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Gene Therapy to Improve Function of T Cells for Adoptive Immunotherapy

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Immunotherapy of Cancer

Part of the book series: Methods in Molecular Biology ((MIMB,volume 651))

Abstract

Adoptive immunotherapy with cytotoxic T cells has shown promising clinical results in patients with metastatic melanoma and post-transplant-associated viral infections. However, the antitumor effect of adoptively transferred tumor-specific cytotoxic T lymphocytes (CTLs) is impaired by the limited capacity of these cells to expand within the tumor microenvironment. Administration of interleukin 2 (IL-2) has been used to overcome this limitation, but the systemic toxicity and the expansion of unwanted cells, including regulatory T cells, limit the clinical value of this strategy. To discover whether transgenic expression of lymphokines by the CTLs themselves might overcome these limitations, we evaluated the effects of transgenic expression of IL-2 and IL-15 in our model of Epstein-Barr Virus-specific CTLs (EBV-CTLs). We found that transgenic expression of IL-2 or IL-15 increased the expansion of EBV-CTLs in vitro and that these gene-modified EBV-CTL had enhanced antitumor activity, while maintaining their antigen-specificity. Although the proliferation of these cytokine gene transduced CTLs remained strictly antigen dependent, clinical application of this approach likely requires the inclusion of a suicide gene to deal with the potential development of T-cell mutants with autonomous growth. We found that the incorporation of an inducible caspase-9 suicide gene allowed efficient elimination of transgenic CTLs after exposure to a chemical inducer of dimerization, thereby increasing the safety and feasibility of the approach.

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References

  1. Waldmann, T. A., Dubois, S., and Tagaya, Y. (2001) Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity. 14, 105–110.

    PubMed  CAS  Google Scholar 

  2. Nakamura, Y., Russell, S. M., Mess, S. A., Friedmann, M., Erdos, M., Francois, C., Jacques, Y., Adelstein, S., and Leonard, W. J. (1994) Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling. Nature 369, 330–333.

    Article  PubMed  CAS  Google Scholar 

  3. Fehniger, T. A., Suzuki, K., VanDeusen, J. B., Cooper, M. A., Freud, A. G., and Caligiuri, M. A. (2001) Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis 27, 223–230.

    Article  PubMed  CAS  Google Scholar 

  4. Lin, J. X., Migone, T. S., Tsang, M., Friedmann, M., Weatherbee, J. A., Zhou, L., Yamauchi, A., Bloom, E. T., Mietz, J., John, S., and Leonard W J. (1995) The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2, 331–339.

    Article  PubMed  CAS  Google Scholar 

  5. Lotze, M. T., Matory, Y. L., Ettinghausen, S. E., Rayner, A. A., Sharrow, S. O., Seipp, C. A., Custer, M. C., and Rosenberg, S. A. (1985) In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 135, 2865–2875.

    PubMed  CAS  Google Scholar 

  6. Whitehead, R. P., Friedman, K. D., Clark, D. A., Pagani, K., and Rapp, L. (1995) Phase I trial of simultaneous administration of interleukin 2 and interleukin 4 subcutaneously. Clin Cancer Res 1, 1145–1152.

    PubMed  CAS  Google Scholar 

  7. Rosenberg, S. A., Lotze, M. T., Yang, J. C., Aebersold, P. M., Linehan, W. M., Seipp, C. A., and White, D. E. (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210, 474–484.

    Article  PubMed  CAS  Google Scholar 

  8. Finnegan, N. M., Redmond, H. P., and Bouchier-Hayes, D. J. (1998) Taurine attenuates recombinant interleukin-2-activated, lymphocyte-mediated endothelial cell injury. Cancer 82, 186–199.

    Article  PubMed  CAS  Google Scholar 

  9. Ahmadzadeh, M., and Rosenberg, S. A. (2006) IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 107, 2409–2414.

    Article  PubMed  CAS  Google Scholar 

  10. Quintarelli, C., Vera, J. F., Savoldo, B., Giordano Attianese, G. M., Pule, M., Foster, A. E., Heslop, H. E., Rooney, C. M., Brenner, M. K., and Dotti, G. (2007) Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes. Blood 110, 2793–2802.

    Article  PubMed  CAS  Google Scholar 

  11. Blau, C. A., Peterson, K. R., Drachman, J. G., and Spencer, D. M. (1997) A proliferation switch for genetically modified cells. Proc Natl Acad Sci USA 94, 3076–3081.

    Article  PubMed  CAS  Google Scholar 

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Quintarelli, C., Savoldo, B., Dotti, G. (2010). Gene Therapy to Improve Function of T Cells for Adoptive Immunotherapy. In: Yotnda, P. (eds) Immunotherapy of Cancer. Methods in Molecular Biology, vol 651. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-786-0_8

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  • DOI: https://doi.org/10.1007/978-1-60761-786-0_8

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-785-3

  • Online ISBN: 978-1-60761-786-0

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