Adeno-associated virus vector-mediated systemic delivery of IFN-beta combined with low-dose cyclophosphamide affects tumor regression in murine neuroblastoma models.
OBJECTIVE
Type I IFNs (IFN-alpha/beta) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models.


METHODS
Continuous liver-generated expression of human IFN-beta (hINF-beta) was achieved through a gene therapy-mediated approach using adeno-associated virus vectors encoding hIFN-beta (AAV hINF-beta). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy.


RESULTS
The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-beta. Continued growth of established retroperitoneal tumors, treated with AAV hINF-beta as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-beta. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-beta was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease.


CONCLUSIONS
AAV-mediated delivery of hIFN-beta when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-beta was able to effect complete tumor regression.
Streck
Christian J
CJ
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
Dickson
Paxton V
PV
Ng
Catherine Y C
CY
Zhou
Junfang
J
Gray
John T
JT
Nathwani
Amit C
AC
Davidoff
Andrew M
AM
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D018906:Antineoplastic Agents, Alkylating; D007370:Interferon Type I; D011994:Recombinant Proteins; D003520:Cyclophosphamide