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Epstein–Barr virus–driven gene therapy for EBV–related lymphomas

Nature Medicine volume 2, pages 1379–1382 (1996)Cite this article

Abstract

Genetic alterations in malignant tissues are potential targets for gene–based cancer therapies. Alternatively, aberrant expression of certain specific genes associated with malignant transformation may be envisioned to enhance the expression of chemosensitizing drugs. Epstein–Barr virus (EBV)–related B–cell lymphomas are fatal complications of immunosuppression due to AIDS, organ transplantation or congenital immune abnormalities. The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes. We tested whether an EBNA2–responsive EBV promoter may selectively target EBV–related lymphoma cells by virus–regulated expression of a suicide gene. Using the BamC promoter driving a hygromycin–thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2. Further, there was complete macroscopic regression of established B–cell lymphomas in mice with severe combined immunodeficiency disease (SCID mice) treated with a single course of ganciclovir. These data provide in vitro and in vivo support for a model of exploiting the molecular basis of tumor development to enhance the specificity of gene therapy.

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References

  1. Rooney, C.M. et al. Host cell and EBNA-2 regulation of Epstein-Barr virus latent-cycle promoter activity in B lymphocytes. J. Virol. 66, 496–504 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang, F., Kikutani, H., Tsang, S. Kishimoto, T. & Kieff, E. Epstein-Barr virus nuclear protein 2 transactivates a cis-acting CD23 DNA element. J. Virol. 65, 4101–4106 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Ghosh, D. & Kieff, E. cis-Acting regulatory elements near the Epstein-Barr virus latent-infection membrane protein transcriptional start site. J. Virol. 64, 1855–1858 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zimber-Strobl, U. et al. Epstein-Barr virus nuclear antigen 2 activates transcription of the terminal protein gene. J. Virol. 65, 415–423 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Grossman, S.R., Johannsen, E. Tong, X., Yalamanchili, R. & Kieff, E. The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the Jκ recombination signal binding protein. Proc. Natl. Acad. Sci. USA 91, 7568–7572 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Henkel, T., Ling, P.D., Hayward, S.D. & Peterson, M.G. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science 265, 92–95 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Calendar, A. et al. Epstein-Barr virus (EBV) induces expression of B-cell activation markers on in vitro infection of EBV-negative B-lymphoma cells. Proc. Natl. Acad. Sci. USA 84, 8060–8064 (1987).

    Article  Google Scholar 

  8. Deisseroth, A.B., Kavanagh, J. & Champlin, R. Use of safety-modified retro-viruses to introduce chemotherapy during the therapy of ovarian cancer: A pilot trial. Hum. Gene Ther. 5, 1507–1522 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Dranoff, G. 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 90, 3539–3543 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shewach, D.S. et al. Enhanced cytotoxicity of antiviral drugs mediated by adenovirus directed transfer of the herpes simplex virus thymidine kinase gene in rat glioma cells. Cancer Gem Ther. 1, 107–112 (1994).

    CAS  Google Scholar 

  11. Han, X., Kasahara, N. & Kan, Y.W. Ligand-directed retroviral targeting of human breast cancer cells. Proc. Natl. Acad. Sci. USA 92, 9747–9751 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huber, B.E., Richards, C.A. & Krenitsky, T.A. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: An innovative approach for cancer therapy. Proc. Natl. Acad. Sci. USA 88, 8039–8043 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vile, R.G. & Hart, I.R. In vitro and in vivo targeting of gene expression to melanoma cells. Cancer Res. 53, 962–967 (1993).

    CAS  PubMed  Google Scholar 

  14. Rea, D. et al. Epstein-Barr virus latent and replicative gene expression in posttransplant lymphoproliferative disorders and AIDS-related non-Hodgkin's lymphomas. French Study Group of Pathology for HIV-associated Tumors. Ann. Oncol. 5 (Suppl. 1), S113–S116 (1994).

    Article  Google Scholar 

  15. Knowles, D.M. Biologic aspects of AIDS-associated non-Hodgkin's lymphoma. Curr. Opin. Oncol. 5, 845–851 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Hamilton-Dutoit, S.J. et al Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma: Correlation of lymphoma phenotype with three distinct patterns of viral latency. Am. J. Pathol. 143, 1072–1085 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bashir, R., Luka, J., Cheloha, K., Chamberlain, M. & Hochberg, F. Expression of Epstein-Barr virus proteins in primary CNS lymphoma in AIDS patients. Neurology 43, 2358–2362 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Carbone, A., Tirelli, U., Gloghini, A., Volpe, R. & Boiocchi, M. Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression. J. Clin. Oncol. 11, 1674–1681 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. daCosta, T.L., Jen, J., He, T.C., Chen, T.A. & Kinzler, K.W. Converting cancer genes into killer genes. Proc. Natl. Acad. Sci. USA 93, 4192–4196 (1996).

    Article  CAS  Google Scholar 

  20. Hasegawa, R., Emi, N. & Shimokata, K. Retroviral transfer of HSV1-TK gene into human lung cancer cell line. J. Mol. Med. 73, 107–112 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Culver, K.W. et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256, 1550–1552 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Hurford, R.K., Dranoff, G., Mulligan, R.C. & Tepper, R.I. Gene therapy of metastatic cancer by in vivo retroviral gene targeting. Nature Genet. 10, 430–435 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Oshiro, E.M. et al Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells. Cancer Gene Ther. 2, 87–95 (1995).

    CAS  PubMed  Google Scholar 

  24. Lupton, S.D., Brunton, L.L., Kalberg, V.A. & Overell, R.W. Dominant positive and negative selection using a hygromycin phosphotransferase-thymidine kinase fusion gene. Mol Cell. Biol. 11, 3374–3378 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Michael Franken

    Present address: Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, USA

Authors and Affiliations

  1. Division of Hematology/Oncology, Harvard Medical School and New England Deaconess Hospital, One Deaconess Road, Boston, Massachusetts, 02215, USA

    Michael Franken, Anita Estabrooks & Lisa Cavacini

  2. Department of Pathology, Harvard Medical School and New England Deaconess Hospital, One Deaconess Road, Boston, Massachusetts, 02215, USA

    Brad Sherburne

  3. Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts, 02115, USA

    Fred Wang

  4. Harvard Medical School and AIDS Research Center, MGH Cancer Center, Massachusetts General Hospital, Building 149, Room 5212,13th Street, Charlestown, Massachusetts, 02129, USA

    David T. Scadden

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  2. Anita Estabrooks
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  3. Lisa Cavacini
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  4. Brad Sherburne
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  5. Fred Wang
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  6. David T. Scadden
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Franken, M., Estabrooks, A., Cavacini, L. et al. Epstein–Barr virus–driven gene therapy for EBV–related lymphomas. Nat Med 2, 1379–1382 (1996). https://doi.org/10.1038/nm1296-1379

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