title: Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma.
abstract: Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F₀) or an IFN antagonistic protein (rNDV-NS1-F₀), as well as rNDV with increased virulence (rNDV-F₃aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F₃aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ -F₀, while inoculation with rNDV-NS1-F₀ resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F₃aa caused markedly more cytotoxicity compared to rNDV-F₀, while inoculation with rNDVβ-hIFN -F₀ and rNDV-NS1-F₀ induced cytotoxic effects comparable to those induced by the parental rNDV-F₀. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F₃aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.
authors.affiliation: Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. p.buijs@erasmusmc.nl.
authors.forename: Pascal
authors.initials: P
authors.lastname: Buijs
authors.affiliation: Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. s.vannieuwkoop@erasmusmc.nl.
authors.forename: Stefan
authors.initials: S
authors.lastname: van Nieuwkoop
authors.affiliation: Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. v.vaes@erasmusmc.nl.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vaes
authors.affiliation: Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. r.fouchier@erasmusmc.nl.
authors.forename: Ron
authors.initials: R
authors.lastname: Fouchier
authors.affiliation: Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. c.vaneijck@erasmusmc.nl.
authors.forename: Casper
authors.initials: C
authors.lastname: van Eijck
authors.affiliation: Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. b.vandenhoogen@erasmusmc.nl.
authors.forename: Bernadette
authors.initials: B
authors.lastname: van den Hoogen
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D009522:Newcastle disease virus / Q000235:genetics / Q000254:growth & development*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
keywords: Newcastle disease virus; immunotherapy; innate immunity; oncolytic virotherapy; oncolytic virus; pancreatic adenocarcinoma