PHASE I TRIAL OF HSVTK GENE THERAPY FOR CNS TUMORS

成人的原发性中枢神经系统恶性肿瘤通常是致命的，无论是 在美国，每年大约有12000人死亡。那里有 结果几乎没有变化，尽管在诊断和治疗方面有所改善 外科技术和放射治疗的进展。化疗 几乎不能起到缓解作用。这项研究将评估使用 腺病毒介导的药物易感基因疱疹病毒的转移 胸苷激酶(HSV-TK)在原发脑肿瘤中的作用 更昔洛韦治疗。目的是(L)确定临床 重组人肝癌细胞瘤内注射的组织毒性 表达HSV-TK的腺病毒(H5.01ORSV-TK)，然后静脉注射 更昔洛韦，用于复发性胶质瘤患者，以及(2)评估 恶性脑胶质瘤对该疗法的反应 ~(18)F-核磁共振容积扫描和正电子发射断层扫描 氟代脱氧葡萄糖。患者术后一定有复发的神经胶质瘤 放射治疗后，肿瘤可进行立体定向注射，效果良好 性能状态。一半的患者(那些有无法切除的病变的患者) 将在立体定向引导下将病毒注射到大脑中 肿瘤给药后静脉注射更昔洛韦，疗程14天。另一个 患者(那些患有可手术切除的肿瘤的患者)将收到 同样的治疗，除了在第7天，他们的肿瘤将进行手术 切除，然后将第二剂病毒注射到残留物中， 肿瘤中不能切除的部分。静脉注射更昔洛韦将是 又持续了14天。患者将被分组招募 三组中，每组依次接受更大剂量的 腺病毒。在切除时切除的组织将被分析 腺病毒蛋白表达的证据，RSV-TK DNA(聚合酶链式反应)， 炎症、脑炎和肿瘤坏死。病人的体液 免疫反应将用免疫印迹和中和来分析。 抗腺病毒抗体的血清抗体检测。他们的手机 免疫反应将通过外周血淋巴细胞进行评估 细胞增殖和细胞毒性T细胞检测。将对患者进行监测 发展为颅内压升高，外科手术 并发症，病毒传播到脑脊液，血液，粪便， 呼吸道分泌物和尿液。的大小和代谢活性 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 注射重组腺病毒。它还将提供证据，证明 腺病毒载体注射HSV-TK的疗效及临床应用价值 为未来媒介的发展提供信息。

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.