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.

Public Health Relevance

Neuroblastoma is the most common extracranial solid tumor of childhood, with 45% of these patients diagnosed with metastatic high-risk tumors and having limited treatment options. Neural stem cells (NSCs) can home to invasive cancer sites, which make them a promising delivery vehicle for therapeutic agents. The goal of this U-01 proposal is to identify the optimal dose and schedule of enzyme-secreting NSCs that will convert the prodrug CPT-11 (Irinotecan) to the potent anti-cancer agent SN-38 locally at the tumor sites -potentially providing a tumor selective, more effective and less toxic treatment for children with high-risk neuoblastoma. NOTE: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Mcgavern, Linda
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City of Hope/Beckman Research Institute
United States
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