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Viruses 2015, 7(6), 2980-2998; doi:10.3390/v7062756

Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma

1
Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
2
Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editors: Martine L.M. Lamfers and E. Antonio Chiocca
Received: 10 February 2015 / Revised: 7 May 2015 / Accepted: 8 June 2015 / Published: 11 June 2015
(This article belongs to the Special Issue Oncolytic Viruses)
View Full-Text   |   Download PDF [980 KB, uploaded 11 June 2015]   |  

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-F\(_{\rm{0}}\)) or an IFN antagonistic protein (rNDV-NS1-F\(_{\rm{0}}\)), as well as rNDV with increased virulence (rNDV-F\(_{\rm{3aa}}\)) 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-F\(_{\rm{3aa}}\)) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ -F\(_{\rm{0}}\), while inoculation with rNDV-NS1-F\(_{\rm{0}}\) resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F\(_{\rm{3aa}}\) caused markedly more cytotoxicity compared to rNDV-F\(_{\rm{0}}\), while inoculation with rNDV-hIFNβ -F\(_{\rm{0}}\) and rNDV-NS1-F\(_{\rm{0}}\) induced cytotoxic effects comparable to those induced by the parental rNDV-F\(_{\rm{0}}\). Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F\(_{\rm{3aa}}\) 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. View Full-Text
Keywords: oncolytic virus; oncolytic virotherapy; Newcastle disease virus; pancreatic adenocarcinoma; innate immunity; immunotherapy oncolytic virus; oncolytic virotherapy; Newcastle disease virus; pancreatic adenocarcinoma; innate immunity; immunotherapy
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Buijs, P.; van Nieuwkoop, S.; Vaes, V.; Fouchier, R.; van Eijck, C.; Hoogen, B. Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma. Viruses 2015, 7, 2980-2998.

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