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

• 批准号: 9327077
• 负责人: Karen S Aboody
• 金额: $ 94.9万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327077
• 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; Engineering; Enzymes; Funding; Glioma; Goals; High Pressure Liquid Chromatography; Histopathology; Home environment; Human; Human Cloning; Image; Intravenous; Investigational New Drug Application; Iron; Label; Magnetic Resonance Imaging; Mediating; Modeling; Monitor; Mus; Neoplasm Metastasis; Neural Crest; Neuroblastoma; Neuroendocrine Tumors; Organ; Patient risk; 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' s Research Hospital; Schedule; Seeds; Site; 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 invasiveness; cancer site; carboxylesterase; cell bank; cell killing; clinically relevant; effective therapy; efficacy study; ferumoxytol; high risk; imaging study; improved; in vivo; in vivo Model; irinotecan; meetings; migration; mouse model; mutant; nanoparticle; neoplastic cell; nerve stem cell; pediatric patients; pre-clinical; preclinical study; public health relevance; response; safety study; subcutaneous; tandem mass spectrometry; tumor

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脊成分，是儿童最常见的颅外实体肿瘤。45%的患者患有高危肿瘤，几乎所有患者在确诊时都是转移性肿瘤(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(NSCs)与CPT-11(伊立替康)联合应用的最佳剂量和方案，用于肿瘤选择性、更有效地治疗高危新生母细胞瘤。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一份研究新药申请，并获得批准，在#年启动这种NSC介导酶/前药物疗法的首个人体临床试验 儿童难治性或复发的高危神经母细胞瘤患者。我们预计，上述方法将在根除高危患者时仍然存在的最低残留疾病方面产生最大影响，这些高危患者已实现临床完全缓解，但其复发和最终死于进展性疾病的可能性很高。我们以前的工作表明：1)在临床前模型中，静脉注射NSCs可以选择性地定位于神经母细胞瘤肿瘤灶；2)NSCs可以被修饰为表达突变CE的水平，结合临床相关的CPT-11时间表，足以显著提高这些体内模型的抗肿瘤效果和长期生存。我们将在目前建立的HB1.F3.CD NSC主细胞库(目前被批准用于复发性胶质瘤患者的临床使用)的基础上扩展GMP工作细胞库。我们将通过腺病毒转导我们的神经干细胞分泌突变的人CE，hCE1M6，我们已经证明它有效地将前药CPT-11(伊立替康)激活到强大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NSCCE和CPT-11的剂量和方案，以证明CPT-11/SN-38在不增加毒性的情况下显著提高局部抗肿瘤效果。将在两个不同的临床前播散性神经母细胞瘤模型中进行长期生存效率研究、NSC生物分布和安全性/毒性研究，通过MRI和异种物质成像监测NSCs和肿瘤大小。