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Illingworth S, Di Y, Bauzon M, et al. Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus. Mol Ther Oncolytics. 2017;5:62-74doi: 10.1016/j.omto.2017.03.003.
Illingworth, S., Di, Y., Bauzon, M., Lei, J., Duffy, M. R., Alvis, S., Champion, B., Lieber, A., Hermiston, T., Seymour, L. W., Beadle, J., & Fisher, K. (2017). Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus. Molecular therapy oncolytics, 562-74. https://doi.org/10.1016/j.omto.2017.03.003
Illingworth, Sam, et al. "Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus." Molecular therapy oncolytics vol. 5 (2017): 62-74. doi: https://doi.org/10.1016/j.omto.2017.03.003
Illingworth S, Di Y, Bauzon M, Lei J, Duffy MR, Alvis S, Champion B, Lieber A, Hermiston T, Seymour LW, Beadle J, Fisher K. Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus. Mol Ther Oncolytics. 2017 Mar 29;5:62-74. doi: 10.1016/j.omto.2017.03.003. eCollection 2017 Jun 16. PMID: 28480328; PMCID: PMC5415321.
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Mol Ther Oncolytics. 2017 Mar 29;5:62-74. doi: 10.1016/j.omto.2017.03.003. eCollection 2017 Jun 16.

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus.

Molecular therapy oncolytics

Sam Illingworth, Ying Di, Maxine Bauzon, Janet Lei, Margaret R Duffy, Simon Alvis, Brian Champion, André Lieber, Terry Hermiston, Len W Seymour, John Beadle, Kerry Fisher

Affiliations

  1. PsiOxus Therapeutics Ltd., Abingdon OX14 4SD, UK.
  2. Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  3. Coagulant Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA 94158, USA.
  4. Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.

PMID: 28480328 PMCID: PMC5415321 DOI: 10.1016/j.omto.2017.03.003

Abstract

Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 10

Keywords: adenovirus; enadenotucirev; mouse model; oncolytic virotherapy; preclinical model

References

  1. Anticancer Res. 2006 Nov-Dec;26(6C):4943-8 - PubMed
  2. Oncogene. 2014 Sep 4;33(36):4451-63 - PubMed
  3. APMIS. 1998 Sep;106(9):869-78 - PubMed
  4. Blood. 2009 Feb 26;113(9):1909-18 - PubMed
  5. Cancer Gene Ther. 2006 Dec;13(12):1072-81 - PubMed
  6. Cancer Gene Ther. 2002 Dec;9(12):979-86 - PubMed
  7. Mol Ther. 2015 Jun;23(6):1066-76 - PubMed
  8. Br J Cancer. 2011 Apr 26;104(9):1426-33 - PubMed
  9. Nanomedicine (Lond). 2012 Nov;7(11):1683-95 - PubMed
  10. Br J Pharmacol. 2009 Jul;157(6):907-21 - PubMed
  11. Transplantation. 2006 May 27;81(10):1398-404 - PubMed
  12. Virology. 2017 May;505:162-171 - PubMed
  13. EMBO J. 2005 Mar 23;24(6):1211-21 - PubMed
  14. J Virol. 2003 Aug;77(15):8263-71 - PubMed
  15. Clin Exp Immunol. 2001 May;124(2):180-9 - PubMed
  16. J Virol. 2008 May;82(9):4585-94 - PubMed
  17. J Gen Virol. 2000 Nov;81(Pt 11):2605-9 - PubMed
  18. J Virol. 2000 Mar;74(6):2567-83 - PubMed
  19. Am J Pathol. 1988 Oct;133(1):95-109 - PubMed
  20. Mol Ther. 2007 Dec;15(12):2088-93 - PubMed
  21. Hum Gene Ther. 2000 Mar 1;11(4):621-7 - PubMed
  22. PLoS One. 2008 Jun 18;3(6):e2409 - PubMed
  23. Tissue Barriers. 2013 Jan 1;1(1):e23647 - PubMed
  24. Toxicol Pathol. 1999 Jan-Feb;27(1):4-7 - PubMed
  25. Invest New Drugs. 2013 Jun;31(3):696-706 - PubMed
  26. Cancer Res. 2008 Jul 15;68(14):5896-904 - PubMed
  27. N Engl J Med. 1968 Mar 28;278(13):700-4 - PubMed
  28. Gene Ther. 1997 Apr;4(4):309-16 - PubMed
  29. Gene Ther. 2009 Sep;16(9):1169-74 - PubMed
  30. Mol Ther. 2006 Jul;14(1):118-28 - PubMed
  31. Cell. 2008 Feb 8;132(3):397-409 - PubMed
  32. Biol Blood Marrow Transplant. 2007 Jan;13(1):74-81 - PubMed
  33. Mol Ther. 2006 Jan;13(1):108-17 - PubMed
  34. Gene Ther. 2014 Apr;21(4):440-3 - PubMed
  35. Cancer Chemother Rep. 1966 May;50(4):219-44 - PubMed
  36. Nucleic Acids Res. 1988 May 11;16(9):3771-86 - PubMed
  37. Liver Int. 2015 Apr;35(4):1274-89 - PubMed
  38. J Virol. 2000 May;74(9):3967-74 - PubMed
  39. J Virol. 1997 Nov;71(11):8798-807 - PubMed
  40. J Oral Pathol Med. 2006 Oct;35(9):560-7 - PubMed
  41. J Biol Chem. 1997 Aug 15;272(33):20793-9 - PubMed
  42. Cancer Res. 2006 Feb 1;66(3):1270-6 - PubMed
  43. Arch Pathol Lab Med. 2014 Jul;138(7):910-9 - PubMed
  44. Virology. 2009 Nov 25;394(2):311-20 - PubMed

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