Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide.
BACKGROUND
We have shown that continuous systemic delivery of interferon beta (IFN-beta) 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-beta could also effect maturation of tumor vasculature without generating high systemic levels of IFN-beta.


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-beta only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-beta in combination with CTX. Two million NPC-IFN-beta 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 (alpha-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 alpha-SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-beta-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either monotherapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver.


CONCLUSIONS
Targeted delivery of IFN-beta with NPCs produced low circulating levels of IFN-beta, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-beta with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.
Sims
Thomas L
TL
Department of Surgery, University of Tennessee Health Science Center, 920 Madison Avenue, Memphis, TN 38163, USA.
Hamner
John B
JB
Bush
Rebecca A
RA
Williams
Regan F
RF
Zhou
Junfang
J
Kim
Seung U
SU
Aboody
Karen S
KS
Danks
Mary K
MK
Davidoff
Andrew M
AM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007275:Injections, Intravenous; D016899:Interferon-beta / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D047368:Tumor Burden
D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D016899:Interferon-beta; D003520:Cyclophosphamide