A Phase I Study of Intracranially Administered Carboxylesterase-Expressing Neural Stem Cells in Combination with Intravenous Irinotecan in Patients with Recurrent High Grade Gliomas

颅内给予表达羧酸酯酶的神经干细胞联合静脉注射伊立替康治疗复发性高级别胶质瘤患者的 I 期研究

• 批准号: 9336834
• 负责人: Karen S Aboody
• 金额: --
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336834
• 关键词: Adenovirus Vector; Adverse effects; Allogenic; Animal Model; Antibody Response; Antibody titer measurement; Antineoplastic Agents; Autopsy; Blood - brain barrier anatomy; Blood specimen; Brain; Brain Neoplasms; Catheters; Cell Line; Cell Therapy; Cell surface; Cells; Central Nervous System Neoplasms; Clinical; Contralateral; Correlative Study; Cytosine deaminase; Data; Development; Dialysis procedure; Distant; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Effectiveness; Enzymes; Extracellular Fluid; Flucytosine; Fluorouracil; Foundations; Future; Generations; Glioma; Goals; Home environment; Human; Immune; Immune response; Immunologics; Intestines; Intravenous; Liver; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediating; Microdialysis; Mus; Neoplasm Metastasis; Neuraxis; Normal tissue morphology; Oncologist; Oral; Participant; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Pilot Projects; Plasma; Primary Brain Neoplasms; Prodrugs; Production; Property; Proteins; Recurrence; Residual Tumors; SN-38; Safety; Sampling Studies; Site; System; T-Cell Development; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment-related toxicity; animal data; base; cancer therapy; carboxylesterase; chemotherapy; clinically relevant; design; fetal; gene product; gene therapy; immunogenicity; improved; in vivo; irinotecan; killings; molecular targeted therapies; neoplastic cell; nerve stem cell; novel therapeutics; patient subsets; phase 1 study; pre-clinical; preclinical efficacy; preclinical safety; prevent; public health relevance; response; safety and feasibility; therapeutic gene; therapeutic transgene; tumor; v-myc Gene

 DESCRIPTION (provided by applicant): Human neural stem cells (NSCs), modified to express a therapeutic transgene, hold great 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 can 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. Our first-in-human pilot study of cytosine deaminase (CD)-expressing NSCs given in combination with oral 5-fluorocytosine (5-FC) demonstrated 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 micro dialysis, we documented proof-of-concept-that the NSCs converted the prodrug 5-FC to 5-fluorouracil in the brain. 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. We have now developed a second generation of NSCs that secrete a modified form of the enzyme carboxylesterase (hCE1m6), which more efficiently converts irinotecan to its more powerful metabolite SN-38. Based on strong preclinical efficacy and safety data, we plan to perform a phase I study of intracranially administered hCE1m6 -NSCs in combination with intravenous irinotecan. Using a standard "3 + 3" dose escalation schema, the primary objective of this study will be to define the phase II recommended doses of this neural stem cell-based treatment in patients with recurrent high grade gliomas (Specific Aim 1). Other important study objectives will be to use intracerebral micro dialysis to establish proof-of-concept regarding the ability of these hCE1m6-NSCs to produce high concentrations of SN-38 locally in the brain (Specific Aim 2), and perform immunologic correlative studies to assess for the possible development of immune responses to these NSCs in study participants (Specific Aim 3).

 描述（由申请人提供）：经过修饰以表达治疗性转基因的人神经干细胞（NSC）由于其固有的亲肿瘤特性以及作为直接向浸润性神经胶质瘤细胞递送化疗的载体的潜在用途，对脑肿瘤治疗具有巨大的前景神经干细胞可以克服限制当前基因治疗策略的药物输送障碍，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神经干细胞在追踪侵袭性肿瘤细胞以及远处的肿瘤细胞方面的安全性和有效性。我们对表达胞嘧啶脱氨酶 (CD) 的 NSC 与口服 5-氟胞嘧啶 (5-FC) 联合进行的首次人体试点研究表明，一剂 NSC 随之而来。通过脑内微透析治疗复发性高级别神经胶质瘤患者进行为期 7 天的 5-FC 治疗是安全可行的，我们记录了概念证明： NSC 在大脑中将前药 5-FC 转化为 5-氟尿嘧啶。 免疫相关研究结果显示，首次暴露后没有 NSC 免疫原性的证据，证明 NSC 迁移到远处的肿瘤部位，并且没有分裂并形成继发性肿瘤。我们现在已经开发出第二代 NSC，它可以分泌经过修饰的羧酸酯酶 (hCE1m6)，它可以更有效地将伊立替康转化为更强大的药物。基于强大的临床前疗效和安全性数据，我们计划使用标准的“3 + 3”剂量递增方案对颅内给药的 hCE1m6 -NSC 进行 I 期研究。这项研究将确定这种基于神经干细胞的治疗对于复发性高级别神经胶质瘤患者的 II 期推荐剂量（具体目标 1）。将使用脑内微透析来建立关于这些能力的概念验证 hCE1m6-NSC 在大脑局部产生高浓度的 SN-38（具体目标 2），并进行免疫相关研究以评估研究参与者对这些 NSC 可能产生的免疫反应（具体目标 3）。