PMID- 29898782 OWN - NLM STAT- MEDLINE DCOM- 20191025 LR - 20240210 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 6 IP - 1 DP - 2018 Jun 13 TI - Expression of human CD46 and trans-complementation by murine adenovirus 1 fails to allow productive infection by a group B oncolytic adenovirus in murine cancer cells. PG - 55 LID - 10.1186/s40425-018-0350-x [doi] LID - 55 AB - BACKGROUND: Oncolytic viruses are currently experiencing accelerated development in several laboratories worldwide, with some forty-seven clinical trials currently recruiting. Many oncolytic viruses combine targeted cytotoxicity to cancer cells with a proinflammatory cell lysis. Due to their additional potential to express immunomodulatory transgenes, they are also often known as oncolytic viral vaccines. However, several types of oncolytic viruses are human-specific and the lack of suitable immune-competent animal models complicates biologically relevant evaluation of their vaccine potential. This is a particular challenge for group B adenoviruses, which fail to infect even those immunocompetent animal model systems identified as semi-permissive for type 5 adenovirus. Here, we aim to develop a murine cell line capable of supporting replication of a group B oncolytic adenovirus, enadenotucirev (EnAd), for incorporation into a syngeneic immunocompetent animal model to explore the oncolytic vaccine potential of group B oncolytic viruses. METHODS: Transgenic murine cell lines were infected with EnAd expressing GFP transgene under replication-independent or -dependent promoters. Virus mRNA expression, genome replication, and late protein expression were determined by qRT-PCR, qPCR, and immunoblotting, respectively. We also use Balb/c immune-competent mice to determine the tumourogenicity and infectivity of transgenic murine cell lines. RESULTS: Our results show that a broad range of human carcinoma cells will support EnAd replication, but not murine carcinoma cells. Murine cells can be readily modified to express surface human CD46, one of the receptors for group B adenoviruses, allowing receptor-mediated uptake of EnAd particles into the murine cells and expression of CMV promoter-driven transgenes. Although the early E1A mRNA was expressed in murine cells at levels similar to human cells, adenovirus E2B and Fibre mRNA expression levels were hampered and few virus genomes were produced. Unlike previous reports on group C adenoviruses, trans-complementation of group B adenoviruses by co-infection with mouse adenovirus 1 did not rescue replication. A panel of group B adenoviruses expressing individual mouse adenovirus 1 genes were also unable to rescue EnAd replication. CONCLUSION: Together, these results indicate that there may be major differences in the early stages of replication of group C and B adenoviruses in murine cells, and that the block to the life cycle of B adenoviruses in murine cells occurs in the early stage of virus replication, perhaps reflecting poor activity of Ad11p E1A in murine cells. FAU - Lei, Janet AU - Lei J AD - 0000 0004 1936 8948grid.4991.5Department of OncologyUniversity of Oxford OX3 7DQ Oxford UK janet.lei@oncology.ox.ac.uk. FAU - Jacobus, Egon J AU - Jacobus EJ AD - 0000 0004 1936 8948grid.4991.5Department of OncologyUniversity of Oxford OX3 7DQ Oxford UK egon.jacobus@oncology.ox.ac.uk. FAU - Taverner, William K AU - Taverner WK AD - 0000 0004 1936 8948grid.4991.5Department of OncologyUniversity of Oxford OX3 7DQ Oxford UK william.taverner@dtc.ox.ac.uk. FAU - Fisher, Kerry D AU - Fisher KD AD - 0000 0004 1936 8948grid.4991.5Department of OncologyUniversity of Oxford OX3 7DQ Oxford UK Kerry.fisher@oncology.ox.ac.uk. FAU - Hemmi, Silvio AU - Hemmi S AD - 0000 0004 1937 0650grid.7400.3Institute of Molecular Life SciencesUniversity of Zurich Zurich Switzerland silvio.hemmi@imls.uzh.ch. FAU - West, Katy AU - West K AD - 0000 0004 0394 8673grid.476643.4PsiOxus Therapeutics Ltd PsiOxus House, 4-10 The Quadrant, Barton Lane OX14 3YS Abingdon Oxfordshire UK katy.west@psioxus.com. FAU - Slater, Lorna AU - Slater L AD - 0000 0004 0394 8673grid.476643.4PsiOxus Therapeutics Ltd PsiOxus House, 4-10 The Quadrant, Barton Lane OX14 3YS Abingdon Oxfordshire UK Lorna.slater@psioxus.com. FAU - Lilley, Fred AU - Lilley F AD - 0000 0004 0394 8673grid.476643.4PsiOxus Therapeutics Ltd PsiOxus House, 4-10 The Quadrant, Barton Lane OX14 3YS Abingdon Oxfordshire UK Fred.Lilley@psioxus.coms. FAU - Brown, Alice AU - Brown A AD - 0000 0004 0394 8673grid.476643.4PsiOxus Therapeutics Ltd PsiOxus House, 4-10 The Quadrant, Barton Lane OX14 3YS Abingdon Oxfordshire UK Alice.Brown@psioxus.com. FAU - Champion, Brian AU - Champion B AD - 0000 0004 0394 8673grid.476643.4PsiOxus Therapeutics Ltd PsiOxus House, 4-10 The Quadrant, Barton Lane OX14 3YS Abingdon Oxfordshire UK Brian.Champion@psioxus.com. FAU - Duffy, Margaret R AU - Duffy MR AD - 0000 0004 1936 8948grid.4991.5Department of OncologyUniversity of Oxford OX3 7DQ Oxford UK Margaret.Duffy@oncology.ox.ac.uk. FAU - Seymour, Len W AU - Seymour LW AUID- ORCID: 0000-0003-3825-0841 AD - 0000 0004 1936 8948grid.4991.5Department of OncologyUniversity of Oxford OX3 7DQ Oxford UK len.seymour@oncology.ox.ac.uk. LA - eng GR - 17720/CRUK_/Cancer Research UK/United Kingdom GR - C552/A17720/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180613 PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Membrane Cofactor Protein) SB - IM MH - Adenoviridae/*pathogenicity MH - Animals MH - Disease Models, Animal MH - Humans MH - Membrane Cofactor Protein/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Transgenic MH - Oncolytic Virotherapy/*methods PMC - PMC6000980 OTO - NOTNLM OT - Adenovirus replication OT - Group B adenovirus OT - Mouse model OT - Oncolytic viruses COIS- ETHICS APPROVAL: All mice were housed and treated in accordance with UK Home Office guidelines outlined in the Animals (Scientific Procedures) Act 1986. COMPETING INTERESTS: KDF, BC and LWS hold equity in PsiOxus Therapeutics Ltd. KW, FL, LS, AB and BC are employees of Psioxus Therapeutics Ltd. JL, EJJ, MRD, and SH declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/06/15 06:00 MHDA- 2019/10/28 06:00 PMCR- 2018/06/13 CRDT- 2018/06/15 06:00 PHST- 2018/02/17 00:00 [received] PHST- 2018/05/07 00:00 [accepted] PHST- 2018/06/15 06:00 [entrez] PHST- 2018/06/15 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2018/06/13 00:00 [pmc-release] AID - 10.1186/s40425-018-0350-x [pii] AID - 350 [pii] AID - 10.1186/s40425-018-0350-x [doi] PST - epublish SO - J Immunother Cancer. 2018 Jun 13;6(1):55. doi: 10.1186/s40425-018-0350-x.