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），由于其固有的肿瘤嗜性特性和作为将化疗直接递送至脑中浸润性胶质瘤细胞的载体的潜在用途，其在脑肿瘤治疗中具有很大的前景。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。我们首次在人类中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表明，在复发性高级别胶质瘤患者中，一剂神经干细胞随后7天疗程的5-FC是安全可行的。通过脑内微透析，我们证明了神经干细胞在脑内将前药5-FC转化为5-氟尿嘧啶的概念。免疫学相关研究结果显示，首次暴露后无NSC免疫原性证据。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。我们现在已经开发了第二代NSC，其分泌羧酸酯酶（hCE 1 m6）的修饰形式，其更有效地将伊立替康转化为其更强大的代谢物SN-38。基于强有力的临床前有效性和安全性数据，我们计划进行一项颅内给予hCE 1 m6-NSC联合静脉注射伊立替康的I期研究。使用标准的“3 + 3”剂量递增方案，本研究的主要目的是确定复发性高级别胶质瘤患者中基于神经干细胞的治疗的II期推荐剂量（具体目标1）。其他重要的研究目标将是使用脑内微透析来建立关于这些功能的概念验证。 hCE 1 m6-NSC在脑中局部产生高浓度的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可能产生的免疫应答（具体目标3）。