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Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors

Cancer Gene Therapy volume 13, pages 1061–1071 (2006)Cite this article

Abstract

Gene therapy-induced expression of immunostimulatory molecules at tumor cell level may evoke antitumor immune mechanisms by recruiting and enhancing viability of antigen-processing cells and specific tumoricidal lymphocytes. The antitumor efficacy of a plasmid, coding for granulocyte–macrophage colony-stimulating factor (GM-CSF) and the B7-1 costimulatory immune molecule, delivered into growing solid tumors by electroporation was investigated. Murine fibrosarcomas (JBS) growing in Balb/C mice (⩽100 mm3) were transfected with GM-CSF/B7-1-expressing plasmid. Complete tumor regression occurred in greater than 60% of treated animals. This response was systemic, durable and tumor specific, with all responding animals resistant to repeat tumor challenge. Using a liver metastatic model, effective cure of distal metastases was achieved following treatment of the primary subcutaneous tumor. This treatment strategy could be applicable in the clinical setting for effective elimination of both primary tumors and associated metastatic disease.

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References

  1. Ramarathinam L, Castle M, Wu Y, Liu Y . T cell costimulation by B7/BB1 induces CD8 T cell-dependent tumor rejection: an important role of B7/BB1 in the induction, recruitment, and effector function of antitumor T cells. J Exp Med 1994; 179: 1205–1214.

    Article  CAS  PubMed  Google Scholar 

  2. Borrello I, Pardoll D . GM-CSF-based cellular vaccines: a review of the clinical experience. Cytokine Growth Factor Rev 2002; 13: 185–193.

    Article  CAS  PubMed  Google Scholar 

  3. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte–macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539–3543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nemunaitis J, Sterman D, Jablons D, Smith II JW, Fox B, Maples P et al. Granulocyte–macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J Natl Cancer Inst 2004; 96: 326–331.

    Article  CAS  PubMed  Google Scholar 

  5. Heller L, Pottinger C, Jaroszeski MJ, Gilbert R, Heller R . In vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunity. Melanoma Res 2000; 10: 577–583.

    Article  CAS  PubMed  Google Scholar 

  6. Thomas MC, Greten TF, Pardoll DM, Jaffee EM . Enhanced tumor protection by granulocyte–macrophage colony-stimulating factor expression at the site of an allogeneic vaccine. Hum Gene Ther 1998; 9: 835–843.

    Article  CAS  PubMed  Google Scholar 

  7. Chong H, Todryk S, Hutchinson G, Hart IR, Vile RG . Tumour cell expression of B7 costimulatory molecules and interleukin-12 or granulocyte–macrophage colony-stimulating factor induces a local antitumour response and may generate systemic protective immunity. Gene Therapy 1998; 5: 223–232.

    Article  CAS  PubMed  Google Scholar 

  8. Matsubara H, Gunji Y, Maeda T, Tasaki K, Koide Y, Asano T et al. Electroporation-mediated transfer of cytokine genes into human esophageal tumors produces anti-tumor effects in mice. Anticancer Res 2001; 21: 2501–2503.

    CAS  PubMed  Google Scholar 

  9. Chi CH, Wang YS, Lai YS, Chi KH . Anti-tumor effect of in vivo IL-2 and GM-CSF electrogene therapy in murine hepatoma model. Anticancer Res 2003; 23: 315–321.

    CAS  PubMed  Google Scholar 

  10. Linsley PS, Clark EA, Ledbetter JA . T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci USA 1990; 87: 5031–5035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Linsley PS, Ledbetter JA . The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993; 11: 191–212.

    Article  CAS  PubMed  Google Scholar 

  12. Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 1992; 71: 1093–1102.

    Article  CAS  PubMed  Google Scholar 

  13. Chen L, McGowan P, Ashe S, Johnston JV, Hellstrom I, Hellstrom KE . B7-1/CD80-transduced tumor cells elicit better systemic immunity than wild-type tumor cells admixed with Corynebacterium parvum. Cancer Res 1994; 54: 5420–5423.

    CAS  PubMed  Google Scholar 

  14. Chen L, McGowan P, Ashe S, Johnston J, Li Y, Hellstrom I et al. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J Exp Med 1994; 179: 523–532.

    Article  CAS  PubMed  Google Scholar 

  15. Townsend SE, Su FW, Atherton JM, Allison JP . Specificity and longevity of antitumor immune responses induced by B7-transfected tumors. Cancer Res 1994; 54: 6477–6483.

    CAS  PubMed  Google Scholar 

  16. Isaka Y, Nakamura H, Mizui M, Takabatake Y, Horio M, Kawachi H et al. DNAzyme for TGF-beta suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 2004; 66: 586–590.

    Article  CAS  PubMed  Google Scholar 

  17. Scheule RK . The role of CpG motifs in immunostimulation and gene therapy. Adv Drug Deliv Rev 2000; 44: 119–134.

    Article  CAS  PubMed  Google Scholar 

  18. Brattain MG, Stobel-Stevens J, Fine D, Webb M, Sarrif AM . Establishment of mouse colonic carcinoma cell lines with different metastatic properties. Cancer Res 1980; 40: 2142–2146.

    CAS  PubMed  Google Scholar 

  19. O'Brien MG, Collins CG, Collins JK, Shanahan F, O'Sullivan GC . Oral immune tolerance to tumor specific antigens may confer growth advantage to esophageal and gastric cancers. Dis Esophagus 2003; 16: 218–223.

    Article  CAS  PubMed  Google Scholar 

  20. Yang S, Vervaert CE, Seigler HF, Darrow TL . Tumor cells cotransduced with B7.1 and gamma-IFN induce effective rejection of established parental tumor. Gene Therapy 1999; 6: 253–262.

    Article  CAS  PubMed  Google Scholar 

  21. Winn HJ . Immune mechanisms in homotransplantations. II. Quantitative assay of the immunologic activity of lymphoid cells stimulated by tumor homografts. J Immunol 1961; 86: 228–239.

    CAS  PubMed  Google Scholar 

  22. Cheng F, Gabrilovich D, Sotomayor EM . Immune tolerance in breast cancer. Breast Dis 2004; 20: 93–103.

    Article  CAS  PubMed  Google Scholar 

  23. Gothelf A, Mir LM, Gehl J . Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat Rev 2003; 29: 371–387.

    Article  CAS  PubMed  Google Scholar 

  24. Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005; 201: 779–791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Murphy J, O'Sullivan GC, Lee G, Madden M, Shanahan F, Collins JK et al. The inflammatory response within Dukes' B colorectal cancers: implications for progression of micrometastases and patient survival. Am J Gastroenterol 2000; 95: 3607–3614.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant from the Health Research Board of Ireland (RP/2005/262).

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Author notes

  1. C G Collins and M Tangney: These authors contributed equally to this work.

Authors and Affiliations

  1. Cork Cancer Research Centre, Mercy University Hospital and Leslie C Quick Jnr Laboratory, University College Cork, Cork, Ireland

    C G Collins, M Tangney, J O Larkin, G Casey, M C Whelan, J Cashman, J Murphy, D Soden, S Vejda, S McKenna, B Kiely, J K Collins, J Barrett, S Aarons & G C O'Sullivan

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  1. C G Collins
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Correspondence to G C O'Sullivan.

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Collins, C., Tangney, M., Larkin, J. et al. Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors. Cancer Gene Ther 13, 1061–1071 (2006). https://doi.org/10.1038/sj.cgt.7700976

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