Neural Stem Cell Mediated CE-CPT11 Therapy for Neuroblastoma

神经干细胞介导的 CE-CPT11 治疗神经母细胞瘤

基本信息

批准号：
8911385
负责人：
Karen S Aboody
金额：
$ 123.89万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911385
关键词：
Adenoviruses Antineoplastic Agents Applications Grants Biodistribution Camptothecin-11 Cell Line Cells Child Childhood Extracranial Solid Tumor Clinic Clinical Clinical Trials Combined Modality Therapy Data Development Diagnosis Disease remission Dose Elements Enzymes Funding Glioma Goals Health High Pressure Liquid Chromatography Histopathology Home environment Human Human Engineering Image Investigational New Drug Application Iron Label Magnetic Resonance Imaging Mediating Modeling Monitor Mus Neoplasm Metastasis Neural Crest Neuroblastoma Neuroendocrine Tumors Organ Patients Pharmaceutical Preparations Phase I Clinical Trials Pre-Clinical Model Preparation Procedures Prodrugs Production Progressive Disease Recombinants Recurrence Refractory Regimen Relapse Research Residual Tumors SN-38 Safety Saint Jude Children&apos s Research Hospital Schedule Seeds Site Staging Statistical Data Interpretation Sympathetic Nervous System Tail Testing Therapeutic Therapeutic Agents Time Tissues Topoisomerase Inhibitors Toxic effect Toxicology Translating Treatment Efficacy United States Food and Drug Administration United States National Institutes of Health Veins Viral Virus Work animal imaging base cancer site carboxylesterase cell bank cell killing clinically relevant effective therapy ferumoxytol high risk improved in vivo in vivo Model irinotecan meetings migration mouse model mutant nanoparticle neoplastic cell nerve stem cell pediatric patients pre-clinical preclinical study response subcutaneous tandem mass spectrometry tumor

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma is a neuroendocrine tumor, arising from neural crest elements of the sympathetic nervous system, and the most common extracranial solid tumor of childhood. 45% of patients have high-risk tumors, nearly all of which are metastatic (stage 4) when diagnosed. The goal of this U-01 proposal is to identify the optimal dose and schedule of carboxylesterase (CE)-secreting neural stem cells (NSCs) in combination with CPT-11 (Irinotecan) for a tumor selective, more effective treatment of high-risk neuoblastoma. Our goal is to submit an Investigational New Drug application to the United States Food and Drug Administration by the end of the 4 year funding period, and to receive approval to initiate first-in-human clinical trials of this NSC- mediated enzyme/prodrug therapy in pediatric patients with refractory or relapsed high-risk neuroblastoma. We expect that the described approach will have greatest impact in eradicating the minimum residual disease still present when high-risk patients who have achieved clinical complete remission but who a high likelihood of relapsing and ultimately dying of progressive disease. Our previous work demonstrates that: 1) intravenously administered NSCs can selectively localize to neuroblastoma tumor foci in preclinical models and 2) the NSCs can be modified to express levels of a mutant CE that in combination with a clinically relevant schedule of CPT-11 is sufficient to significantly enhance anti-tumor efficacy and long-term survival in these in vivo models. We will expand a GMP Working Cell Bank from our currently established HB1.F3.CD NSC Master Cell Bank (currently approved for clinical use in recurrent glioma patients). We will adenovirally transduce our NSCs to secrete a mutant human CE, hCE1m6, which we have shown efficiently activates the prodrug CPT-11 (irinotecan) to the potent topoisomerase inhibitor and anti-cancer agent SN-38. Preclinical studies will be performed to optimize the NSC.CE and CPT-11 dose and regimen to demonstrate a significant increase the localized anti-tumor efficacy of CPT-11/SN-38 without additional toxicity. Long-term survival efficacy studies, NSC biodistribution, and safety/toxicity studies will be performed in two different preclinical disseminated neuroblastoma models, monitoring NSCs and tumor size by MRI and xenogen imaging.

描述（申请人提供）：神经母细胞瘤是一种神经内分泌肿瘤，起源于交感神经系统的神经嵴元件，是儿童期最常见的颅外实体瘤。 45% 的患者患有高危肿瘤，几乎所有肿瘤在诊断时均已转移（第 4 期）。该 U-01 提案的目标是确定分泌羧酸酯酶 (CE) 的神经干细胞 (NSC) 与 CPT-11（伊立替康）组合的最佳剂量和方案，以对高危肿瘤进行选择性、更有效的治疗神经母细胞瘤。我们的目标是在 4 年资助期结束前向美国食品和药物管理局提交研究性新药申请，并获得批准启动这种 NSC 介导的酶/前药疗法的首次人体临床试验在患有难治性或复发性高危神经母细胞瘤的儿科患者。我们预计，当高危患者已实现临床完全缓解但很有可能复发并最终死于进行性疾病时，所描述的方法将对根除仍然存在的最小残留疾病产生最大影响。我们之前的工作表明：1）静脉注射 NSC 可以在临床前模型中选择性定位于神经母细胞瘤肿瘤灶，2）NSC 可以被修饰以表达突变 CE 的水平，与临床相关的 CPT-11 方案相结合就足够了显着增强这些体内模型的抗肿瘤功效和长期存活率。我们将从目前建立的 HB1.F3.CD NSC 主细胞库（目前已批准用于临床用于复发性神经胶质瘤患者）扩展 GMP 工作细胞库。我们将通过腺病毒转导我们的 NSC 来分泌突变的人类 CE，hCE1m6，我们已经证明它可以有效地将前药 CPT-11（伊立替康）激活为有效的拓扑异构酶抑制剂和抗癌剂 SN-38。将进行临床前研究以优化 NSC.CE 和 CPT-11 的剂量和方案，以证明 CPT-11/SN-38 的局部抗肿瘤功效显着增加，且没有额外的毒性。长期生存疗效研究、NSC 生物分布和安全性/毒性研究将在两种不同的临床前播散性神经母细胞瘤模型中进行，通过 MRI 和异种成像监测 NSC 和肿瘤大小。