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.

  • Original Article
  • Published:

Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice

Gene Therapy volume 14, pages 20–29 (2007)Cite this article

Abstract

Vaccinia virus has been shown to efficiently infect tumor cells. Therefore, vaccinia virus represents a potentially safe and effective antitumor agent against ovarian cancer. Here, we assessed the ability of vaccinia virus to preferentially infect and control both human and murine ovarian tumors in vivo. We used the non-invasive luminescence imaging system to monitor the infection and suppression of ovarian tumors by vaccinia in live mice. Our data indicated that vaccinia was able to effectively infect and kill both human and murine ovarian tumors. Vaccinia virus administered to mice intraperitoneally was specifically targeted to the murine or human ovarian tumors and led to antitumor responses. These findings suggest that vaccinia virus is capable of selectively targeting and controlling ovarian tumors. Thus, intraperitoneal injection with vaccinia virus may provide a potentially effective strategy for treating advanced-stage ovarian cancers.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women [see comments]. Lancet 1992; 339: 1–15.

  2. Baum M, Ebb S, Brooks M . Biological fall out from trials of adjuvant tamoxifen in early ovarian cancer. In: Salmon SE (ed). Adjuvant Therapy of Cancer V1. WB Saunders: Philadelphia, 1990, pp 269–274.

    Google Scholar 

  3. Swain SM . Selection of therapy for stage III breast cancer. Surg Clin N Am 1990; 70: 1061–1080.

    Article  CAS  PubMed  Google Scholar 

  4. Peng KW, TenEyck CJ, Galanis E, Kalli KR, Hartmann LC, Russell SJ . Intraperitoneal therapy of ovarian cancer using an engineered measles virus. Cancer Res 2002; 62: 4656–4662.

    CAS  PubMed  Google Scholar 

  5. Shen Y, Nemunaitis J . Fighting cancer with vaccinia virus: teaching new tricks to an old dog. Mol Ther 2005; 11: 180–195.

    Article  CAS  PubMed  Google Scholar 

  6. Tseng JC, Levin B, Hurtado A, Yee H, Perez de Castro I, Jimenez M et al. Systemic tumor targeting and killing by Sindbis viral vectors. Nat Biotechnol 2004; 22: 70–77.

    Article  CAS  PubMed  Google Scholar 

  7. Nakamori M, Fu X, Meng F, Jin A, Tao L, Bast Jr RC et al. Effective therapy of metastatic ovarian cancer with an oncolytic herpes simplex virus incorporating two membrane fusion mechanisms. Clin Cancer Res 2003; 9: 2727–2733.

    CAS  PubMed  Google Scholar 

  8. Hu Y, Lee J, McCart JA, Xu H, Moss B, Alexander HR et al. Yaba-like disease virus: an alternative replicating poxvirus vector for cancer gene therapy. J Virol 2001; 75: 10300–10308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Puhlmann M, Brown CK, Gnant M, Huang J, Libutti SK, Alexander HR 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 

  10. Gnant MF, Puhlmann M, Alexander Jr HR, 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: 3396–3403.

    CAS  PubMed  Google Scholar 

  11. Gnant MF, Puhlmann M, Bartlett DL, Alexander Jr HR . Regional versus systemic delivery of recombinant vaccinia virus as suicide gene therapy for murine liver metastases. Ann Surg 1999; 230: 352–360 (discussion 360–351).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McCart JA, Ward JM, Lee J, Hu Y, Alexander HR, Libutti SK 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.

    CAS  PubMed  Google Scholar 

  13. Amara RR, Villinger F, Altman JD, Lydy SL, O'Neil SP, Staprans SI et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 2001; 292: 69–74.

    Article  CAS  PubMed  Google Scholar 

  14. Marshall JL, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R et al. Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte–macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol 2005; 23: 720–731.

    Article  CAS  PubMed  Google Scholar 

  15. Slobod KS, Lockey TD, Howlett N, Srinivas RV, Rencher SD, Freiden PJ et al. Subcutaneous administration of a recombinant vaccinia virus vaccine expressing multiple envelopes of HIV-1. Eur J Clin Microbiol Infect Dis 2004; 23: 106–110.

    Article  CAS  PubMed  Google Scholar 

  16. Rochlitz C, Figlin R, Squiban P, Salzberg M, Pless M, Herrmann R et al. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer. J Gene Med 2003; 5: 690–699.

    Article  CAS  PubMed  Google Scholar 

  17. Mastrangelo MJ, Maguire Jr HC, Eisenlohr LC, Laughlin CE, Monken CE, McCue PA et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 1999; 6: 409–422.

    Article  CAS  PubMed  Google Scholar 

  18. Gomella LG, Mastrangelo MJ, McCue PA, Maguire HJ, Mulholland SG, Lattime EC . Phase i study of intravesicle vaccinia virus as a vector for gene therapy of bladder cancer. J Urol 2001; 166: 1291–1295.

    Article  CAS  PubMed  Google Scholar 

  19. Kadish AS, Einstein MH . Vaccine strategies for human papillomavirus-associated cancers. Curr Opin Oncol 2005; 17: 456–461.

    Article  CAS  PubMed  Google Scholar 

  20. Thorne SH, Hwang TH, Kirn DH . Vaccinia virus and oncolytic virotherapy of cancer. Curr Opin Mol Ther 2005; 7: 359–365.

    PubMed  Google Scholar 

  21. Luker KE, Hutchens M, Schultz T, Pekosz A, Luker GD . Bioluminescence imaging of vaccinia virus: effects of interferon on viral replication and spread. Virology 2005; 341: 284–300.

    Article  CAS  PubMed  Google Scholar 

  22. Yu YA, Shabahang S, Timiryasova TM, Zhang Q, Beltz R, Gentschev I et al. Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nat Biotechnol 2004; 22: 313–320.

    Article  CAS  PubMed  Google Scholar 

  23. Gnant MF, Noll LA, Irvine KR, Puhlmann M, Terrill RE, Alexander Jr HR et al. Tumor-specific gene delivery using recombinant vaccinia virus in a rabbit model of liver metastases. J Natl Cancer Inst 1999; 91: 1744–1750.

    Article  CAS  PubMed  Google Scholar 

  24. Karupiah G, Coupar B, Ramshaw I, Boyle D, Blanden R, Andrew M . Vaccinia virus-mediated damage of murine ovaries and protection by virus-expressed interleukin-2. Immunol Cell Biol 1990; 68 (Part 5): 325–333.

    Article  CAS  PubMed  Google Scholar 

  25. Sedger L, Ruby J . Heat shock response to vaccinia virus infection. J Virol 1994; 68: 4685–4689.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen B, Timiryasova TM, Haghighat P, Andres ML, Kajioka EH, Dutta-Roy R et al. Low-dose vaccinia virus-mediated cytokine gene therapy of glioma. J Immunother 2001; 24: 46–57.

    Article  CAS  PubMed  Google Scholar 

  27. Wu T-C, Guarnieri FG, Staveley-O'Carroll KF, Viscidi RP, Levitsky HI, Hedrick L et al. Engineering an intracellular pathway for MHC class II presentation of HPV-16 E7. Proc Natl Acad Sci 1995; 92: 11671–11675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chisholm SE, Reyburn HT . Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors. J Virol 2006; 80: 2225–2233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Timiryasova TM, Li J, Chen B, Chong D, Langridge WH, Gridley DS et al. Antitumor effect of vaccinia virus in glioma model. Oncol Res 1999; 11: 133–144.

    CAS  PubMed  Google Scholar 

  30. Fodor I, Timiryasova T, Denes B, Yoshida J, Ruckle H, Lilly M . Vaccinia virus mediated p53 gene therapy for bladder cancer in an orthotopic murine model. J Urol 2005; 173: 604–609.

    Article  CAS  PubMed  Google Scholar 

  31. Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ et al. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 2004; 10: 950–958.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Richard Roden for helpful discussions. We gratefully acknowledge Dr Ralph Hruban and David Boyd for critical review of this paper, and Roanne Calizo for the preparation of the manuscript. We also thank Bela Denes for the purification of vaccinia virus (Lister strain, rVV4). This work was supported by ovarian cancer grants from Department of Defense and the Alliance for Cancer Gene Therapy (ACGT).

Author information

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    C-F Hung, Y-C Tsai, L He & T-C Wu

  2. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    C-F Hung, L Qin, H Levitsky & T-C Wu

  3. Abramson Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA

    G Coukos

  4. Center for Research on Reproduction and Women's Health, Philadelphia, PA, USA

    G Coukos

  5. Departments of Biochemistry and Microbiology, Center for Molecular Biology and Gene Therapy, Loma Linda University, Loma Linda, CA, USA

    I Fodor

  6. Departments of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  7. Departments of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

Authors
  1. C-F Hung
    View author publications

    Search author on:PubMed Google Scholar

  2. Y-C Tsai
    View author publications

    Search author on:PubMed Google Scholar

  3. L He
    View author publications

    Search author on:PubMed Google Scholar

  4. G Coukos
    View author publications

    Search author on:PubMed Google Scholar

  5. I Fodor
    View author publications

    Search author on:PubMed Google Scholar

  6. L Qin
    View author publications

    Search author on:PubMed Google Scholar

  7. H Levitsky
    View author publications

    Search author on:PubMed Google Scholar

  8. T-C Wu
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to C-F Hung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hung, CF., Tsai, YC., He, L. et al. Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Ther 14, 20–29 (2007). https://doi.org/10.1038/sj.gt.3302840

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.gt.3302840

Keywords

This article is cited by

Search

Advanced search

Quick links