Abstract
In the past years, a number of clinical trials involving the adoptive transfer of genetically modified T lymphocytes have been reported [1–3]. Gene marking studies were the first gene transfer protocols to enter clinical practice. The principal objective of a gene marking study is to introduce, in the target cells, a gene which does not modify the function of the cells but allows them to be detected, providing information on survival, distribution, and function of the infused genetically-modified cells. Moreover, gene marking studies provided crucial informations about the feasibility, safety, and efficacy of genetically-modified cells, an important pre-requisite for future gene therapy trials. To date, two general groups of marking studies have been conducted. The first group of protocols focuses on the transduction of lymphocytes with potential antitumor or antiviral activity. Target cells of these studies include tumor infiltrating lymphocytes (TIL), virus-specific cytotoxic T cells (anti-Epstein-Barr virus specific CTLs and anti-HIV specific CTLs), and donor-derived lymphocytes infused in the context of allogeneic bone marrow transplantation (BMT). The second group of gene marking studies focuses on the transduction of autologous bone marrow cells from patients with neoplastic diseases. These studies provided important information concerning the biology of BMT and the source of post-BMT relapse of neoplastic diseases. The principal purpose of these studies was to determine whether neoplastic cells, present in unpurged autologous bone marrow, contribute to relapse following autologous BMT. In all disease settings (acute leukemia, chronic myelogenous leukemia, and neuroblastoma) gene marked tumor cells were found in relapsed patients [4, 5]. This observation represents the basis for ongoing second generation studies, which focus on the comparison of different purging techniques performed prior to transplantation. The second purpose of these studies was to investigate ex vivo the possibility of introducing a gene into normal hematopoietic progenitors. The presence of the marker gene in hematopoietic progenitor cells was confirmed ex vivo by clonogenic assays. The marker gene continued to be detected and expressed for up to 4 years in the mature progeny of marrow precursor cells, suggesting that a relatively immature hematopoietic cell population had been transduced.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Anderson, W. E (1992) Hum. Gene Ther. Science 256: 808–813.
Brenner, M. (1996) Gene marking. Hum. Gene Ther. 7: 1927–1936.
Hege, K. M., Roberts, M. R. (1996) T-cell gene therapy. Curr. Opin. Biotechnol. 7: 629–634.
Brenner, M. K., Rill, D. R., Moen, R. C. et al. (1993) Gene–marking to trace origin of relapse after autologous bone–marrow transplantation. Lancet 341: 85–86.
Deisseroth, A. B., Zu, Z., Claxton, D. et al. (1994) Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 83: 3068–3076.
Crystal, R. G. (1995) Transfer of genes to humans: early lessons and obstacles to success. Science 270: 404–410.
Bunnell, B. A., Muul, L. M., Donahue, R. E. et al. (1995) High–efficiency retroviral–mediated gene transfer into human and nonhuman primate peripheral blood lymphocytes. Proc. Natl. Acad. Sci. USA 92: 7739–7743.
Blease, M., Blankenstein, T., Brenner, M. et al. (1995) Vectors in cancer therapy: how will they deliver? Cancer Gene Ther. 2: 219–297.
Miller, A. D., Buttimore, C. (1986) Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol. Cell. Biol. 6: 2895–2902.
Cornetta, K., Morgan, R. A., Anderson, W. E. (1991) Safety issues related to retroviralmediated gene transfer in humans. Hum. Gen. Ther. 2: 5–14.
Donahue, R. E., Kessler, S. W., Bodine, D. et al. (1992) Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J. Exp. Med. 176: 1125–1135.
Rosenberg, S. A., Aebersold, P., Cornetta, K. et al. (1990) Gene transfer into humans — immunotherapy of patients with advanced melanoma, using tumor–infiltrating lymphocytes modified by retroviral gene transduction. N. Engl. J. Med. 323: 570–578.
Rosenberg, S. A., Packard, B. S., Aebersold, P. M. et al. (1988) Use of tumor–infiltrating lymphocytes and interleukin–2 in the immunotherapy of patients with metastatic
melanoma, special report. N. Engl. J. Med. 319: 1676–1680.
Cai, Q., Rubin, J. T., Lotze, M. T. (1995) Genetically marking human cells–results of the first clinical gene transfer studies. Cancer Gene Ther. 2: 125–136.
Economou, J. S., Belldegrun, A. S., Glaspy, J. et al. (1996) In vivo trafficking of adoptively transferred interleukin–2 expanded tumor–infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial. J. Clin. Invest. 97: 515–521.
Thomas, E. D., Clift, R. A., Fefer, A. et al. (1986) Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann. Int. Med. 104: 155–163.
O’Reilly, R. (1993) Bone Marrow Transplantation. Curr. Opin. Hematol.: 221–222.
Horowitz, M. M., Gale, R. P., Sondel, P. M. et al. (1990) Graft versus leukemia reactions after bone marrow transplantation. Blood 75: 555–562.
Kernan, N. A., Bordignon, C., Collins, N. H. et al. (1989) Bone marrow failure in HLAidentical T–cell depleted allogeneic transplants for leukemia: I. Clinical aspects. Blood 74: 2227–2236.
Kolb, H. J., Schattenberg, A., Goldman, J. M. et al. (1995) Graft–versus–leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86: 2041–2050.
Slavin, S., Naparstek, E., Nagler, A. et al. (1996) Allogeneic cell therapy with donor peripheral bl000d cells and recombinant human interleukin–2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood 87: 2195–2204.
Tricot, G., Vesole, D. H., Jagganath, S. et al. (1996) Graft–versus–myeloma effect: proof of principle. Blood 87: 1196–1198.
Papadopoulos, E. B., Ladanyi, M., Emanuel, D. et al. (1994) Infusions of donor leukocytes to treat Epstein–Barr virus–associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 330: 1185–1191.
Riddell, S. R., Watanabe, K. S., Goodrich, J. M. et al. (1992) Restoration of viral immunity in immunodeficient humans by adoptive transfer of T cell clones. Science 257.
Riddell, S. R., Greenberg, P. D. (1995) Principles for adoptive T cell therapy of human viral diseases. Annu. Rev. Immunol. 13: 545–586.
Reusser, P., Riddel, S. R., Meyers, J. D. et al. (1991) Cytotoxic T–lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 83: 1373–1380.
Reddehase, M. J., Mutter, W., Munch, K. et al. (1987) CD8–positive T lymphocytes specific for murine cytomegalovirus immediate–early antigens mediate protective immunity. J. Virol. 61: 3102–3108.
Lucin, P., Pavic, I., Polic, B. et al. (1992) Gamma interferon–dependant clearance of cytomegalovirus infection in salivary gland. J. Virol. 66: 1977–1984.
Rooney, C. M., Smith, C. A., Ng, C. Y. C. et al. (1995) Use of gene–modified virus–specific T lymphocytes to control Epstein–Barr–virus related lymphoproliferation. Lancet 345: 9–13.
Strauss, S. E., Cohen, J. I., Tosato, G. et al. (1992) Epstein–Barr virus infection: biology, pathogenesis and management. Ann. Intern. Med. 118: 45–58.
Heslop, H. E., Ng, C. Y. C., Li, C. et al. (1996) Long–term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene–modified virus–specific T lymphocytes. Nat. Med. 2: 551–555.
McCune, J. M. (1991) HIV–1: the infective process in vivo. Cell 64: 351–363.
Borrow, P., Lewicki, H., Hahn, B. H. et al. (1994) Virus–specific CD8+ cytotoxic T–lymphocyte activity associated with control of viremia in primary human immunodeficiency
virus type 1 infection. J. Virol. 68: 6103–6110.
Fauci, A. S. (1988) The human immunodeficiency virus: infectivity and mechanism of pathogenesis. Science 239: 617–622.
Carmichael, A., Jin, X., Sissons, P. et al. (1993) Quantitative analysis of the human immunodeficiency virus type 1 (HIV–1)–specific cytotoxic T lymphocytes (CTL) response at different stages of HIV–1 infection: differential CTL responses to HIV–1 and Epstein–Barr virus in late disease. J. Exp. Med. 177: 249–256.
Riddell, S. R., Elliott. M., Lewinsohn, D. A. et al. (1996) T–cell mediated rejection of gene–modified HIV–specific cytotoxic lymphocytes in HIV–infected patients. Nat. Med. 2: 216–223.
Bordignon, C., Bonini, C. (1995) A clinical protocol for gene transfer into peripheral blood lymphocytes for in vivo immunomodulation of donor anti–tumor immunity in patients affected by recurrent disease after allogeneic bone marrow transplantation. Hum. Gene Ther. 2: 813–819.
Mavilio, E, Ferrari, G., Rossini, S. et al. (1994) Peripheral blood lymphocytes as target cells of retroviral vector–mediated gene transfer. Blood 83: 1988–1997.
Bonini, C., Ferrari, G., Verzeletti, S. et al. (1997) HSV–TK gene transfer into donor lymphocytes for control of allogenic graft–versus–leukemia. Science 276: 1719–1724.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Birkhäuser Verlag Basel
About this chapter
Cite this chapter
Bonini, C., Bordignon, C. (1999). Gene Marking of T Lymphocytes. In: Blankenstein, T. (eds) Gene Therapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7011-5_13
Download citation
DOI: https://doi.org/10.1007/978-3-0348-7011-5_13
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-0348-7013-9
Online ISBN: 978-3-0348-7011-5
eBook Packages: Springer Book Archive