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Neural Progenitor Cell-mediated Delivery of Interferon Beta Improves Neuroblastoma Response to Cyclophosphamide

¹ Department of Surgery, University of Tennessee Health Science Center, 920 Madison Avenue, Memphis, TN 38163, USA
² Department of Surgery, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
³ Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
⁴ Institute for Regenerative Medicine, Gachon University Gil Hospital, Inchon, Korea
⁵ Department of Medicine, University of British Columbia, Koerner Pavilion, 211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5
⁶ Division of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, 1500 E Duarte Road, Duarte, CA 91010, USA

Correspondence: Address correspondence and reprint requests to: Andrew M. Davidoff, MD; E-mail: andrew.davidoff{at}stjude.org

Background: We have shown that continuous systemic delivery of interferon beta (IFN-b) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-b could also effect maturation of tumor vasculature without generating high systemic levels of IFN-b.

Methods: Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-b only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-b in combination with CTX. Two million NPC-IFN-b cells were administered twice, 7 days apart, starting 21 days after tail vein administration of tumor cells. CTX was administered every 6 days for three doses. Mice were killed at 6 weeks, livers and kidneys weighed, and tumor removed for immunohistochemical staining for endothelial cells (CD34), pericytes (-SMA), apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick-end labeling]), and diI-labeled NPCs.

Results: Fluorescent-labeled NPCs confirmed localization of these cells to tumors. The -SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-b-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either mono-therapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver.

Conclusions: Targeted delivery of IFN-b with NPCs produced low circulating levels of IFN-b, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-b with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.