634. Translation of a Neural Stem Cell-Mediated Enzyme/Prodrug Gene Therapy for Metastatic Neuroblastoma

Neuroblastoma (NB), a neuroendocrine tumor, is the most common extracranial solid tumor of childhood. Forty-five percent of these patients are diagnosed with metastatic high-risk tumors, for which treatment options are limited both in anti-tumor efficacy and patient tolerance. We have previously shown that neural stem cells (NSCs), engineered to secrete a modified rabbit carboxylesterase (CE), can home to metastatic NB tumor foci, and convert the prodrug CPT-11 (Irinotecan; IRN) to the 1000-fold more potent anti-cancer agent SN-38, resulting in significant therapeutic efficacy. The goal of our current biodistribution, efficacy and safety/toxicity IND-enabling studies is to identify the optimal dose and schedule of intravenously administered clinically relevant NSCs secreting a modified human CE (hCE1m6), followed by human equivalent doses of irinotecan. This would ideally provide a tumor selective, more effective and less toxic treatment for children with high-risk NB.In vitro cytotoxicity studies demonstrated IC50 values for four human NB tumors were significantly more sensitive to CPT-11 in the presence of hCE1m6 (similar to treatment with SN-38) compared to IRN alone. The sensitivity of NB tumor cells to CPT-11 was enhanced ≈6000-fold by hCE1m6 for KCNR tumor, while the sensitivity of SKNAS cells was enhanced ≈1200-fold for SKNAS, and approximately 150 to 600-fold decrease in IC50s of IRN for CHLA-136 and CHLA-255 NB cells. In vivo qPCR and MRI studies demonstrate NSC clearance through normal circulation and organs (lung, liver, brain) in naive non-tumor bearing Es1e/SCID mice is 24h following intravenous adminstration. In subcutaneous models of human NB we have quantified NSC tumor distribution and performed pharmacokinetics studies demonstrating a significant increase in tumor specific conversion of IRN to SN-38 with the CE-NSCs. Therapeutic efficacy studies are ongoing. If successful, we plan to be in Phase I studies in pediatric patients with refractory or relapsed high-risk neuroblastoma. This would be a first-in-human use of NSC-mediated enzyme/prodrug therapy in metastatic cancer patients.