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Intratumoral expression of a fusogenic membrane glycoprotein enhances the efficacy of replicating adenovirus therapy

Gene Therapy volume 10, pages 1663–1671 (2003)Cite this article

Abstract

We describe here a novel strategy to enhance the in vivo efficacy of replicating adenovirus therapy, using coinjection of plasmid DNA encoding a fusogenic viral glycoprotein. The combination of fusogenic membrane glycoprotein (FMG)-induced tumor cell fusion and infection with replicating adenovirus effectively treats even large established tumors at doses of plasmid DNA and virus that alone are ineffective. Adenoviral infection appears to increase the transduction of the tumor cells to a modest degree thereby boosting the FMG-mediated component of the therapy. Simultaneously, syncytial formation enhances the therapeutic effects of viral infection by increasing spread of adenoviral particles through the tumor cell population and by increasing titer of virus released from the tumor cells. This effect is due probably to release of intracellular viral particles upon tumor cell death and also to increased levels of E1A protein within syncytia, whose increased metabolic rate is associated with enhanced levels of protein expression. Cotransduction of tumor cells with replicating adenovirus and FMG-expressing vectors could either be combined within single replicating vectors or could be used in strategies using separate administration of two components, both at lower doses than required for either therapy alone.

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References

  1. Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.

    Article  CAS  PubMed  Google Scholar 

  2. Alemany R, Balague C, Curiel DT . Replicative adenoviruses for cancer therapy. Nat Biotechnol 2000; 18: 723–727.

    Article  CAS  PubMed  Google Scholar 

  3. Curiel DT . The development of conditionally replicative adenoviruses for cancer therapy. Clin Cancer Res 2000; 6: 3395–3399.

    CAS  PubMed  Google Scholar 

  4. Vile RG . Vironcology – not yet, but soon? Nat Biotechnol 2001; 19: 1020–1022.

    Article  CAS  PubMed  Google Scholar 

  5. Biederer C, Ries S, Brandts CH, McCormick F . Replication-selective viruses for cancer therapy. J Mol Med 2002; 80: 163–175.

    Article  CAS  PubMed  Google Scholar 

  6. Krasnykh V et al. Genetic targeting of an adenovirus vector via replacement of the fiber protein with the phage T4 fibritin. J Virol 2001; 75: 4176–4183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rodriguez R et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57: 2559–2563.

    CAS  PubMed  Google Scholar 

  8. Nettlebeck DM et al. Novel oncolytic adenoviruses targeted to melanoma: specific viral replication and cytolysis by expression of E1A mutants from the tyrosinase enhancer/promoter. Cancer Res 2002; 62: 4663–4670.

    Google Scholar 

  9. Bischoff J et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  PubMed  Google Scholar 

  10. Ramachandra M et al. Reengineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy. Nat Biotechnol 2001; 19: 1035–1041.

    Article  CAS  PubMed  Google Scholar 

  11. Freytag SO et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002; 62: 4968–4976.

    CAS  PubMed  Google Scholar 

  12. Vile RG, Ando D, Kirn DH . The oncolytic virotherapy treatment platform for cancer: unique biological and biosafety points to consider. Cancer Gene Ther 2002; 9: 1062–1067.

    Article  CAS  PubMed  Google Scholar 

  13. Ganly I et al. A phase 1 study of Onyx-O15, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res 2000; 6: 798–806.

    CAS  PubMed  Google Scholar 

  14. Wu Q, Moyana T, Xiang J . Cancer gene therapy by adenovirus-mediated gene transfer. Curr Gene Ther 2001; 1: 101–122.

    Article  CAS  PubMed  Google Scholar 

  15. Heise C et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med 2000; 6: 1134–1139.

    Article  CAS  PubMed  Google Scholar 

  16. Sauthoff H, Heitner S, Rom WN, Hay JG . Deletion of the adenoviral E1b-19kD gene enhances tumor cell killing of a replicating adenoviral vector. Hum Gene Ther 2000; 11: 379–388.

    Article  CAS  PubMed  Google Scholar 

  17. Fielding AK et al. A hyperfusogenic Gibbon Ape Leukaemia envelope glycoprotein: targeting of a cytotoxic gene by ligand display. Hum Gene Ther 2000; 11: 817–826.

    Article  CAS  PubMed  Google Scholar 

  18. Bateman A et al. Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth. Cancer Res 2000; 60: 1492–1497.

    CAS  PubMed  Google Scholar 

  19. Diaz RM et al. A lentiviral vector expressing a fusogenic glycoprotein for cancer gene therapy. Gene Therapy 2000; 7: 1656–1663.

    Article  CAS  PubMed  Google Scholar 

  20. Higuchi H et al. Viral fusogenic membrane glycoprotein expression causes syncytia formation with bioenergetic cell death: implications for gene therapy. Cancer Res 2000; 60: 6396–6402.

    CAS  PubMed  Google Scholar 

  21. Linardakis E et al. Enhancing the efficacy of a weak allogeneic melanoma vaccine by viral fusogenic membrane glycoprotein-mediated tumor cell – tumor cell fusion. Cancer Res 2002; 62: 5495–5504.

    CAS  PubMed  Google Scholar 

  22. Bateman A et al. Viral fusogenic membrane glycoproteins kill solid tumor cells by non-apoptotic mechanisms which promote cross presentation of tumor antigens by dendritic cells. Cancer Res 2002; 62: 5466–6578.

    Google Scholar 

  23. Li H et al. Human immunodeficiency virus type 1-mediated syncytium formation is compatible with adenovirus replication and facilitates efficient dispersion of viral gene products and de novo-synthesized virus particles. Hum Gene Ther 2001; 12: 2155–2165.

    Article  CAS  PubMed  Google Scholar 

  24. Fu X et al. Expression of a fusogenic membrane glycoprotein by an oncolytic herpes simplex virus provides potent synergistic anti-tumor effect. Mol Ther 2003 (In press).

  25. Bateman A . FMG: a cancer gene therapy. PhD thesis, Open University, UK, 2002.

    Google Scholar 

  26. Mi S et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis [see comments]. Nature 2000; 403: 785–789.

    Article  CAS  PubMed  Google Scholar 

  27. Eslahi NK et al. Fusogenic activity of vesicular stomatitis virus glycoprotein plasmid in tumors as an enhancer of IL-12 gene therapy. Cancer Gene Ther 2001; 8: 55–62.

    Article  CAS  PubMed  Google Scholar 

  28. Ahmed A et al. A conditionally replicating adenovirus targeted to tumor cells through activated RAS/MAPK-selective mRNA stabilisation. Nat Biotechnol 2003 (In Press).

  29. Hawkins LK, Hermiston T . Gene delivery from the E3 region of replicating human adenovirus: evaluation of the E3B region. Gene Therapy 2001; 8: 1142–1148.

    Article  CAS  PubMed  Google Scholar 

  30. Hawkins LK, Hermiston TW . Gene delivery from the E3 region of replicating human adenovirus: evaluation of the ADP region. Gene Therapy 2001; 8: 1132–1141.

    Article  CAS  PubMed  Google Scholar 

  31. Hawkins LK et al. Gene delivery from the E3 region of replicating human adenovirus: evaluation of the 6.7 K/gp19K region. Gene Therapy 2001; 8: 1123–1131.

    Article  CAS  PubMed  Google Scholar 

  32. Emiliusen L et al. A transcriptional feedback loop for tissue-specific expression of highly cytotoxic genes which incorporates an immunostimulatory component. Gene Theraphy 2001; 8: 987–998.

    Article  CAS  Google Scholar 

  33. Hallenbeck PL et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther 1999; 10: 1721–1733.

    Article  CAS  PubMed  Google Scholar 

  34. Kurihara T, Brough DE, Kovesdi I, Kufe DW . Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen. J Clin Invest 2000; 106: 763–771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Siders WM, Halloran PJ, Fenton RG . Transcriptional targeting of recombinant adenoviruses to human and murine melanoma cells. Cancer Res 1996; 56: 5638–5646.

    CAS  PubMed  Google Scholar 

  36. Blackburn RV, Galoforo SS, Corry PM, Lee YJ . Adenoviral-mediated transfer of a heat-inducible double suicide gene into prostate carcinoma cells. Cancer Res 1998; 58: 1358–1362.

    CAS  PubMed  Google Scholar 

  37. Chong H et al. A system for small-molecule control of conditionally replication-competent adenoviral vectors. Mol Ther 2002; 5: 195–203.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Toni Higgins for expert secretarial assistance. This work was supported by NIH Grants RO1 CA85931, RO1 CA094180, and P50 CA91956, AstraZeneca, and by the Mayo Foundation.

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Authors and Affiliations

  1. Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA

    A Ahmed, D Jevremovic, K Suzuki, T Kottke, J Thompson, A Bateman & R Vile

  2. Cancer and Infection Bioscience Department, AstraZeneca, Alderley Park, Cheshire, UK

    S Emery

  3. Chester Beatty Laboratories, London, UK

    K Harrington

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  1. A Ahmed
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Ahmed, A., Jevremovic, D., Suzuki, K. et al. Intratumoral expression of a fusogenic membrane glycoprotein enhances the efficacy of replicating adenovirus therapy. Gene Ther 10, 1663–1671 (2003). https://doi.org/10.1038/sj.gt.3302064

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