Abstract
Adoptive therapy with allogeneic or tumor-specific T-cells has shown substantial clinical effects for several human tumors, but the widespread application of this strategy remains a daunting task. The antigen specificity of T-lymphocytes is solely determined by the T-cell receptor (TCR) α and β chains. Consequently, genetic transfer of TCR chains may form an alternative and potentially appealing strategy to impose a desirable tumor-antigen specificity onto cytotoxic or helper T-cell populations. In this strategy, autologous or donor-derived T-cell populations are equipped with a TCR of defined reactivity in short-term ex vivo cultures, and re-infusion of the redirected cells is used to supply T-cell reactivity against defined tumor-specific antigens. We have previously described the genetic introduction of T-cell receptor genes into peripheral T-cells in mouse model systems. Here we discuss the requirements for the successful genetic modification of murine T-lymphocytes and the subsequent use of such genetically modified cells in in vivo models.
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References
Dudley, M. E., Wunderlich, J. R., Robbins, P. F., et al. (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854.
Yee, C., Thompson, J. A., Byrd, D., et al. (2002) Adoptive T cell therapy using antigen-specific CD8+T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc. Natl. Acad. Sci. USA 99, 16,168–16,173.
Dembic, Z., Haas, W., Weiss, S., et al. (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320, 232–238.
Kessels, H. W., Wolkers, M. C., and Schumacher, T. N. (2002) Adoptive transfer of T-cell immunity. Trends Immunol. 23, 5, 264–269.
Kitamura, T. (1998) New experimental approaches in retro virus-mediated expression screening. Int. J. Hematol. 67, 351–359.
Naviaux, R. K., Costanzi, E., Haas, M., and Verma, I. M. (1996) The pCL vector sys-tem: rapid production of helper-free, high-titer, recombinant retroviruses. J. Virol. 70, 5701–5705.
Kolen, S., Dolstra, H., van de Locht, L., et al. (2002) Biodistribution and retention time of retrovirally labeled T lymphocytes in mice is strongly influenced by the culture period before infusion. J. Immunother. 25, 385–395.
Altman, J. D., Moss, P. A., Goulder, P. J., et al. (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96.
Schepers, K., Toebes, M., Sotthewes, G., et al. (2002) Differential kinetics of antigen-specific CD4+and CD8+T cell responses in the regression of retrovirus-induced sarco-mas. J. Immunol. 169, 3191–3199.
Uckert, W., Becker, C., Gladow, M., et al. (2000) Efficient gene transfer into primary human CD8+T lymphocytes by MuLV-10A1 retrovirus pseudotype. Hum. Gene Ther. 11, 1005–1014.
Masopust, D., Vezys, V., Marzo, A. L., and Lefrancois, L. (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417.
Riddell, S. R., Elliott, M., Lewinsohn, D. A., et al. (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat. Med. 2, 216–223.
Jung, D., Jaeger, E., Cayeux, S., et al. (1998) Strong immunogenic potential of a B7 retro viral expression vector: generation of HLA-B7-restricted CTL response against select-able marker genes. Hum. Gene Ther. 9, 53–62.
Stripecke, R., Carmen Villacres, M., Skelton, D., Satake, N., Halene, S., and Kohn, D. (1999) Immune response to green fluorescent protein: implications for gene therapy. Gene Ther. 6, 1305–1312.
Skelton, D., Satake, N., and Kohn, D. B. (2001) The enhanced green fluorescent protein (eGFP) is minimally immunogenic in C57BL/6 mice. Gene Ther. 8, 1813–1814.
Davodeau, F., Peyrat, M. A., Romagne, F., et al. (1995) Dual T cell receptor beta chain expression on human T lymphocytes. J. Exp. Med. 181, 1391–1398.
Padovan, E., Giachino, C., Cella, M., Valitutti, S., Acuto, O., and Lanzavecchia, A. (1995) Normal T lymphocytes can express two different T cell receptor beta chains: implications for the mechanism of allelic exclusion. J. Exp. Med. 181, 1587–1591.
Balomenos, D., Balderas, R. S., Mulvany, K. P., Kaye, J., Kono, D. H., and Theofilopoulos, A. N. (1995) Incomplete T cell receptor V beta allelic exclusion and dual V beta-expressing cells. J. Immunol. 155, 3308–3312.
Topham, D. J., Castrucci, M.R., Wingo, F.S., Belz, G.T., and Doherty, P.C. (2001) The role of antigen in the localization of naive, acutely activated, and memory CD8(+) T cells to the lung during influenza pneumonia. J. Immunol. 167, 6983–6990.
Moskophidis, D. and Kioussis, D. (1998) Contribution of virus-specific CD8+cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model. J. Exp. Med. 188, 223–232.
Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., et al. (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255–256.
van Os, R., Sheridan, T. M., Robinson, S., Drukteinis, D., Ferrara, J. L., and Mauch, P. M. (2001) Immunogenicity of Ly5 (CD45)-antigens hampers long-term engraftment follow-ing minimal conditioning in a murine bone marrow transplantation model. Stem Cells 19, 80–87.
Gladow, M., Becker, C., Blankenstein, T., and Uckert, W. (2000) MLV-10A1 retrovirus pseudotype efficiently transduces primary human CD4+T lymphocytes. J. Gene Med. 2, 409–415.
Kinsella, T. M. and Nolan, G. P. (1996) Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. Hum. Gene Ther. 7, 1405–1413.
Unutmaz, D., KewalRamani, V. N., Marmon, S., and Littman, D. R. (1999) Cytokine sig-nals are sufficient for HIV-1 infection of resting human T lymphocytes. J. Exp. Med. 189, 1735–1746.
Cavalieri, S., Cazzaniga, S., Geuna, M., et al. (2003) Human T lymphocytes transduced by lentiviral vectors in the absence of TCR-activation maintain an intact immune compe-tence. Blood 102(2), 497–505.
Labrecque, N., Whitfield, L. S., Obst, R., Waltzinger, C., Benoist, C., and Mathis, D. (2001) How much TCR does a T cell need? Immunity 15, 71–82.
Zufferey, R., Donello, J. E., Trono, D., and Hope, T. J. (1999) Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J. Virol. 73, 2886–2892.
Schumacher, T. N. (2002) T-cell-receptor gene therapy. Nat Rev Immunol 7, 512–519.
Eshhar, Z. (1997) Tumor-specific T-bodies: towards clinical application. Cancer Immunol. Immunother. 45, 131–136.
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Kessels, H.W.H.G., Wolkers, M.C., Schumacher, T.N.M. (2005). Gene Transfer of MHC-Restricted Receptors. In: Ludewig, B., Hoffmann, M.W. (eds) Adoptive Immunotherapy: Methods and Protocols. Methods in Molecular Medicine™, vol 109. Humana Press. https://doi.org/10.1385/1-59259-862-5:201
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DOI: https://doi.org/10.1385/1-59259-862-5:201
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