Ixovex-1, a novel oncolytic E1B-mutated adenovirus.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
04
01
2021
accepted:
05
05
2022
revised:
28
03
2022
pubmed:
21
5
2022
medline:
18
11
2022
entrez:
20
5
2022
Statut:
ppublish
Résumé
There is a great demand for improved oncolytic viruses that selectively replicate within cancer cells while sparing normal cells. Here, we describe a novel oncolytic adenovirus, Ixovex-1, that obtains a cancer-selective replication phenotype by modulating the level of expression of the different, alternatively spliced E1B mRNA isoforms. Ixovex-1 is a recombinant adenovirus that carries a single point mutation in the E1B-93R 3' splice acceptor site that results in overexpression of the E1B-156R splice isoform. In this paper, we studied the characteristics of this novel oncolytic adenovirus by validating its in vitro behaviour in a panel of normal cells and cancer cells. We additionally studied its anti-tumour efficacy in vivo. Ixovex-1 significantly inhibited tumour growth and prolonged survival of mice in an immune-deficient lung carcinoma tumour implantation model. In complementation experiments, overexpression of E1B-156R was shown to increase the oncolytic index of both Ad5wt and ONYX-015. In contrast to prior viruses of similar type, Ixovex-1 includes a functional E3B region for better in vivo efficacy. Throughout this study, the Ixovex-1 virus has been proven to be superior in competency compared to a virus with multiple deletions.
Identifiants
pubmed: 35596069
doi: 10.1038/s41417-022-00480-3
pii: 10.1038/s41417-022-00480-3
pmc: PMC9663300
doi:
Substances chimiques
Adenovirus E1B Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1628-1635Informations de copyright
© 2022. The Author(s).
Références
Cheng PH, Wechman SL, McMasters KM, Zhou HS. Oncolytic replication of E1b-deleted adenoviruses. Viruses. 2015;7:5767–79.
doi: 10.3390/v7112905
pubmed: 26561828
pmcid: 4664978
Turnbull S, West EJ, Scott KJ, Appleton E, Melcher A, Ralph C. Evidence for oncolytic virotherapy: where have we got to and where are we going? Viruses. 2015;7:6291–312.
doi: 10.3390/v7122938
pubmed: 26633468
pmcid: 4690862
Uusi-Kerttula H, Hulin-Curtis S, Davies J, Parker AL. Oncolytic adenovirus: strategies and insights for vector design and immuno-oncolytic applications. Viruses. 2015;7:6009–42.
doi: 10.3390/v7112923
pubmed: 26610547
pmcid: 4664994
Wang X, Simpson ER, Brown KA. p53: protection against tumor growth beyond effects on cell cycle and apoptosis. Cancer Res. 2015;75:5001–7.
doi: 10.1158/0008-5472.CAN-15-0563
pubmed: 26573797
Moore PS, Chang Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer. 2010;10:878–89.
doi: 10.1038/nrc2961
pubmed: 21102637
pmcid: 3718018
Berk AJ. Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus. Oncogene. 2005;24:7673–85.
doi: 10.1038/sj.onc.1209040
pubmed: 16299528
Hung G, Flint SJ. Normal human cell proteins that interact with the adenovirus type 5 E1B 55kDa protein. Virology. 2017;504:12–24.
doi: 10.1016/j.virol.2017.01.013
pubmed: 28135605
Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med. 1997;3:639–45.
doi: 10.1038/nm0697-639
pubmed: 9176490
Eager RM, Nemunaitis J. Clinical development directions in oncolytic viral therapy. Cancer Gene Ther. 2011;18:305–17.
doi: 10.1038/cgt.2011.7
pubmed: 21436867
Wang Y, Hallden G, Hill R, Anand A, Liu TC, Francis J, et al. E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nat Biotechnol. 2003;21:1328–35.
doi: 10.1038/nbt887
pubmed: 14555956
Chartier C, Degryse E, Gantzer M, Dieterle A, Pavirani A, Mehtali M. Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J Virol. 1996;70:4805–10.
doi: 10.1128/jvi.70.7.4805-4810.1996
pubmed: 8676512
pmcid: 190422
Philipson L. Adenovirus assay by the fluorescent cell-counting procedure. Virology. 1961;15:263–8.
doi: 10.1016/0042-6822(61)90357-9
pubmed: 14486210
Sarnow P, Sullivan CA, Levine AJ. A monoclonal antibody detecting the adenovirus type 5-E1b-58Kd tumor antigen: characterization of the E1b-58Kd tumor antigen in adenovirus-infected and -transformed cells. Virology. 1982;120:510–7.
doi: 10.1016/0042-6822(82)90054-X
pubmed: 7048730
Gonzalez RA, Flint SJ. Effects of mutations in the adenoviral E1B 55-kilodalton protein coding sequence on viral late mRNA metabolism. J Virol. 2002;76:4507–19.
doi: 10.1128/JVI.76.9.4507-4519.2002
pubmed: 11932416
pmcid: 155063
Sieber T, Dobner T. Adenovirus type 5 early region 1B 156R protein promotes cell transformation independently of repression of p53-stimulated transcription. J Virol. 2007;81:95–105.
doi: 10.1128/JVI.01608-06
pubmed: 17050591
Wimmer P, Blanchette P, Schreiner S, Ching W, Groitl P, Berscheminski J, et al. Cross-talk between phosphorylation and SUMOylation regulates transforming activities of an adenoviral oncoprotein. Oncogene. 2012;32:1626–37.
doi: 10.1038/onc.2012.187
pubmed: 22614022
Schreiner S, Wimmer P, Groitl P, Chen SY, Blanchette P, Branton PE, et al. Adenovirus type 5 early region 1B 55K oncoprotein-dependent degradation of cellular factor Daxx is required for efficient transformation of primary rodent cells. J Virol. 2011;85:8752–65.
doi: 10.1128/JVI.00440-11
pubmed: 21697482
pmcid: 3165851
Schreiner S, Wimmer P, Sirma H, Everett RD, Blanchette P, Groitl P, et al. Proteasome-dependent degradation of Daxx by the viral E1B-55K protein in human adenovirus-infected cells. J Virol. 2010;84:7029–38.
doi: 10.1128/JVI.00074-10
pubmed: 20484509
pmcid: 2898266
Flint SJ, Gonzalez RA. Regulation of mRNA production by the adenoviral E1B 55-kDa and E4 Orf6 proteins. Curr Top Microbiol Immunol. 2003;272:287–330.
pubmed: 12747554
Dobner T, Kzhyshkowska J. Nuclear export of adenovirus RNA. Curr Top Microbiol Immunol. 2001;259:25–54.
pubmed: 11417126
Blackford AN, Grand RJ. Adenovirus E1B 55-kilodalton protein: multiple roles in viral infection and cell transformation. J Virol. 2009;83:4000–12.
doi: 10.1128/JVI.02417-08
pubmed: 19211739
pmcid: 2668481
Sarnow P, Hearing P, Anderson CW, Halbert DN, Shenk T, Levine AJ. Adenovirus early region 1B 58,000-dalton tumor antigen is physically associated with an early region 4 25,000-dalton protein in productively infected cells. J Virol. 1984;49:692–700.
doi: 10.1128/jvi.49.3.692-700.1984
pubmed: 6699935
pmcid: 255526
Martin ME, Berk AJ. Adenovirus E1B 55K represses p53 activation in vitro. J Virol. 1998;72:3146–54.
doi: 10.1128/JVI.72.4.3146-3154.1998
pubmed: 9525640
pmcid: 109770
Barker DD, Berk AJ. Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection. Virology. 1987;156:107–21.
doi: 10.1016/0042-6822(87)90441-7
pubmed: 2949421
Miller DL, Rickards B, Mashiba M, Huang W, Flint SJ. The adenoviral E1B 55-kilodalton protein controls expression of immune response genes but not p53-dependent transcription. J Virol. 2009;83:3591–603.
doi: 10.1128/JVI.02269-08
pubmed: 19211769
pmcid: 2663238
Chahal JS, Gallagher C, DeHart CJ, Flint SJ. The repression domain of the E1B 55-kilodalton protein participates in countering interferon-induced inhibition of adenovirus replication. J Virol. 2013;87:4432–44.
doi: 10.1128/JVI.03387-12
pubmed: 23388716
pmcid: 3624377
Shen Y, Kitzes G, Nye JA, Fattaey A, Hermiston T. Analyses of single-amino-acid substitution mutants of adenovirus type 5 E1B-55K protein. J Virol. 2001;75:4297–307.
doi: 10.1128/JVI.75.9.4297-4307.2001
pubmed: 11287579
pmcid: 114175
Oberg D, Yanover E, Adam V, Sweeney K, Costas C, Lemoine NR, et al. Improved potency and selectivity of an oncolytic E1ACR2 and E1B19K deleted adenoviral mutant in prostate and pancreatic cancers. Clin Cancer Res. 2010;16:541–53.
doi: 10.1158/1078-0432.CCR-09-1960
pubmed: 20068104
pmcid: 2825678
Larson C, Oronsky B, Scicinski J, Fanger GR, Stirn M, Oronsky A, et al. Going viral: a review of replication-selective oncolytic adenoviruses. Oncotarget. 2015;6:19976–89.
doi: 10.18632/oncotarget.5116
pubmed: 26280277
pmcid: 4652981