Phase 1 Study of Neural Stem Cells & 5-FC/Leucovorin for the Treatment of Recurrent High Grade Gliomas

描述（由申请人提供）： 经修饰以表达治疗性转基因的人神经干细胞（NSC）可能有望用于脑肿瘤治疗，这是由于其固有的肿瘤嗜性特性和作为用于将化疗直接递送至脑中的浸润性胶质瘤细胞的载体的潜在用途。神经干细胞可以克服药物递送的障碍，这些障碍限制了目前的基因治疗策略，以提供有效的抗肿瘤反应。 来自动物模型的数据已经证明了NSC用于追踪侵袭性肿瘤细胞以及远端微肿瘤病灶并向肿瘤细胞递送治疗性基因产物的安全性和有效性。研究人员最近完成了一项首次在人体内进行的胞嘧啶脱氨酶（CD）表达的神经干细胞与口服5-氟胞嘧啶（5-FC）联合给药的初步研究，证明了一剂神经干细胞随后7天疗程的5-FC在复发性高级别胶质瘤患者中是安全可行的。通过脑内微透析，研究人员报告说，他们记录了概念验证-NSC在大脑中将前药5-FC转化为其活性代谢物5-FU。据报道，免疫学相关研究结果显示，首次暴露后无NSC免疫原性的证据。尸检数据提供的证据表明，神经干细胞迁移到远处的肿瘤部位，并没有分裂和形成继发性肿瘤。 研究人员建议，这种新的神经胶质瘤治疗策略的临床开发的下一步是进行1期试验，以评估颅内重复给予这些同种异体神经干细胞的可行性，同时继续剂量递增，以确定2期推荐的研究治疗剂量。一旦确定了NSC和5-FC联合治疗的MTD，将在治疗方案中添加可增强5-FU疗效并可穿过血脑屏障的甲酰四氢叶酸。研究者将继续监测患者是否可能发生针对NSC的免疫反应，通过铁标记NSC研究NSC在MRI上的分布，并在研究治疗的MTD下通过脑内微透析测量NSC将5-FC转化为5-FU。 预期在多种癌症中对这种治疗策略进行更大规模的疗效研究 中心，这项拟议的单中心I期研究将评估最近优化的NSC生产和最终制备标准操作规程的可行性。研究人员建议，在给予患者之前建立一个简化的最终NSC制备过程，将使NSC能够在未来的多中心NSC试验中在其他治疗地点分发和轻松使用。

DESCRIPTION (provided by applicant): Human neural stem cells (NSCs), modified to express a therapeutic transgene, may hold promise for brain tumor therapy due to their inherent tumor-tropic properties and potential use as vehicles for delivering chemotherapy directly to infiltrating glioma cells in the brain. NSCs ca overcome obstacles of drug-delivery that limit current gene therapy strategies to provide an effective anti-tumor response. Data from animal models have demonstrated the safety and efficacy of NSCs for tracking to invasive tumor cells as well as to distant micro-tumor foci and delivering therapeutic gene products to tumor cells. The investigators have recently completed a first-in-human pilot study of cytosine deaminase (CD)-expressing NSCs given in combination with oral 5-fluorocytosine (5-FC), demonstrating that one dose of NSCs followed by a 7-day course of 5-FC in recurrent high-grade glioma patients was safe and feasible. With intracerebral microdialysis, the investigators reported that they documented proof-of-concept-that the NSCs convert the prodrug 5-FC to its active metabolite 5-FU in the brain. It was reported that results of immunologic correlative studies showed no evidence of NSC immunogenicity after first exposure. Autopsy data provided evidence that NSCs migrated to distant tumor sites and did not divide and form secondary tumors. The investigators propose that the next step in the clinical development of this new treatment strategy for gliomas is to perform a Phase 1 trial to assess the feasibility of intracranially administering repeat doses of these allogeneic NSCs while continuing to dose escalate to determine the Phase 2 recommended doses of study treatment. Leucovorin, which enhances the efficacy of 5-FU and can cross the blood-brain barrier, will be added to the treatment regimen once the MTD for the combination of NSCs and 5-FC has been identified. The investigators will continue to monitor patients for possible development of immune reactivity against NSCs, study the distribution NSCs on MRI by iron-labeling the NSCs, and measure NSC conversion of 5-FC to 5-FU via intracerebral microdialysis at the MTD of study treatment. In anticipation of performing larger efficacy studies of this treatment strategy at multiple cancer centers, this proposed single center Phase 1 study will assess the feasibility of recently optimized NSC manufacturing and final preparation standard operating procedures. The investigators propose that establishing a simplified process for final NSC preparation before administering to a patient will enable the NSCs to be distributed and easily used at other treatment sites in future multi-center NSC trials.