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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., Competing Interests: The authors have declared that no competing interests exist.

Oncolytic virotherapies, including the modified herpes simplex virus talimogene laherparepvec (T-VEC), have shown great promise as potent instigators of anti-tumour immune effects. The OPTiM trial, in particular, demonstrated the superior anti-cancer effects of T-VEC as compared to systemic immunotherapy treatment using exogenous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Theoretically, a combined approach leveraging exogenous cytokine immunotherapy and oncolytic virotherapy would elicit an even greater immune response and improve patient outcomes. However, regimen scheduling of combination immunostimulation and T-VEC therapy has yet to be established. Here, we calibrate a computational biology model of sensitive and resistant tumour cells and immune interactions for implementation into an in silico clinical trial to test and individualize combination immuno- and virotherapy. By personalizing and optimizing combination oncolytic virotherapy and immunostimulatory therapy, we show improved simulated patient outcomes for individuals with late-stage melanoma. More crucially, through evaluation of individualized regimens, we identified determinants of combination GM-CSF and T-VEC therapy that can be translated into clinically-actionable dosing strategies without further personalization. Our results serve as a proof-of-concept for interdisciplinary approaches to determining combination therapy, and suggest promising avenues of investigation towards tailored combination immunotherapy/oncolytic virotherapy., Competing Interests: The authors have declared that no competing interests exist.

While virus growth dynamics have been well-characterized in several infections, data are typically collected once the virus population becomes easily detectable. Earlier dynamics, however, remain less understood. We recently reported unusual early dynamics in an experimental system using adenovirus infection of human embryonic kidney (293) cells. Under identical experimental conditions, inoculation at low infection multiplicities resulted in either robust spread, or in limited spread that eventually stalled, with both outcomes occurring with approximately equal frequencies. The reasons underlying these observations have not been understood. Here, we present further experimental data showing that inhibition of interferon-induced antiviral states in cells results in a significant increase in the percentage of robust infections that are observed, implicating a race between virus replication and the spread of the anti-viral state as a central mechanism. Analysis of a variety of computational models, however, reveals that this alone cannot explain the simultaneous occurrence of both viral growth outcomes under identical conditions, and that additional biological mechanisms have to be invoked to explain the data. One such mechanism is the ability of the virus to overcome the antiviral state through multiple infection of cells. If this is included in the model, two outcomes of viral spread are found to be simultaneously stable, depending on initial conditions. In stochastic versions of such models, the system can go by chance to either state from identical initial conditions, with the relative frequency of the outcomes depending on the strength of the interferon-based anti-viral response, consistent with the experiments. This demonstrates considerable complexity during the early phase of the infection that can influence the ability of a virus to become successfully established. Implications for the initial dynamics of oncolytic virus spread through tumors are discussed., Competing Interests: The authors have declared that no competing interests exist.

Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.