Poster Presentation Advances in Neuroblastoma Research Congress 2016

Neural stem cell-mediated enzyme/prodrug therapy for neuroblastoma: translation to the clinic (#281)

Margarita Gutova 1 , Leanne Goldstein 2 , Marianne Metz 1 , Anahit Hovsepyan 3 , Lyudmila Tsurkan 4 , Revathiswari Tirughana 1 , Zhongqi Li 1 , Timothy W Synold 5 , Robert Seeger 6 , Philip M Potter 4 , Clarke Anderson 1 , Rex A Moats 3 , Karen S Aboody 1
  1. Department of Developmental and Stem Cell Biology, City of Hope National Cancer Center and Beckman Research Imstitute, Duarte, CA, USA
  2. Department of Biostatistics, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
  3. Departments of Radiology, Childre's Hospital Los Angeles, Keck School of Medicine, Los Angeles, CA, USA
  4. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
  5. Department of Cancer Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
  6. Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California, USA
Although survival for neuroblastoma (NB) in newly diagnosed high-risk children has improved, recurrent disease remains a significant problem with treatment options limited by both anti-tumor efficacy and patient tolerance. We previously demonstrated that neural stem cells (NSCs), engineered to secrete a modified rabbit carboxylesterase (rCE-NSCs) can distribute 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, 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 NSCs adenovirally transduced to secrete a modified human CE (hCE1m6), followed by human equivalent doses of IRN. This would ideally provide a tumor selective, more effective and potentially less toxic delivery of treatment for children with recurrent high-risk NB. We have now determined the in vitro IC50 values of 4 human derived NB lines to SN-38, IRN only and IRN + hCE1m6-NSC conditioned media. IC50 values of IRN were decreased by 500 to 6000-fold when IRN was used in combination with the hCE1m6 conditioned media for all NB cell lines (KCNR, SKNAS, CHLA-136 and CHLA-255). In subcutaneous models of human NB we demonstrated tumor-specific conversion of IRN to SN-38. We have also shown clearance of hCE1m6-NSCs through peripheral organs and circulation in non-tumor bearing Es1e/SCID mice by quantitative PCR. Repeated treatments with hCE1m6-NSCs in combination with intravenous IRN (15 mg/kg x 3 days) had a significant decrease of tumor burden (as measured by bioluminescent imaging) for CHLA-136 (1.6-fold /p = 0.003) and CHLA-255 (0.6-fold/p= 0.04) vs. IRN only group in metastatic tumor models. hCE1m6-NSCs with IRN increased long-term survival of mice bearing CHLA-136 and CHLA-255 NB tumors. These studies suggest NSC-mediated enzyme/prodrug therapy may have potential benefit for NB patients.