title: 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 virus-encoded 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.
authors.affiliation: Imperial College London, Faculty of Medicine, Division of Infectious Disease, 8 Norfolk Place, London W2 1PG, UK.
authors.forename: Matteo Samuele
authors.initials: MS
authors.lastname: Pizzuto
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Silic-Benussi
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ciminale
authors.affiliation: Imperial College London, Faculty of Medicine, Division of Infectious Disease, 8 Norfolk Place, London W2 1PG, UK.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Elderfield
authors.affiliation: OIE/FAO and National Reference Laboratory for Avian Influenza A Virus, Istituto Zooprofilattico Sperimentale delle Venezie, Padua, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Capua
authors.affiliation: Imperial College London, Faculty of Medicine, Division of Infectious Disease, 8 Norfolk Place, London W2 1PG, UK.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Barclay
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism; D057920:Influenza A Virus, H7N3 Subtype / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000302:isolation & purification*; D017384:Sequence Deletion; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: C085820:INS1 protein, influenza virus; D007155:Immunologic Factors; D017361:Viral Nonstructural Proteins