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.

  • Acquired Diseases
  • Published:

The treatment of established intracranial tumors by in situ retroviral IFN-γ transfer

Gene Therapy volume 7, pages 1715–1724 (2000)Cite this article

Abstract

Current treatments for malignant gliomas are still largely ineffective in significantly improving prognosis. We have investigated the efficacy of treating established rat C6 glioma by in situ retroviral delivery of IFN-γ cDNA. Ecotropic retrovirus packaging cells were transfected with a retroviral vector containing the mouse IFN-γ gene. The IFN-γ packaging cells were stereotactically implanted into established intracranial C6 glioma in immunocompetent Wistar rats, resulting in the eradication of these tumors. All IFN-γ-treated rats survived to 92 days after C6 implantation (an arbitrary end point) compared with 14 days for controls. Analysis of these treated brains showed that the established C6 tumors had been completely eradicated by this time-point with brain morphology appearing normal. The IFN-γ-mediated tumoricidal activity resulted from an apparent interplay of B and T cell components of the immune system, as well as the inhibition of tumor angiogenesis. This therapeutic strategy may provide an effective method of eradicating established intracranial tumors.

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
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Walker MD et al. Evaluation of BCNU and/or radiation therapy in the treatment of anaplastic gliomas: a cooperative clinical trial J Neurosurg 1978 49: 333–343

    Article  CAS  PubMed  Google Scholar 

  2. Bubenik J, Simova J, Jandlova T . Immunotherapy of cancer using local administration of lymphoid cells transformed by IL-2 cDNA and constitutively producing IL-2 Immunol Lett 1990 23: 287–292

    Article  CAS  PubMed  Google Scholar 

  3. Yu JS et al. Gene therapy for metastatic brain tumors by vaccination with granulocyte–macrophage colony-stimulating factor-transduced tumor cells Hum Gene Ther 1997 8: 1065–1072

    Article  CAS  PubMed  Google Scholar 

  4. Tseng SH, Hwang LH, Lin SM . Induction of antitumor immunity by intracerebrally implanted rat C6 glioma cells genetically engineered to secrete cytokines J Immunother 1997 20: 334–342

    Article  CAS  PubMed  Google Scholar 

  5. Tahara H et al. Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector J Immunol 1995 154: 6466–6474

    CAS  PubMed  Google Scholar 

  6. Saleh M et al. Effect of in situ retroviral interleukin-4 transfer on established intracranial tumors J Natl Cancer Inst 1999 91: 438–445

    Article  CAS  PubMed  Google Scholar 

  7. Saleh M, Davis IA, Wilks AF . The paracrine role of tumor-derived mIL-4 on tumor-associated endothelium Int J Cancer 1997 72: 664–672

    Article  CAS  PubMed  Google Scholar 

  8. Grivnik K, Anderson J . The role of T cell growth stimulating factors in T cell triggering Immunol Rev 1980 51: 35–59

    Article  Google Scholar 

  9. Ralph P, Nakoinz I, Rennick D . Role of interleukin 2, interleukin 4, and alpha, beta and gamma interferon in stimulating macrophage antibody-dependent tumoricidal activity J Exp Med 1988 167: 712–717

    Article  CAS  PubMed  Google Scholar 

  10. Maraskovsky E, Chen W-F, Shortman K . IL-2 and IFN-gamma are two necessary lymphokines in the development of cytolytic T cells J Immunol 1989 143: 1210–1214

    CAS  PubMed  Google Scholar 

  11. Wallach D, Fellous M, Revel M . Preferential effect of interferon on the synthesis of HLA antigens and their mRNAs in human cells Nature 1982 299: 833–836

    Article  CAS  PubMed  Google Scholar 

  12. Carrel S, Schmidt-Kessen A, Giuffre L . Recombinant interferon-γ can induce the expression of HLA-DR and -DC on DR-negative melanoma cells and enhance the expression of HLA-ABC and tumor-associated antigens Eur J Immunol 1985 15: 118–123

    Article  CAS  PubMed  Google Scholar 

  13. Gross N et al. In vitro antigenic modulation of human neuroblastoma cells induced by interferon-γ, retinoic acid and dibutyryl cyclic AMP Int J Cancer 1987 39: 521–529

    Article  CAS  PubMed  Google Scholar 

  14. Maheshwari RK et al. Differential effects of interferon gamma and alpha on in vitro model of angiogenesis J Cell Physiol 1991 146: 164–169

    Article  CAS  PubMed  Google Scholar 

  15. Kardamakis D . Interferons in the treatment of malignancies In Vivo 1991 5: 589–598

    CAS  PubMed  Google Scholar 

  16. Stadler R, Ruszczak Z . Interferons: new additions and indications for use Dermatol Clin 1993 11: 187–199

    Article  CAS  PubMed  Google Scholar 

  17. Gansbacher B et al. Retroviral vector-mediated γ-interferon gene transfer into tumour cells generates potent and long-lasting anti-tumour immunity Cancer Res 1990 50: 7820–7825

    CAS  PubMed  Google Scholar 

  18. Miyatake S-I et al. Efficient tumor supression by glioma specific murine cytotoxic T lymphocytes transfected with interferon γ gene J Natl Cancer Inst 1990 82: 217–220

    Article  CAS  PubMed  Google Scholar 

  19. Watanabe Y . Transfection of interferon γ gene in animal tumors a model for local cytokine production and tumor immunity Semin Cancer Biol 1992 3: 43–46

    CAS  PubMed  Google Scholar 

  20. Howard B et al. Retrovirus mediated gene transfer of the human gamma IFN gene: a therapy for cancer Ann NY Acad Sci 1994 716: 167–187

    Article  CAS  PubMed  Google Scholar 

  21. Nanni P et al. The immune response elicited by mammary adenocarcinoma cells transduced with interferon-γ and cytosine deaminase genes cures lung metastases by parental cells Hum Gene Ther 1998 9: 217–224

    Article  CAS  PubMed  Google Scholar 

  22. Kanno H et al. Experimental gene therapy against subcutaneously implanted glioma with a herpes simplex virus-defective vector expressing interferon-γ Cancer Gene Ther 1999 6: 147–154

    Article  CAS  PubMed  Google Scholar 

  23. Karavodin LM et al. Generation of a systemic antitimor response with regional intratumoral injections of interferon γ retroviral therapy Hum Gene Ther 1998 9: 2231–2241

    Article  CAS  PubMed  Google Scholar 

  24. Saleh M . A retroviral vector that allows efficient coexpression of two genes and the versatility of alternate selection markers Hum Gene Ther 1997 8: 979–983

    Article  CAS  PubMed  Google Scholar 

  25. Jonas NK, Saleh M . The expression of vascular endothelial platelet endothelial cell adhesion molecule-1 is not regulated by IFN-γ treatment of C6 tumors in vivo Int J Oncol (in press)

  26. Visse E et al. Regression of intracerebral rat glioma isografts by therapeutic subcutaneous immunization with interferon-γ, interleukin-7, or B7–1-transfected tumor cells Cancer Gene Ther 1999 6: 37–44

    Article  CAS  PubMed  Google Scholar 

  27. Nemunaitis J et al. Phase I trial of interferon γ retroviral vector administered intratumorally with multiple courses in patients with metastatic melanoma Hum Gene Ther 1999 10: 1289–1298

    Article  CAS  PubMed  Google Scholar 

  28. Romer LH et al. IFN-γ and TNF-α induce redistribution of PECAM-1 (CD31) on human endothelial cells J Immunol 1995 154: 6582–6592

    CAS  PubMed  Google Scholar 

  29. Rival Y et al. Inhibition of platelet endothelial cell adhesion molecule-1 synthesis and leukocyte transmigration in endothelial cells by the combined action of TNF-α and IFN-γ J Immunol 1996 157: 1233–1241

    CAS  PubMed  Google Scholar 

  30. Stewart RJ, Kashour TS, Marsden PA . Vascular endothelial platelet endothelial cell adhesion molecule-1 (PECAM-1) expression is decreased by TNF-alpha and IFN-gamma J Immunol 1996 156: 1221–1228

    CAS  PubMed  Google Scholar 

  31. Vanguri P, Farber J . Identification of CRG-2. An interferon-inducible mRNA predicted to encode a murine monokine J Biol Chem 1990 265: 15049–15057

    CAS  PubMed  Google Scholar 

  32. Farber JM . A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines Proc Natl Acad Sci USA 1990 87: 5238–5242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Angiolillo AL et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo J Exp Med 1995 182: 155–162

    Article  CAS  PubMed  Google Scholar 

  34. Streiter RM et al. The functional role of ELR motif in CXC chemokine-mediated angiogenesis J Biol Chem 1995 270: 27348–27357

    Article  Google Scholar 

  35. Fathallah-Shaykh HM et al. Gene transfer of IFN-gamma into established brain tumors represses growth by antiangiogenesis J Immunol 2000 164: 217–222

    Article  CAS  PubMed  Google Scholar 

  36. Ram Z et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral-producing cells Nature Med 1997 3: 1354–1361

    Article  CAS  PubMed  Google Scholar 

  37. Saleh M, Stacker SA, Wilks AF . Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor (VEGF) sequence Cancer Res 1996 56: 393–401

    CAS  PubMed  Google Scholar 

  38. Markowitz D et al. Retroviral gene transfer using safe and efficient packaging cell lines Ann NY Acad Sci 1990 612: 407–414

    Article  CAS  PubMed  Google Scholar 

  39. Lauren J, Gunji Y, Alitalo K . Is angiopoietin-2 necessary for the initiation of tumor angiogenesis Am J Pathol 1998 153: 1333–1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gray PW, Goeddel DV . Cloning and expression of murine immune interferon cDNA Proc Natl Acad Sci USA 1983 80: 5842–5846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mountford P et al. Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression Proc Natl Acad Sci USA 1994 91: 4303–4307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saleh M et al. The expression of antisense vascular endothelial growth factor (VEGF) sequences inhibit intracranial glioma growth in vivo by suppressing tumour angiogenesis J Clin Neurosci 1996 3: 366–372

    Article  CAS  PubMed  Google Scholar 

  43. Rongish BJ et al. Relationship of the extracellular matrix to coronary neovascularisation during development J Mol Cell Cardiol 1996 28: 2203–2215

    Article  CAS  PubMed  Google Scholar 

  44. Williams KC et al. PECAM-1 (CD31) expression in the central nervous system and its role in experimental allergic encephalomyelitis in the rat J Neurosci Res 1996 45: 747–757

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank AF Wilks and I Peroulis for invaluable discussion and critical review of the manuscript. We also thank P Motram and L Murray-Segal for providing antibodies and J Boyle for the mIFN-γ cDNA. This work was supported in part by the National Health and Medical Research Council, Health Care Australia (Mayne Nickless P/L) and the Anti-Cancer Council of Victoria.

Author information

Authors and Affiliations

  1. The Department of Surgery, Gene Therapy Laboratory, The University of Melbourne and The Royal Melbourne Hospital, Parkville, Victoria, Australia

    M Saleh, N K Jonas & A Wiegmans

  2. The Department of Surgery, Cell Biology Laboratory, The University of Melbourne and The Royal Melbourne Hospital, Parkville, Victoria, Australia

    S S Stylli

Authors
  1. M Saleh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N K Jonas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Wiegmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S S Stylli
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saleh, M., Jonas, N., Wiegmans, A. et al. The treatment of established intracranial tumors by in situ retroviral IFN-γ transfer. Gene Ther 7, 1715–1724 (2000). https://doi.org/10.1038/sj.gt.3301273

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301273

Keywords

This article is cited by

Search

Advanced search

Quick links