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 rNDV-hIFNβ-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.
Highlights
Patients with pancreatic adenocarcinoma still have very poor survival rates, and current therapies are of limited effect [1,2]
Five different recombinant NDVs (rNDVs) were generated which were used throughout this study: rNDV-F0, rNDV-GFP-F0, rNDV-hIFNβ-F0, rNDV-NS1-F0 and rNDV-F3aa (Figure 1a)
In our efforts to further develop oncolytic viro-therapy for pancreatic cancer, we focused our attention on the use of recombinant Newcastle disease virus (NDV)
Summary
Patients with pancreatic adenocarcinoma still have very poor survival rates, and current therapies are of limited effect [1,2]. Numerous clinical trials have employed wild type NDV strains either as a direct oncolytic agent, or as an oncolysate vaccine for treatment of patients with various types of advanced stage cancer [6,7,8,9,10,11]. Results of these early trials have been relatively disappointing, illustrated by the lack of further development of these treatment strategies. With the advent of recombinant DNA techniques it has become possible to genetically engineer NDV [12], and interest in the use of recombinant NDV (rNDV) as an oncolytic virus has revived over the last decade [13]
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