PILOT STUDY OF DOSE INTENSIFIED PROCARBAZINE, CCNU, VINCRISTINE FOR BRAIN TUMORS

对新诊断的“预后不良”脑肿瘤患者和既往未接受过化疗和全脑放射治疗的复发脑肿瘤患者，采用由丙卡巴肼、环己亚硝脲和阿曲斯汀（PCV）组成的时间压缩化疗4个疗程。 治疗前将通过单采术程序采集外周血干细胞，并在每个化疗疗程后返还给患者。 为了增加骨髓对化疗药物的耐受性，我们建议收集一部分外周血干细胞，从中分离CD 34+细胞，并在逆转录病毒构建体PGK-MGMT中用人O 6-甲基鸟嘌呤DNA甲基转移酶（MGMT）c DNA转导。 这些细胞将在化疗疗程后与未经处理的干细胞一起沿着在疗程#4后返还给患者。 在疗程#2和#3后，仅将未操作的干细胞返还给患者。 这是一种非清髓性方案，在每个周期中输注大量未经操作的单核细胞可最大限度地降低植入不良的风险。主要目的包括以下：1）确定与输注用表达O 6-甲基鸟嘌呤DNA甲基转移酶的逆转录病毒载体转导的CD 34+衍生细胞相关的毒性; 2）确定在重组纤连蛋白片段CH-296存在下进行的细胞遗传修饰的安全性，所述重组纤连蛋白片段CH-296用于帮助逆转录病毒进入哺乳动物细胞; 3）确定在逆转录病毒转导期间暴露于CH-296的细胞植入的任何证据; 4）确定在离体逆转录病毒转导期间输注暴露于CH-296的细胞后针对FN的抗体的证据。

Patients with newly diagnosed "poor prognosis" brain tumors and patients with recurrent brain tumors who have received no prior chemotherapy and no craniospinal radiation therapy will treated with 4 courses of time compressed chemotherapy composed of Procarbazine, CCNU and Vincristine (PCV). Peripheral blood stem cells will be collected by an apheresis procedure prior to treatment and given back to the patient following each course of chemotherapy. To increase the tolerablility of the marrow to the chemotherapy drugs, we propose to collect a portion of the peripheral blood stem cells from which the CD34+ cells will be separated and transduced with the human O6-methylguanine DNA methyltransferase (MGMT) c DNA in the retrovirus construct, PGK-MGMT. These cells, will be given back to the patient following chemotherapy courses, along with unmanipulated stem cells, after course #4. Only unmanipulated stem cells will be given back to the patient following courses #2 and #3. This is a non-myeloablative protocol and the infusion of large number of unmanipulated mononuclear cells during each cycle minimizes the risk of poor engraftment. The primary objectives include the following 1) to determine toxicity associated with infusion of CD34+ derived cells transduced with a retroviral vector expressing O6-methylguanine DNA methyltransferase; 2) to determine the safety of genetic modification of cells carried out in the presence of recombinant fibronectin fragment, CH-296, utilized to assist in retroviral entry into mammalian cells; 3) to determine any evidence of engraftment of cells exposed to CH-296 during retroviral transduction; 4) to determine evidence of antibodies to FN following infusion of cells exposed to CH-296 during ex vivo retroviral transduction.