STEM-01: NEURAL STEM CELL-MEDIATED ENZYME/PRODRUG THERAPY FOR NEUROBLASTOMA: TRANSLATION TO THE CLINIC

Neuroblastoma (NB), a neuroendocrine tumor, is the most common extracranial solid tumor of childhood. 45% of these patients are diagnosed with metastatic high-risk tumors, for which treatment options are limited. Neural stem cells (NSCs), engineered to secrete a modified carboxylesterase (CE) can home to metastatic neuroblastoma tumor foci in multiple organs, and convert the prodrug CPT-11 (Irinotecan; IRN) to the 1000 fold more potent topoisomerase-1 inhibitor SN-38. The goal of our current efficacy and safety/toxicity IND-enabling studies is to identify the optimal dose and schedule of IV administered NSCs adenovirally transduced to secrete a modified human CE (hCE1m6-NSCs), followed by human equivalent doses of IRN. This would ideally provide a tumor selective, more effective and less toxic treatment for children with high-risk NB. We have determined the in vitro IC50 values of 4 human derived neuroblastoma lines to SN-38, IRN only and IRN + hCE1m6-NSC conditioned media. All NB lines were 500-2000 fold more sensitive to hCE1m6-NSC conditioned media + IRN as compared to IRN alone. In vivo clearance of hCE1m6-NSCs through peripheral organs and circulation in naïve non-tumor bearing Es1^e/SCID mice was within 24h, as detected using PCR analysis. In subcutaneous models of human NB we have quantified NSC tumor distribution and performed pharmacokinetic studies demonstrating tumor-specific conversion of IRN to SN-38. In our metastatic NB mouse models, preliminary results showed that hCE1m6-NSCs in combination with 3 days of IRN (15 mg/kg) had a significant decrease in bioluminescent signal as an indicator of tumor burden, as compared to the IRN only group. Treatment with hCE1m6-NSCs and IRN increased long-term survival of mice bearing CHLA-136 NB tumors. If ongoing IND-enabling studies are successful, we plan to be in phase I studies in pediatric patients with refractory or relapsed high-risk NB by 2018.