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: 6278036
• 负责人: ROBERT G GROSSMAN
• 金额: $ 2.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6278036
• 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.

原发性脑瘤新增1.5万例死亡1.1万例 每年在美国，脑肿瘤是第二大 儿童和年轻人癌症死亡的原因。 即使有 积极的外科手术和放射治疗，许多患者的大脑 肿瘤的存活时间只有9到10个月。 因此， 因为这种疾病是暗淡的，迫使研究新的治疗方法 大道。 将治疗性基因直接导入肿瘤细胞可以提供 一种有效的治疗脑瘤的方法 一种策略是将药物 通过向肿瘤细胞中插入重组基因来增强其对肿瘤细胞的敏感性。 这种基因来自普通疱疹病毒，它编码酶 胸苷激酶（HSV-tk）酶。 胸苷激酶将抗- 病毒药物更昔洛韦变成一种对快速分裂有毒的形式， 细胞，如肿瘤细胞。 不分裂不受伤害。 这种方法 特别适用于治疗脑肿瘤， 正常的脑组织主要由不分裂的细胞组成。 几 已经使用技术将治疗基因引入肿瘤。 的 病毒介导的转移是目前最有效的方法 最有效的病毒是基因工程腺病毒。 我们已经用两种动物模型证明了腺病毒介导的 转移HSV-tk基因和更昔洛韦治疗导致 切除肿瘤和显著延长寿命。 这项I期研究旨在研究基因治疗的安全性和有效性。 脑肿瘤患者的治疗。 脑恶性肿瘤患者 将治疗所有潜在治愈疗法均难治的肿瘤 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。 初始 测试将使用低剂量的病毒。 然后将是更昔洛韦 以10 mg/kg/天静脉内给药14天。 只有一道菜 将给予治疗。 每一位患者都将认真 监测一个月的不良反应。 5名患者将 在另一组患者接受治疗之前， 更高的剂量 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著毒性 检测到 将通过MRI和/或CT扫描监测有效性， 通过比较生存时间与历史生存时间， 复发性脑肿瘤患者。 这项工作的主要目的是 最初的研究是确定治疗是否与 毒性显著。