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

神经干细胞的一期研究

• 批准号: 8896311
• 负责人: Karen S Aboody
• 金额: $ 20万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896311
• 关键词: Phase; Study; Neural; Stem; Cells

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.

描述（由申请人提供）： 经过修饰以表达治疗性转基因的人类神经干细胞（NSC）可能有望用于脑肿瘤治疗，因为它们具有固有的亲肿瘤特性，并且有可能用作直接向大脑中浸润的神经胶质瘤细胞提供化疗的载体。 NSC 可以克服限制当前基因治疗策略的药物递送障碍，以提供有效的抗肿瘤反应。 来自动物模型的数据证明了 NSC 追踪侵袭性肿瘤细胞以及远处微肿瘤灶并向肿瘤细胞递送治疗基因产物的安全性和有效性。研究人员最近完成了一项针对表达胞嘧啶脱氨酶 (CD) 的 NSC 与口服 5-氟胞嘧啶 (5-FC) 联合给药的首次人体试验研究，结果表明，一剂 NSC 后接受为期 7 天的疗程5-FC治疗复发性高级别胶质瘤患者是安全可行的。研究人员报告称，通过脑内微透析，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，首次暴露后没有证据表明 NSC 具有免疫原性。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，并且没有分裂并形成继发性肿瘤。 研究人员提出，这种新的神经胶质瘤治疗策略临床开发的下一步是进行一期试验，以评估颅内重复剂量这些同种异体 NSC 的可行性，同时继续增加剂量以确定二期推荐剂量研究治疗。一旦 NSC 和 5-FC 组合的 MTD 确定后，亚叶酸可以增强 5-FU 的功效并可以穿过血脑屏障，将被添加到治疗方案中。研究人员将继续监测患者可能出现的针对 NSC 的免疫反应，通过对 NSC 进行铁标记来研究 MRI 上 NSC 的分布，并通过脑内微透析在研究治疗的 MTD 下测量 NSC 向 5-FU 的转化。 预计对该治疗策略对多种癌症进行更大规模的疗效研究 中心，这项拟议的单中心第一阶段研究将评估最近优化的 NSC 制造和最终制备标准操作程序的可行性。研究人员建议，在给予患者之前建立一个最终 NSC 制备的简化流程，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。