Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Review Article

Development of a replication-selective, oncolytic poxvirus for the treatment of human cancers

Cancer Gene Therapy volume 9, pages 1001–1012 (2002)Cite this article

Abstract

Tumor directed gene therapy for the purpose of destroying cancer cells through replicative “oncolysis” or by intratumoral expression of toxic or immunostimulatory genes requires an efficient, tumor targeted vector. Vectors are limited by inefficient replication in vivo, inefficient tumor targeting, and safety concerns. As a unique approach to addressing these limitations, our laboratory has studied poxviruses as tumor selective replicating vectors. The best in vivo antitumor results achieved to date have been with a mutated WR strain of vaccinia virus. The unique advantage of this strain of vaccinia over other vectors currently being explored for this purpose is the efficiency of in vivo replication. Intradermal injection of 106 pfu of the wild type (non-mutated) vaccinia in non-human primates leads to a 108 cm2 zone of necrosis in 8 days – directly related to cellular destruction from viral replication. We have mutated the virus through insertional deletion of both the thymidine kinase (TK) gene and vaccinia growth factor (VGF) gene. The mutant virus no longer causes destruction of normal tissue, but has completely preserved replication efficiency in tumor tissue and can safely be delivered systematically to successfully treat subcutaneous tumors in mice. Plans are now underway for clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Fenner F . In: Fields BN, Knipe DM, Howley PM, eds Fields Virology Lippincott-Raven: Philadelphia 1996 2673–2700

    Google Scholar 

  2. Fentiman IS, Rubens RD, Hayward JI . A comparison of intracavitary talcum and tetracycline for the control of pleural effusion secondary to breast cancer Eur J Cancer Clin Oncol 1986 22: 1079

    Article  CAS  PubMed  Google Scholar 

  3. Fenner F, Wittek R, Dumbell KR . The Orthopoxviruses Academic Press: New York 1989 143–170

    Book  Google Scholar 

  4. Antoine G, Scheiflinger F, Dorner F, Falkner FG . The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses Virology 1998 242: 365–396

    Article  Google Scholar 

  5. Goebel SJ, Johnson GP, Perkus ME, Davis SW, Winslow JP, Paoletti E . The complete DNA sequence of vaccinia virus Virology 1990 179: 247–266

    Article  CAS  PubMed  Google Scholar 

  6. Hsiao JC, Chung CS, Chang W . Vaccinia virus envelope D8L protein binds to cell surface chondroitin sulfate and mediates the adsorption of intracellular mature virions to cells J Virol 1999 73: 8750–8761

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Chung CS, Hsiao JC, Chang YS, Chang W . A27L protein mediates vaccinia virus interaction with cell surface heparan sulfate J Virol 1998 72: 1577–1585

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Moss B, Earl PL . Expression of proteins in mammalian cells using vaccinia viral vectors Curr Prot Mol Biol 1998 43: 16

    Google Scholar 

  9. McIntosh AAG, Smith GL . Vaccinia virus glycoprotein A34R is required for infectivity of extracellular enveloped virus J Virol 1996 70: 272–281

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Seet BT, McFadden G . Viral chemokine-binding proteins J Leukoc Biol 2002 72: 24–34

    CAS  PubMed  Google Scholar 

  11. Alcami A, Symons JA, Collins PD, Williams TJ, Smith GL . Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus J Immunol 1998 160: 624–633

    CAS  PubMed  Google Scholar 

  12. Mahalingam S, Karupiah G . Modulation of chemokines by poxvirus infections Curr Opin Immunol 2000 12: 409–412

    Article  CAS  PubMed  Google Scholar 

  13. Symons JA, Alcami A, Smith GL . Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity Cell 1995 81: 551–560

    Article  CAS  PubMed  Google Scholar 

  14. Najarro P, Traktman P, Lewis JA . Vaccinia virus blocks gamma interferon signal transduction: viral VH1 phosphatase reverses Stat1 activation J Virol 2001 75: 3185–3196

    Article  CAS  PubMed  Google Scholar 

  15. Smith VP, Bryant NA, Alcami A . Ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18–binding proteins J Gen Virol 2000 81: 1223–1230

    Article  CAS  PubMed  Google Scholar 

  16. Calderara S, Xiang Y, Moss B . Orthopoxvirus IL-18 binding proteins: affinities and antagonist activities Virology 2001 279: 22–26

    Article  CAS  PubMed  Google Scholar 

  17. Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M . Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response Immunity 1999 10: 127–136

    Article  CAS  PubMed  Google Scholar 

  18. Engelstad M, Howard ST, Smith GL . A constitutively expressed vaccinia gene encodes a 42-kDa glycoprotein related to complement control factors that forms part of the extracellular virus envelope Virology 1992 188: 801–810

    Article  CAS  PubMed  Google Scholar 

  19. Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK, O'Neill LA . A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling Proc Natl Acad Sci USA 2000 97: 10162–10167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Howard ST, Chan YS, Smith GL . Vaccinia virus homologues of the Shope fibroma virus inverted terminal repeat proteins and a discontinuous ORF related to the tumor necrosis factor receptor family Virology 1991 180: 633–647

    Article  CAS  PubMed  Google Scholar 

  21. Smith GL, Howard ST, Chan YS . Vaccinia virus encodes a family of genes with homology to serine proteinase inhibitors J Gen Virol 1989 70: 2333–2343

    Article  CAS  PubMed  Google Scholar 

  22. Sutter G, Moss B . Novel vaccinia vector derived from the host range restricted and highly attenuated MVA strain of vaccinia virus Dev Biol Stand 1995 84: 195–200

    CAS  PubMed  Google Scholar 

  23. Blanchard TJ, Alcami A, Andrea P, Smith GL . Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: implications for use as a human vaccine J Gen Virol 1998 79: 1159–1167

    Article  CAS  PubMed  Google Scholar 

  24. Deonarain R, Alcami A, Alexiou M, Dallman MJ, Gewert DR, Porter AC . Impaired antiviral response and alpha/beta interferon induction in mice lacking beta interferon J Virol 2000 74: 3404–3409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van Den Broek M, Bachmann MF, Kohler G, Barner M, Escher R, Zinkernagel R, Kopf M . IL-4 and IL-10 antagonize IL-12–mediated protection against acute vaccinia virus infection with a limited role of IFN-gamma and nitric oxide synthetase 2 J Immunol 2000 164: 371–378

    Article  CAS  PubMed  Google Scholar 

  26. Whitman ED, Tsung K, Paxson J, Norton JA . In vitro and in vivo kinetics of recombinant vaccinia virus cancer-gene therapy Surgery 1994 116: 183–188

    CAS  PubMed  Google Scholar 

  27. Moss B, Carroll MW, Wyatt LS et al. Host range restricted, non-replicating vaccinia virus vectors as vaccinia candidates, in Design and Production of Vaccines New York: Plenum Press 1996 7–13

    Google Scholar 

  28. Ricketts TF . Diagnosis of Smallpox London: Cassell and Company 1966 6–13

    Google Scholar 

  29. Neeman M, Abramovitch R, Schiffenbauer YS, Tempel C . Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle Int J Exp Pathol 1997 78: 57–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McCart JA, Hu YK, Alexander HR, Libutti SK, Moss B, Bartlett DL . A combined thymidine kinase/vaccinia growth factor deleted vaccinia virus as a vector for cancer gene therapy Proc Am Soc Gene Ther 1999 2: 160

    Google Scholar 

  31. Puhlmann M, Brown CK, Gnant M et al. Vaccinia as a vector for tumor directed gene therapy: biodistribution of a thymidine kinase deleted mutant Cancer Gene Ther 2000 7: 66–73

    Article  CAS  PubMed  Google Scholar 

  32. Gnant MF, Noli LA, Irvine KR et al. Tumor specific gene delivery using recombinant vaccinia virus in a rabbit model of unresectable liver metastases — pattern of gene expression, vector elimination and immune response J Natl Cancer Inst 1999 91: 1744–1750

    Article  CAS  PubMed  Google Scholar 

  33. McCart JA, Puhlmann M, Lee J et al. Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression Gene Ther 2000 7: 1217–1223

    Article  CAS  PubMed  Google Scholar 

  34. Gnant MFX, Puhlmann M, Alexander HR Jr, Bartlett DL . Systemic administration of a recombinant vaccinia virus expressing the cytosine deaminase gene and subsequent treatment with 5-fluorocytosine leads to tumor specific gene expression and prolongation of survival in mice Cancer Res 1999 59: 3396–3404

    CAS  PubMed  Google Scholar 

  35. Puhlmann M, Gnant M, Brown CK, Alexander HR, Bartlett DL . Thymidine kinase deleted vaccinia virus expressing purine nucleoside phosphorylase as a vector for tumor directed gene therapy Hum Gene Ther 1999 10: 649–657

    Article  CAS  PubMed  Google Scholar 

  36. McCart JA, Ward JM, Lee J et al. Systemic cancer therapy with a tumor selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes Cancer Res 2001 61: 8751–8757 12-15 (Reference Type: Generic)

    CAS  PubMed  Google Scholar 

  37. Buller RML, Chakrabarti S, Cooper JA, Twardzik DR, Moss B . Deletion of the vaccinia virus growth factor gene reduces virus virulence J Virol 1988 62: 866–874

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bischoff JR, Kim DH, Williams A et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [see comments] Science 1996 274: 373–376

    Article  CAS  PubMed  Google Scholar 

  39. Ray C, Black RA, Kronheim SR et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1α converting enzyme Cell 1992 69: 597–604

    Article  CAS  PubMed  Google Scholar 

  40. Kettle S, Blake NW, Law KM, Smith GL . Vaccinia virus serpins B13R (SPI-2) and B22R (SPI-1) encode Mr 385 and 40K, intracellular polypeptides that do not affect virus virulence in a murine intranasal model Virology 1995 206: 136–147

    Article  CAS  PubMed  Google Scholar 

  41. Shisler JL, Isaacs SN, Moss B . Vaccinia virus serpin-1 deletion mutant exhibits a host range defect characterized by low levels of intermediate and late mRNAs Virology 1999 262: 298–311

    Article  CAS  PubMed  Google Scholar 

  42. Perkus ME, Goebel SJ, Davis SW et al. Vaccinia virus host range genes Virology 1990 179: 276–286

    Article  CAS  PubMed  Google Scholar 

  43. Chung CS, Vasilevskaya IA, Wang SC, Bair CH, Chang W . Apoptosis and host restriction of vaccinia virus in RK13 cells Virus Res 1997 52: 121–132

    Article  CAS  PubMed  Google Scholar 

  44. Oguiura N, Spehner D, Drillien R . Detection of a protein encoded by the vaccinia virus C7L open reading frame and study of its effect on virus multiplication in different cell lines J Gen Virol 1993 74: 1409–1413

    Article  CAS  PubMed  Google Scholar 

  45. Ramsey-Ewing AL, Moss B . Complementation of a vaccinia virus host-range K1L gene deletion by the nonhomologous CP77 gene Virology 1996 222: 75–86

    Article  CAS  PubMed  Google Scholar 

  46. Galmiche MC, Rindisbacher L, Wels W, Wittek R, Buchegger F . Expression of a functional single chain antibody on the surface of extracellular enveloped vaccinia virus as a step towards selective tumour cell targeting J Gen Virol 1997 78: 3019–3027

    Article  CAS  PubMed  Google Scholar 

  47. Hu Y, Lee J, McCart JA et al. Yaba like disease virus: an alternating replicating pox vector for cancer gene therapy J Virol 2001 75: 10300–10308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sharma DP, Ramsay AJ, Maguire DJ, Rolph MS, Ramshaw IA . Interleukin-4 mediates down regulation of antiviral cytokine expression and cytotoxic T-lymphocyte responses and exacerbates vaccinia virus infection in vivo J Virol 1996 70: 7103–7107

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Perera LP, Goldman CK, Waldmann TA . Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice Proc Natl Acad Sci USA 2001 98: 5146–5151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Karupiah G, Woodhams CE, Blanden RV, Ramshaw IA . Immunobiology of infection with recombinant vaccinia virus encoding murine IL-2. Mechanisms of rapid viral clearance in immunocompetent mice J Immunol 1991 147: 4327–4332

    CAS  PubMed  Google Scholar 

  51. Ruby J, Bluethmann H, Aguet M, Ramshaw IA . CD40 ligand has potent antiviral activity Nat Med 1995 1: 437–441

    Article  CAS  PubMed  Google Scholar 

  52. Sambhi SK, Kohonen-Corish MR, Ramshaw IA . Local production of tumor necrosis factor encoded by recombinant vaccinia virus is effective in controlling viral replication in vivo Proc Natl Acad Sci USA 1991 88: 4025–4029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ramirez JC, Gherardi MM, Rodriguez D, Esteban M . Attenuated modified vaccinia virus Ankara can be used as an immunizing agent under conditions of preexisting immunity to the vector J Virol 2000 74: 7651–7655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gherardi MM, Ramirez JC, Rodriguez D et al. IL-12 delivery from recombinant vaccinia virus attenuates the vector and enhances the cellular immune response against HIV-1 Env in a dose-dependent manner J Immunol 1999 162: 6724–6733

    CAS  PubMed  Google Scholar 

  55. Lattime EC, Lee SS, Eisenlohr LC, Mastrangelo MJ . In situ cytokine gene transfection using vaccinia virus vectors Semin Oncol 1996 23: 88–100

    CAS  PubMed  Google Scholar 

  56. Mastrangelo MJ, Maguire HC Jr, Eisenlohr LC et al. Intratumoral recombinant GM-CSF–encoding virus as gene therapy in patients with cutaneous melanoma Cancer Gene Ther 1998 6: 409–422

    Article  Google Scholar 

  57. Overwijk W, Lee DS, Surman DR et al. Vaccination with a recombinant vaccinia virus encoding a “self” antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4+ T lymphocytes Proc Natl Acad Sci 1999 96: 2982–2987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rosenberg SA, Blaese RM, Brenner MK et al. Human gene marker/therapy clinical protocols Hum Gene Ther 1999 10: 3067–3123

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Surgical Oncology, University of Pittsburgh, University of Pittsburgh Cancer Institute, PB02 Cancer Pavilion, Pittsburgh, 15232, Pennsylvania, USA

    Herbert J Zeh & David L Bartlett

Authors
  1. Herbert J Zeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David L Bartlett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David L Bartlett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zeh, H., Bartlett, D. Development of a replication-selective, oncolytic poxvirus for the treatment of human cancers. Cancer Gene Ther 9, 1001–1012 (2002). https://doi.org/10.1038/sj.cgt.7700549

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700549

Keywords

This article is cited by

Search

Advanced search

Quick links