title: Optimization of a Neural Stem-Cell-Mediated Carboxylesterase/Irinotecan Gene Therapy for Metastatic Neuroblastoma.
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.
authors.affiliation: Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Gutova
authors.affiliation: Information Sciences, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Leanne
authors.initials: L
authors.lastname: Goldstein
authors.affiliation: Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Metz
authors.affiliation: Departments of Radiology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Anahit
authors.initials: A
authors.lastname: Hovsepyan
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Tsurkan
authors.affiliation: Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Revathiswari
authors.initials: R
authors.lastname: Tirughana
authors.affiliation: Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Lusine
authors.initials: L
authors.lastname: Tsaturyan
authors.affiliation: Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Annala
authors.affiliation: Department of Cancer Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.affiliation: Children's Center for Cancer and Blood Diseases, CHLA/Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Zesheng
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Children's Center for Cancer and Blood Diseases, CHLA/Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Seeger
authors.affiliation: Department of Pediatric Oncology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Clarke
authors.initials: C
authors.lastname: Anderson
authors.affiliation: Departments of Radiology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Moats
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.affiliation: Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
keywords: CPT-11; NSC; drug delivery; enzyme prodrug; gene therapy; irinotecan; neural stem cells; neuroblastoma