An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virusencoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.

Backward Hopf bifurcation in a mathematical model for oncolytic virotherapy with the infection delay and innate immune effects

“…Acidification of maturing endosomes can induce conformation changes in viral attachment proteins to promote membrane approximation and fusion [26]. An example for this mechanism is the H protein of influenza viruses, which are also studied as potential oncolytic vectors [40,41,42]. Non-enveloped viruses omit the need for membrane fusion and rely on endocytic pathways for entry [39]."…”

Synthetic Virology: Building Viruses to Better Understand Them

“…This not only advances our knowledge about that system and those comparable with it, but it can often lead to entirely new applications. For IAV, reverse genetics has not only enabled a much greater understanding of virus biology, but we are now using the platform to generate recombinant viruses that can be used to treat cancer, generate biologics, or even perform RNA editing (Schmid et al 2014;Pizzuto et al 2016;Hamilton et al 2018). This new area of synthetic virology not only provides greater knowledge through virus building, but it may also hold significant potential as a platform for future therapeutics.…”

Fighting Cancer with Mathematics and Viruses

“…Acidification of maturing endosomes can induce conformation changes in viral attachment proteins to promote membrane approximation and fusion [ 63 ]. An example for this mechanism is the H protein of influenza viruses, which are also studied as potential oncolytic vectors [ 64 , 65 , 66 ]. Non-enveloped viruses omit the need for membrane fusion and rely on endocytic pathways for entry (reviewed in [ 67 ]).…”