Neural Stem Cell Mediated CE-CPT11 Therapy for Neuroblastoma

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素，是儿童最常见的颅外实体瘤。45%的患者患有高危肿瘤，几乎所有的患者在诊断时都已转移（第4期）。这项U-01提案的目标是确定羧酸酯酶（CE）分泌神经干细胞（NSCs）联合CPT-11（伊立替康）的最佳剂量和时间表，以实现肿瘤选择性，更有效地治疗高风险神经母细胞瘤。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一份新药研究申请，并获得批准，在美国开展这种NSC介导的酶/药物前治疗的首次人体临床试验

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.