Related Experiment Video
Updated: Mar 5, 2026
Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model
Published on: June 4, 2017
Optimization of a Neural Stem-Cell-Mediated Carboxylesterase/Irinotecan Gene Therapy for Metastatic Neuroblastoma
Margarita Gutova1, Leanne Goldstein2, Marianne Metz1
1Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Abstract:
Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000-fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy. We sought to extend these studies by using a clinically relevant NSC line expressing a modified human CE (hCE1m6-NSCs) to establish proof of concept and identify an intravenous dose and treatment schedule that gave maximal efficacy. Human-derived NB cell lines were significantly more sensitive to treatment with hCE1m6-NSCs and irinotecan as compared with drug alone. This was supported by pharmacokinetic studies in subcutaneous NB mouse models demonstrating tumor-specific conversion of irinotecan to SN-38. Furthermore, NB-bearing mice that received repeat treatment with intravenous hCE1m6-NSCs and irinotecan showed significantly lower tumor burden (1.4-fold, p = 0.0093) and increased long-term survival compared with mice treated with drug alone. These studies support the continued development of NSC-mediated gene therapy for improved clinical outcome in NB patients.
Insights
Neural stem cell (NSC)-mediated gene therapy using human carboxylesterase 1 modified NSCs (hCE1m6-NSCs) effectively targets recurrent neuroblastoma (NB). This approach enhances irinotecan
Area of Science:
- Oncology
- Gene Therapy
- Neuroscience
Background:
- Recurrent neuroblastoma (NB) presents significant challenges due to limited treatment options and cumulative toxicity.
- Previous studies showed efficacy using rabbit carboxylesterase (rCE)-expressing neural stem cells (NSCs) to convert irinotecan to its toxic form, SN-38, in NB mouse models.
- Developing a clinically relevant human-derived NSC system is crucial for advancing this therapeutic strategy.
Purpose of the Study:
- To evaluate the therapeutic potential of human carboxylesterase 1 modified NSCs (hCE1m6-NSCs) in treating neuroblastoma.
- To establish proof of concept for intravenous delivery and optimize dosing and treatment schedules for maximal efficacy.
- To assess the sensitivity of human NB cell lines and the in vivo efficacy in NB mouse models.
Main Methods:
- Utilized a clinically relevant human-derived NSC line engineered to express a modified human carboxylesterase (hCE1m6-NSCs).
- Administered hCE1m6-NSCs and the prodrug irinotecan (CPT-11) intravenously to subcutaneous and metastatic NB mouse models.
- Conducted pharmacokinetic studies to confirm tumor-specific conversion of irinotecan to SN-38 and assessed tumor burden and survival rates.
Main Results:
- Human-derived NB cell lines demonstrated significantly increased sensitivity to hCE1m6-NSCs and irinotecan compared to irinotecan alone.
- Pharmacokinetic studies confirmed tumor-specific conversion of irinotecan to SN-38 in vivo.
- Mice receiving repeat intravenous treatment with hCE1m6-NSCs and irinotecan exhibited a 1.4-fold reduction in tumor burden and improved long-term survival.
Conclusions:
- NSC-mediated gene therapy using hCE1m6-NSCs offers a promising strategy for treating neuroblastoma.
- The approach demonstrates tumor-specific drug activation and enhances therapeutic efficacy, reducing tumor burden and improving survival.
- These findings support the further clinical development of NSC-based gene therapy for improved neuroblastoma patient outcomes.
