛韦转化为对快速分裂有毒的形式 细胞，例如肿瘤细胞。 不分裂则不受伤害。 这种做法 特别适合治疗脑肿瘤 正常脑组织主要由非分裂细胞组成。 一些 技术已被用于将治疗基因引入肿瘤。 的 这些，病毒介导的转移是目前最有效的方法 而最有效的病毒是基因工程腺病毒。 我们已经使用两种动物模型证明了腺病毒介导的 HSV-tk 基因转移和更昔洛韦治疗导致 肿瘤消融并显着延长寿命。 该I期研究旨在研究基因的安全性和有效性 脑肿瘤患者的治疗。 脑部恶性肿瘤患者 对所有潜在治疗方法均无效的肿瘤将得到治疗 肿瘤内注射复制缺陷型腺病毒载体 递送单纯疱疹病毒胸苷激酶基因。 最初的 测试将使用低剂量的病毒。 那么更昔洛韦将是 以 10 mg/kg/天的剂量静脉内给药，持续 14 天。 只有一门课程 将进行治疗。 每一位患者都会细心 监测一个月的不良反应。 五名患者将 在治疗另一组患者之前用这种低剂量进行测试 使用较高剂量并密切监测1个月。 这将是 重复直至达到目标剂量或出现显着毒性 检测到。 有效性将通过 MRI 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 复发性脑肿瘤患者。 此举的首要目标 初步研究是为了确定治疗是否与 具有显着的毒性。