Neural Stem Cell Mediated CE-CPT11 Therapy for Neuroblastoma

描述（由申请人提供）：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成分，是儿童期最常见的颅外实体瘤。45%的患者患有高风险肿瘤，几乎所有这些肿瘤在诊断时都是转移性的（4期）。该U-01提案的目标是确定羧酸酯酶（CE）分泌神经干细胞（NSC）与CPT-11（伊立替康）联合使用的最佳剂量和时间表，用于高风险神经母细胞瘤的肿瘤选择性，更有效的治疗。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， 患有难治性或复发性高危神经母细胞瘤的儿科患者。我们期望所描述的方法将在消除最小残留疾病方面产生最大的影响，当高风险患者已经达到临床完全缓解，但复发并最终死于疾病进展的可能性很高时仍然存在。我们先前的工作证明：1）静脉内施用的NSC可以选择性地定位于临床前模型中的神经母细胞瘤肿瘤病灶，和2）NSC可以被修饰以表达突变CE的水平，其与CPT-11的临床相关方案组合足以显著增强这些体内模型中的抗肿瘤功效和长期存活。我们将从我们目前建立的HB1.F3.CD NSC主细胞库（目前已批准用于复发性胶质瘤患者的临床使用）中扩增GMP工作细胞库。我们将通过腺病毒转导我们的神经干细胞以分泌突变的人CE（hCE 1 m6），我们已经证明它可以有效地激活前药CPT-11（伊立替康），成为强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著增加而没有额外的毒性。将在两种不同的临床前播散性神经母细胞瘤模型中进行长期生存疗效研究、NSC生物分布和安全性/毒性研究，通过MRI和异种成像监测NSC和肿瘤大小。

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.