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:

Dynamics of melanoma tumor therapy with vesicular stomatitis virus: explaining the variability in outcomes using mathematical modeling

Gene Therapy volume 19, pages 543–549 (2012)Cite this article

Abstract

Tumor selective, replication competent viruses are being tested for cancer gene therapy. This approach introduces a new therapeutic paradigm due to potential replication of the therapeutic agent and induction of a tumor-specific immune response. However, the experimental outcomes are quite variable, even when studies utilize highly inbred strains of mice and the same cell line and virus. Recognizing that virotherapy is an exercise in population dynamics, we utilize mathematical modeling to understand the variable outcomes observed when B16ova malignant melanoma tumors are treated with vesicular stomatitis virus in syngeneic, fully immunocompetent mice. We show how variability in the initial tumor size and the actual amount of virus delivered to the tumor have critical roles on the outcome of therapy. Virotherapy works best when tumors are small, and a robust innate immune response can lead to superior tumor control. Strategies that reduce tumor burden without suppressing the immune response and methods that maximize the amount of virus delivered to the tumor should optimize tumor control in this model system.

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. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ . Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225–249.

    Article  PubMed  Google Scholar 

  2. Vogelstein B, Kinzler KW . Cancer genes and the pathways they control. Nat Med 2004; 10: 789–799.

    Article  CAS  PubMed  Google Scholar 

  3. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. The consensus coding sequences of human breast and colorectal cancers. Science (New York, NY) 2006; 314: 268–274.

    Article  Google Scholar 

  4. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. Patterns of somatic mutation in human cancer genomes. Nature 2007; 446: 153–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Qiao J, Wang H, Kottke T, Diaz RM, Willmon C, Hudacek A et al. Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors. Gene Therapy 2008; 15: 604–616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Qiao J, Wang H, Kottke T, White C, Twigger K, Diaz RM et al. Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus. Clin Cancer Res 2008; 14: 259–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Diaz RM, Galivo F, Kottke T, Wongthida P, Qiao J, Thompson J et al. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res 2007; 67: 2840–2848.

    Article  CAS  PubMed  Google Scholar 

  8. Vile R, Ando D, Kirn D . 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 

  9. Kottke T, Diaz RM, Kaluza K, Pulido J, Galivo F, Wongthida P et al. Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. Mol Ther 2008; 16: 1910–1918.

    Article  CAS  PubMed  Google Scholar 

  10. Lun X, Senger DL, Alain T, Oprea A, Parato K, Stojdl D et al. Effects of intravenously administered recombinant vesicular stomatitis virus (VSV(deltaM51)) on multifocal and invasive gliomas. J Natl Cancer Inst 2006; 98: 1546–1557.

    Article  CAS  PubMed  Google Scholar 

  11. Galivo F, Diaz RM, Thanarajasingam U, Jevremovic D, Wongthida P, Thompson J et al. Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. Hum Gene Ther 2010; 21: 439–450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Galivo F, Diaz RM, Wongthida P, Thompson J, Kottke T, Barber G et al. Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma. Gene Therapy 2010; 17: 158–170.

    Article  CAS  PubMed  Google Scholar 

  13. Wongthida P, Diaz RM, Galivo F, Kottke T, Thompson J, Melcher A et al. VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol Ther 2010; 19: 150–158.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wongthida P, Diaz RM, Galivo F, Kottke T, Thompson J, Pulido J et al. Type III IFN interleukin-28 mediates the antitumor efficacy of oncolytic virus VSV in immune-competent mouse models of cancer. Cancer Res 2010; 70: 4539–4549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Russell SJ . RNA viruses as virotherapy agents. Cancer Gene Ther 2002; 9: 961–966.

    Article  CAS  PubMed  Google Scholar 

  17. Russell SJ, Peng KW . Viruses as anticancer drugs. Trends Pharmacol Sci 2007; 28: 326–333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aghi M, Chou TC, Suling K, Breakefield XO, Chiocca EA . Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganciclovir/herpes simplex virus thymidine kinase gene therapies. Cancer Res 1999; 59: 3861–3865.

    CAS  PubMed  Google Scholar 

  19. Dingli D, Peng KW, Harvey ME, Greipp PR, O’Connor MK, Cattaneo R et al. Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. Blood 2004; 103: 1641–1646.

    Article  CAS  PubMed  Google Scholar 

  20. Kim JH, Oh JY, Park BH, Lee DE, Kim JS, Park HE et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol Ther 2006; 14: 361–370.

    Article  CAS  PubMed  Google Scholar 

  21. Luo C, Mori I, Goshima F, Ushijima Y, Nawa A, Kimura H et al. Replication-competent, oncolytic herpes simplex virus type 1 mutants induce a bystander effect following ganciclovir treatment. J Gene Med 2007; 9: 875–883.

    Article  CAS  PubMed  Google Scholar 

  22. Wodarz D . Viruses as antitumor weapons: defining conditions for tumor remission. Cancer Res 2001; 61: 3501–3507.

    CAS  PubMed  Google Scholar 

  23. Wodarz D . Gene therapy for killing p53-negative cancer cells: use of replicating versus nonreplicating agents. Hum Gene Ther 2003; 14: 153–159.

    Article  CAS  PubMed  Google Scholar 

  24. Wein LM, Wu JT, Ianculescu AG, Puri RK . A mathematical model of the impact of infused targeted cytotoxic agents on brain tumours: implications for detection, design and delivery. Cell Proliferation 2002; 35: 343–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wein LM, Wu JT, Kirn DH . Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery. Cancer Res 2003; 63: 1317–1324.

    CAS  PubMed  Google Scholar 

  26. Wu JT, Byrne HM, Kirn DH, Wein LM . Modeling and analysis of a virus that replicates selectively in tumor cells. Bull Math Biol 2001; 63: 731–768.

    Article  CAS  PubMed  Google Scholar 

  27. Wu JT, Kirn DH, Wein LM . Analysis of a three-way race between tumor growth, a replication-competent virus and an immune response. Bull Math Biol 2004; 66: 605–625.

    Article  PubMed  Google Scholar 

  28. Dingli D, Cascino MD, Josic K, Russell SJ, Bajzer Z . Mathematical modeling of cancer radiovirotherapy. Math Biosci 2006; 199: 55–78.

    Article  PubMed  Google Scholar 

  29. Friedman A, Tian JP, Fulci G, Chiocca EA, Wang J . Glioma virotherapy: effects of innate immune suppression and increased viral replication capacity. Cancer Res 2006; 66: 2314–2319.

    Article  CAS  PubMed  Google Scholar 

  30. Karev GP, Novozhilov AS, Koonin EV . Mathematical modeling of tumor therapy with oncolytic viruses: effects of parametric heterogeneity on cell dynamics. Biol Direct 2006; 1: 30.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Novozhilov AS, Berezovskaya FS, Koonin EV, Karev GP . Mathematical modeling of tumor therapy with oncolytic viruses: regimes with complete tumor elimination within the framework of deterministic models. Biol Direct 2006; 1: 6.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bajzer Z, Carr T, Josic K, Russell SJ, Dingli D . Modeling of cancer virotherapy with recombinant measles viruses. J Theor Biol 2008; 252: 109–122.

    Article  PubMed  Google Scholar 

  33. Dingli D, Offord C, Myers R, Peng KW, Carr TW, Josic K et al. Dynamics of multiple myeloma tumor therapy with a recombinant measles virus. Cancer Gene Ther 2009; 16: 873–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mok W, Stylianopoulos T, Boucher Y, Jain RK . Mathematical modeling of herpes simplex virus distribution in solid tumors: implications for cancer gene therapy. Clin Cancer Res 2009; 15: 2352–2360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Paiva LR, Binny C, Ferreira Jr SC, Martins ML . A multiscale mathematical model for oncolytic virotherapy. Cancer Res 2009; 69: 1205–1211.

    Article  CAS  PubMed  Google Scholar 

  36. Wodarz D, Komarova N . Towards predictive computational models of oncolytic virus therapy: basis for experimental validation and model selection. PLoS ONE 2009; 4: e4271.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bieseker M, Kimn JH, Lu H, Dingli D, Bajzer Z . Optimization of virotherapy for cancer. Bull Math Biol 2010; 72: 469–489.

    Article  Google Scholar 

  38. Komarova NL, Wodarz D . ODE models for oncolytic virus dynamics. J Theor Biol 2010; 263: 530–543.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Reis C, Pacheco JM, Ennis MK, Dingli D . In silico evolutionary dynamics of tumour virotherapy. Integr Biol 2010; 2: 41–45.

    Article  CAS  Google Scholar 

  40. Cohn M, Mitchison NA, Paul WE, Silverstein AM, Talmage DW, Weigert M . Reflections on the clonal-selection theory. Nat Rev Immunol 2007; 7: 823–830.

    Article  CAS  PubMed  Google Scholar 

  41. Peng KW, Hadac EM, Anderson BD, Myers R, Harvey M, Greiner SM et al. Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model. Cancer Gene Ther 2006; 13: 732–738.

    Article  CAS  PubMed  Google Scholar 

  42. Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res 2002; 62: 6070–6079.

    CAS  PubMed  Google Scholar 

  43. Pecora AL, Rizvi N, Cohen GI, Meropol NJ, Sterman D, Marshall JL et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 2002; 20: 2251–2266.

    Article  CAS  PubMed  Google Scholar 

  44. Galanis E, Hartmann LC, Cliby WA, Long HJ, Peethambaram PP, Barrette BA et al. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res 2010; 70: 875–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Martinez-Quintanilla J, Cascallo M, Fillat C, Alemany R . Antitumor therapy based on cellular competition. Hum Gene Ther 2009; 20: 728–738.

    Article  CAS  PubMed  Google Scholar 

  46. Martinez-Quintanilla J, Cascallo M, Gros A, Fillat C, Alemany R . Positive selection of gene-modified cells increases the efficacy of pancreatic cancer suicide gene therapy. Mol Cancer Ther 2009; 8: 3098–3107.

    Article  CAS  PubMed  Google Scholar 

  47. Luo R, Cannon L, Hernandez J, Piovoso MJ, Zurakowski R . Controlling the evolution of resistance. J Process Control 2011; 21: 367–378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li H, Zeng Z, Fu X, Zhang X . Coadministration of a herpes simplex virus-2 based oncolytic virus and cyclophosphamide produces a synergistic antitumor effect and enhances tumor-specific immune responses. Cancer Res 2007; 67: 7850–7855.

    Article  CAS  PubMed  Google Scholar 

  49. Nagano S, Perentes JY, Jain RK, Boucher Y . Cancer cell death enhances the penetration and efficacy of oncolytic herpes simplex virus in tumors. Cancer Res 2008; 68: 3795–3802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Stohrer M, Boucher Y, Stangassinger M, Jain RK . Oncotic pressure in solid tumors is elevated. Cancer Res 2000; 60: 4251–4255.

    CAS  PubMed  Google Scholar 

  51. Linardakis E, Bateman A, Phan V, Ahmed A, Gough M, Olivier K 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 

  52. Fernandez M, Porosnicu M, Markovic D, Barber GN . Genetically engineered vesicular stomatitis virus in gene therapy: application for treatment of malignant disease. J Virol 2002; 76: 895–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bajzer Z, Marusic M, Vuk-Pavlovic S . Conceptual frameworks for mathematical modeling of tumor growth dynamics. Math Comput Modelling 1996; 23: 31–46.

    Article  Google Scholar 

  54. Spratt JA, von Fournier D, Spratt JS, Weber EE . Decelerating growth and human breast cancer. Cancer 1993; 71: 2013–2019.

    Article  CAS  PubMed  Google Scholar 

  55. Offord C, Bajzer Z . A hybrid global optimization algorithm involving simple and inductive search. Lecture Notes Comput Sci 2006; 2074: 680–688.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by R01 CA130878 and R01 CA107082 (RGV) and the Minnesota Partnership for Biotechnology and Medical Genomics (DD and ZB). Technical support from J Thompson and T Kottke is greatly appreciated.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    D M Rommelfanger, J Dev, R G Vile & D Dingli

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    D M Rommelfanger

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

    C P Offord & Z Bajzer

  4. Department of Physiology and Biomedical Engineering, Rochester, MN, USA

    Z Bajzer

  5. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    D Dingli

Authors
  1. D M Rommelfanger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C P Offord
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Dev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z Bajzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R G Vile
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Dingli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Dingli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rommelfanger, D., Offord, C., Dev, J. et al. Dynamics of melanoma tumor therapy with vesicular stomatitis virus: explaining the variability in outcomes using mathematical modeling. Gene Ther 19, 543–549 (2012). https://doi.org/10.1038/gt.2011.132

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2011.132

Keywords

This article is cited by

Search

Advanced search

Quick links