PHASE I TRIAL OF HSVTK GENE THERAPY FOR CNS TUMORS

HSVTK 基因治疗 CNS 肿瘤的 I 期试验

• 批准号: 2458175
• 负责人: JANE B ALAVI
• 金额: $ 23.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-30 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458175
• 关键词: biopsy; blood chemistry; central nervous system neoplasms; clinical trials; cytotoxicity; dosage; drug adverse effect; encephalitis; ganciclovir; gene expression; gene therapy; genetic transduction; glioma; histopathology; human subject; human therapy evaluation; magnetic resonance imaging; neoplasm /cancer relapse /recurrence; neoplasm /cancer therapy; neutralizing antibody; polymerase chain reaction; positron emission tomography; thymidine kinase; urinalysis; western blottings

Primary CNS malignancies in adults are uniformly fatal, accounting or approximately 12,000 deaths annually in the United States. There has been little change in the outcome, despite improvements in diagnostic and surgical techniques and advances in radiation therapy. Chemotherapy provides little palliation. This study will evaluate the use of adenovirus-mediated transfer of the drug susceptibility gene herpes virus thymidine kinase (HSV-TK) into primary brain tumors followed by systemic treatment with ganciclovir. The aims are (l) to determine the clinical and histological toxicity of intra-tumor injection of recombinant adenovirus expressing HSV-TK (H5.O1ORSV-TK), followed by intravenous ganciclovir, in patients with recurrent glioma, and (2) to assess the response of malignant glioma to this treatment by brain imaging with volumetric MRI scans and positron emission tomography with l8F- fluorodeoxyglucose. The patients must have gliomas recurrent after radiation therapy, tumors accessible for stereotactic injection and good performance status. Half the patients (those with unresectable lesions) will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. The other patients (those with tumors amenable to surgical debulking) will receive the same treatment, except at day 7 their tumors will be surgically resected, and a second dose of virus will be injected into the residual, unresectable portion of the tumor. Intravenous ganciclovir will be continued for an additional 14 days. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. Tissue removed at the time of resection will be analyzed for evidence of adenovirus protein expression, RSV-TK DNA (by PCR), inflammation, encephalitis, and tumor necrosis. The patient's humoral immunologic response will be analyzed using western blot and neutralizing antibody assays of serum for anti-adenovirus antibodies. Their cellular immune response will be assessed with peripheral blood lymphocyte proliferation and cytotoxic T-cell assays. Patients will be monitored for development of increased intracranial pressure, surgical complications, and dissemination of the virus to CSF, blood, feces, respirating secretions, and urine. The size and metabolic activity of the tumors after treatment will be assessed by volumetric MRI scans and PET scans. This study will determine the safety of intracranially administered recombinant adenoviruses. It will also provide evidence for efficacy of adenovirally administered HSV-TK and provide valuable information for the development of future vectors.

成人原发性中枢神经系统恶性肿瘤均是致命的，无论是 美国每年约有 12,000 人死亡。 有 尽管诊断和治疗方面有所改进，但结果几乎没有变化 外科技术和放射治疗的进展。 化疗 几乎没有缓解作用。 本研究将评估使用 腺病毒介导的药敏基因转移疱疹病毒 胸苷激酶（HSV-TK）进入原发性脑肿瘤，然后全身 用更昔洛韦治疗。 目的是 (l) 确定临床 重组人瘤内注射的情况及组织学毒性 表达 HSV-TK (H5.O1ORSV-TK) 的腺病毒，然后静脉注射 更昔洛韦，用于复发性神经胶质瘤患者，以及（2）评估 通过脑成像观察恶性神经胶质瘤对此治疗的反应 体积 MRI 扫描和 18F- 正电子发射断层扫描 氟脱氧葡萄糖。 患者必须在手术后复发胶质瘤 放射治疗，肿瘤可进行立体定向注射，效果良好 性能状态。 一半患者（病变无法切除的患者） 将接受立体定向引导下的病毒注射到大脑中 肿瘤，然后静脉注射更昔洛韦 14 天。 另一个 患者（患有适合手术减瘤的肿瘤的患者）将接受 相同的治疗，除了在第 7 天他们的肿瘤将接受手术 切除，然后将第二剂病毒注射到残留物中， 肿瘤的不可切除部分。 静脉注射更昔洛韦将 又持续了14天。 患者将被分组入组 三组，每组依次接受更大剂量的 腺病毒。 将分析切除时取出的组织 腺病毒蛋白表达、RSV-TK DNA（通过 PCR）的证据， 炎症、脑炎和肿瘤坏死。 病人的体液 将使用蛋白质印迹和中和来分析免疫反应 血清中抗腺病毒抗体的抗体测定。 他们的细胞 将通过外周血淋巴细胞评估免疫反应 增殖和细胞毒性 T 细胞测定。 患者将受到监测 对于颅内压增高的发展，手术 并发症以及病毒传播到脑脊液、血液、粪便、 呼吸分泌物和尿液。大小和代谢活性 治疗后的肿瘤将通过体积 MRI 扫描和 PET 进行评估 扫描。 这项研究将确定颅内注射的安全性 施用重组腺病毒。它还将提供证据 腺病毒施用 HSV-TK 的功效并提供有价值的 未来载体开发的信息。