Abstract
Newcastle Disease Virus (NDV) is an avian RNA virus, which was shown to be effective and safe for use in oncolytic viral therapy for several tumour malignancies. The presence of a multi basic cleavage site (MBCS) in the fusion protein improved its oncolytic efficacy in vitro and in vivo. However, NDV with a MBCS can be virulent in poultry. We aimed to develop an NDV with a MBCS but with reduced virulence for poultry while remaining effective in killing human tumour cells. To this end, the open reading frame of the V protein, an avian specific type I interferon antagonist, was disrupted by introducing multiple mutations. NDV with a mutated V gene was attenuated in avian cells and chicken and duck eggs. Although this virus still killed tumour cells, the efficacy was reduced compared to the virulent NDV. Introduction of various mutations in the fusion (F) and hemagglutinin-neuraminidase (HN) genes slightly improved this efficacy. Taken together, these data demonstrated that NDV with a MBCS but with abrogation of the V protein ORF and mutations in the F and HN genes can be safe for evaluation in oncolytic viral therapy.
Highlights
In the last few decades, the use of oncolytic viruses (OVs) as therapy in cancer patients has shown to be a promising treatment strategy with encouraging results for a variety of tumours
The V protein open reading frame (ORF) is only transcribed after a frameshift occurs as the result of stuttering by Optimizing Newcastle Disease Virus (NDV) for use in cancer therapy the viral polymerase protein [24]
In total 95 mutations were introduced, which resulted in the introduction of 15 stop codons in the V protein ORF, yielding the viruses NDV F3aa-STOPV1 and NDV F3aa-STOPV2, respectively (Fig 1A and 1B)
Summary
In the last few decades, the use of oncolytic viruses (OVs) as therapy in cancer patients has shown to be a promising treatment strategy with encouraging results for a variety of tumours. Several oncolytic viruses have been tested in clinical trials with promising results, including Newcastle Disease Virus (NDV) [1,2,3,4]. Several studies have shown that OV therapy using NDV resulted in promising responses in several cancer types both in vitro and in vivo and was even capable of inhibiting metastases and inducing prolonged protection to tumour reoccurrence [5,6,7].
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