title: Oncolytic Group B Adenovirus Enadenotucirev Mediates Non-apoptotic Cell Death with Membrane Disruption and Release of Inflammatory Mediators.
abstract: Enadenotucirev (EnAd) is a chimeric group B adenovirus isolated by bioselection from a library of adenovirus serotypes. It replicates selectively in and kills a diverse range of carcinoma cells, shows effective anticancer activity in preclinical systems, and is currently undergoing phase I/II clinical trials. EnAd kills cells more quickly than type 5 adenovirus, and speed of cytotoxicity is dose dependent. The EnAd death pathway does not involve p53, is predominantly caspase independent, and appears to involve a rapid fall in cellular ATP. Infected cells show early loss of membrane integrity; increased exposure of calreticulin; extracellular release of ATP, HSP70, and HMGB1; and influx of calcium. The virus also causes an obvious single membrane blister reminiscent of ischemic cell death by oncosis. In human tumor biopsies maintained in ex vivo culture, EnAd mediated release of pro-inflammatory mediators such as TNF-α, IL-6, and HMGB1. In accordance with this, EnAd-infected tumor cells showed potent stimulation of dendritic cells and CD4+T cells in a mixed tumor-leukocyte reaction in vitro. Whereas many viruses have evolved for efficient propagation with minimal inflammation, bioselection of EnAd for rapid killing has yielded a virus with a short life cycle that combines potent cytotoxicity with a proinflammatory mechanism of cell death.
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Dyer
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Di
authors.affiliation: PsiOxus Therapeutics, Ltd., Milton Park, Abingdon OX14 4SD, UK.
authors.forename: Hugo
authors.initials: H
authors.lastname: Calderon
authors.affiliation: PsiOxus Therapeutics, Ltd., Milton Park, Abingdon OX14 4SD, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Illingworth
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Gray
authors.initials: G
authors.lastname: Kueberuwa
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Tedcastle
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Jakeman
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Suet Lin
authors.initials: SL
authors.lastname: Chia
authors.affiliation: PsiOxus Therapeutics, Ltd., Milton Park, Abingdon OX14 4SD, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Brown
authors.affiliation: Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Barlow
authors.affiliation: PsiOxus Therapeutics, Ltd., Milton Park, Abingdon OX14 4SD, UK.
authors.forename: John
authors.initials: J
authors.lastname: Beadle
authors.affiliation: Bayer HealthCare, 455 Mission Bay Blvd. S., San Francisco, CA 94158, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Hermiston
authors.affiliation: Nuffield Department of Clinical Laboratory Science, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.affiliation: PsiOxus Therapeutics, Ltd., Milton Park, Abingdon OX14 4SD, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Champion
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Kerry D
authors.initials: KD
authors.lastname: Fisher
authors.affiliation: Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Seymour
keywords: adenovirus; apoptosis; cell death; membrane permeabilization; oncolytic virus; oncosis