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TCR transgenes and transgene cassettes for TCR gene therapy: status in 2008

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Abstract

The genetic introduction of T cell receptor genes into T cells has been developed over the past decade as a strategy to induce defined antigen-specific T cell immunity. With the potential value of TCR gene therapy well-established in murine models and the feasibility of infusion of TCR-modified autologous T cells shown in a first phase I trial, the next key step will be to transform TCR gene transfer from an experimental technique into a robust clinical strategy. In this review, we discuss the different properties of the TCR transgene and transgene cassette that can strongly affect both the efficacy and the safety of TCR gene transfer.

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References

  1. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ (2004) Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103:767–776

    Article  PubMed  CAS  Google Scholar 

  2. Gottschalk S, Heslop HE, Rooney CM (2005) Adoptive immunotherapy for EBV-associated malignancies. Leuk Lymphoma 46:1–10

    Article  PubMed  CAS  Google Scholar 

  3. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854

    Article  PubMed  CAS  Google Scholar 

  4. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346–2357

    Article  PubMed  CAS  Google Scholar 

  5. Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR (2008) Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118:294–305

    Article  PubMed  CAS  Google Scholar 

  6. Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393

    Article  PubMed  CAS  Google Scholar 

  7. Dembic Z, Haas W, Weiss S, McCubrey J, Kiefer H, von Boehmer H, Steinmetz M (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320:232–238

    Article  PubMed  CAS  Google Scholar 

  8. Kessels HW, Wolkers MC, van den Boom MD, van der Valk MA, Schumacher TN (2001) Immunotherapy through TCR gene transfer. Nat Immunol 2:957–961

    Article  PubMed  CAS  Google Scholar 

  9. Abad JD, Wrzensinski C, Overwijk W, De Witte MA, Jorritsma A, Hsu C, Gattinoni L, Cohen CJ, Paulos CM, Palmer DC, Haanen JB, Schumacher TN, Rosenberg SA, Restifo NP, Morgan RA (2008) T-cell receptor gene therapy of established tumors in a murine melanoma model. J Immunother 31:1–6

    Article  PubMed  CAS  Google Scholar 

  10. de Witte MA, Bendle GM, van den Boom MD, Coccoris M, Schell TD, Tevethia SS, van Tinteren H, Mesman EM, Song JY, Schumacher TN (2008) TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation. J Immunol 181:2563–2571

    PubMed  Google Scholar 

  11. de Witte MA, Coccoris M, Wolkers MC, van den Boom MD, Mesman EM, Song JY, van der Valk M, Haanen JB, Schumacher TN (2006) Targeting self-antigens through allogeneic TCR gene transfer. Blood 108:870–877

    Article  PubMed  CAS  Google Scholar 

  12. Coccoris M, Swart E, de Witte MA, van Heijst JW, Haanen JB, Schepers K, Schumacher TN (2008) Long-term functionality of TCR-transduced T cells in vivo. J Immunol 180:6536–6543

    PubMed  CAS  Google Scholar 

  13. Kessels HW, Schepers K, van den Boom MD, Topham DJ, Schumacher TN (2006) Generation of T cell help through a MHC class I-restricted TCR. J Immunol 177:976–982

    PubMed  CAS  Google Scholar 

  14. Morris EC, Tsallios A, Bendle GM, Xue SA, Stauss HJ (2005) A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection. Proc Natl Acad Sci USA 102:7934–7939

    Article  PubMed  CAS  Google Scholar 

  15. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    Article  PubMed  CAS  Google Scholar 

  16. Kaneko S, Mastaglio S, Bondanza A, Ponzoni M, Sanvito F, Aldrighetti L, Radrizzani M, La Seta-Catamancio S, Provasi E, Mondino A, Nagasawa T, Fleischhauer K, Russo V, Traversari C, Ciceri F, Bordignon C, Bonini C (2008) IL–7 and IL–15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes. Blood [epub ahead of print]. doi:10.1182/blood-2008-05-156059

  17. Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, Restifo NP (2006) Increased intensity lymphodepletion and adoptive immunotherapy–how far can we go? Nat Clin Pract Oncol 3:668–681

    Article  PubMed  CAS  Google Scholar 

  18. de Witte MA, Jorritsma A, Kaiser A, van den Boom MD, Dokter M, Bendle GM, Haanen JB, Schumacher TN (2008) Requirements for effective anti-tumor responses of TCR transduced T cells. J Immunol 181:5128–5136

    PubMed  Google Scholar 

  19. Newrzela S, Cornils K, Li Z, Baum C, Brugman MH, Hartmann M, Meyer J, Hartmann S, Hansmann ML, Fehse B, von Laer D (2008) Resistance of mature T cells to oncogene transformation. Blood 112:2278–2286

    Article  PubMed  CAS  Google Scholar 

  20. Heemskerk MH, Hoogeboom M, Hagedoorn R, Kester MG, Willemze R, Falkenburg JH (2004) Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med 199:885–894

    Article  PubMed  CAS  Google Scholar 

  21. van der Veken LT, Hagedoorn RS, van Loenen MM, Willemze R, Falkenburg JH, Heemskerk MH (2006) Alphabeta T-cell receptor engineered gammadelta T cells mediate effective antileukemic reactivity. Cancer Res 66:3331–3337

    Article  PubMed  CAS  Google Scholar 

  22. Coccoris M, de Witte MA, Schumacher TN (2005) Prospects and limitations of T cell receptor gene therapy. Curr Gene Ther 5:583–593

    Article  PubMed  CAS  Google Scholar 

  23. Engels B, Uckert W (2007) Redirecting T lymphocyte specificity by T cell receptor gene transfer—a new era for immunotherapy. Mol Aspects Med 28:115–142

    Article  PubMed  CAS  Google Scholar 

  24. Heemskerk MH, Griffioen M, Falkenburg JH (2008) T-cell receptor gene transfer for treatment of leukemia. Cytotherapy 10:108–115

    Article  PubMed  CAS  Google Scholar 

  25. Schumacher TN (2002) T-cell-receptor gene therapy. Nat Rev Immunol 2:512–519

    Article  PubMed  CAS  Google Scholar 

  26. Stauss HJ, Cesco-Gaspere M, Thomas S, Hart DP, Xue SA, Holler A, Wright G, Perro M, Little AM, Pospori C, King J, Morris EC (2007) Monoclonal T-cell receptors: new reagents for cancer therapy. Mol Ther 15:1744–1750

    Article  PubMed  CAS  Google Scholar 

  27. Labrecque N, Whitfield LS, Obst R, Waltzinger C, Benoist C, Mathis D (2001) How much TCR does a T cell need? Immunity 15:71–82

    Article  PubMed  CAS  Google Scholar 

  28. Weinhold M, Sommermeyer D, Uckert W, Blankenstein T (2007) Dual T cell receptor expressing CD8+ T cells with tumor- and self-specificity can inhibit tumor growth without causing severe autoimmunity. J Immunol 179:5534–5542

    PubMed  CAS  Google Scholar 

  29. Lam JS, Reeves ME, Cowherd R, Rosenberg SA, Hwu P (1996) Improved gene transfer into human lymphocytes using retroviruses with the gibbon ape leukemia virus envelope. Hum Gene Ther 7:1415–1422

    Article  PubMed  CAS  Google Scholar 

  30. Uckert W, Becker C, Gladow M, Klein D, Kammertoens T, Pedersen L, Blankenstein T (2000) Efficient gene transfer into primary human CD8+ T lymphocytes by MuLV–10A1 retrovirus pseudotype. Hum Gene Ther 11:1005–1014

    Article  PubMed  CAS  Google Scholar 

  31. Hagani AB, Riviere I, Tan C, Krause A, Sadelain M (1999) Activation conditions determine susceptibility of murine primary T-lymphocytes to retroviral infection. J Gene Med 1:341–351

    Article  PubMed  CAS  Google Scholar 

  32. Engels B, Cam H, Schuler T, Indraccolo S, Gladow M, Baum C, Blankenstein T, Uckert W (2003) Retroviral vectors for high-level transgene expression in T lymphocytes. Hum Gene Ther 14:1155–1168

    Article  PubMed  CAS  Google Scholar 

  33. Jorritsma A, Gomez-Eerland R, Dokter M, van de Kasteele W, Zoet YM, Doxiadis II, Rufer N, Romero P, Morgan RA, Schumacher TN, Haanen JB (2007) Selecting highly affine and well-expressed TCRs for gene therapy of melanoma. Blood 110:3564–3572

    Article  PubMed  CAS  Google Scholar 

  34. Tsuji T, Yasukawa M, Matsuzaki J, Ohkuri T, Chamoto K, Wakita D, Azuma T, Niiya H, Miyoshi H, Kuzushima K, Oka Y, Sugiyama H, Ikeda H, Nishimura T (2005) Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 106:470–476

    Article  PubMed  CAS  Google Scholar 

  35. Joseph A, Zheng JH, Follenzi A, Dilorenzo T, Sango K, Hyman J, Chen K, Piechocka-Trocha A, Brander C, Hooijberg E, Vignali DA, Walker BD, Goldstein H (2008) Lentiviral vectors encoding human immunodeficiency virus type 1 (HIV–1)-specific T-cell receptor genes efficiently convert peripheral blood CD8 T lymphocytes into cytotoxic T lymphocytes with potent in vitro and in vivo HIV-1-specific inhibitory activity. J Virol 82:3078–3089

    Article  PubMed  CAS  Google Scholar 

  36. Yang S, Cohen CJ, Peng PD, Zhao Y, Cassard L, Yu Z, Zheng Z, Jones S, Restifo NP, Rosenberg SA, Morgan RA (2008) Development of optimal bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell recognition. Gene Ther 15:1411–1423

    Article  PubMed  CAS  Google Scholar 

  37. Amendola M, Venneri MA, Biffi A, Vigna E, Naldini L (2005) Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat Biotechnol 23:108–116

    Article  PubMed  CAS  Google Scholar 

  38. Unutmaz D, KewalRamani VN, Marmon S, Littman DR (1999) Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J Exp Med 189:1735–1746

    Article  PubMed  CAS  Google Scholar 

  39. Thornhill SI, Schambach A, Howe SJ, Ulaganathan M, Grassman E, Williams D, Schiedlmeier B, Sebire NJ, Gaspar HB, Kinnon C, Baum C, Thrasher AJ (2008) Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther 16:590–598

    Article  PubMed  CAS  Google Scholar 

  40. Zhao Y, Zheng Z, Cohen CJ, Gattinoni L, Palmer DC, Restifo NP, Rosenberg SA, Morgan RA (2006) High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol Ther 13:151–159

    Article  PubMed  CAS  Google Scholar 

  41. Schaft N, Dorrie J, Muller I, Beck V, Baumann S, Schunder T, Kampgen E, Schuler G (2006) A new way to generate cytolytic tumor-specific T cells: electroporation of RNA coding for a T cell receptor into T lymphocytes. Cancer Immunol Immunother 55:1132–1141

    Article  PubMed  CAS  Google Scholar 

  42. Huang X, Wilber AC, Bao L, Tuong D, Tolar J, Orchard PJ, Levine BL, June CH, McIvor RS, Blazar BR, Zhou X (2006) Stable gene transfer and expression in human primary T cells by the Sleeping Beauty transposon system. Blood 107:483–491

    Article  PubMed  CAS  Google Scholar 

  43. Emerman M, Temin HM (1984) Genes with promoters in retrovirus vectors can be independently suppressed by an epigenetic mechanism. Cell 39:449–467

    Article  PubMed  CAS  Google Scholar 

  44. Rubinstein MP, Salem ML, Kadima AN, Nguyen CL, Gillanders WE, Nishimura MI, Cole DJ (2008) Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo. Cancer Gene Ther [epub ahead of print]. doi: 10.1038/cgt.2008.63

  45. Ghattas IR, Sanes JR, Majors JE (1991) The encephalomyocarditis virus internal ribosome entry site allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos. Mol Cell Biol 11:5848–5859

    PubMed  CAS  Google Scholar 

  46. Hughes MS, Yu YY, Dudley ME, Zheng Z, Robbins PF, Li Y, Wunderlich J, Hawley RG, Moayeri M, Rosenberg SA, Morgan RA (2005) Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. Hum Gene Ther 16:457–472

    Article  PubMed  CAS  Google Scholar 

  47. Holst J, Vignali KM, Burton AR, Vignali DA (2006) Rapid analysis of T-cell selection in vivo using T cell-receptor retrogenic mice. Nat Methods 3:191–197

    Article  PubMed  CAS  Google Scholar 

  48. Scholten KB, Kramer D, Kueter EW, Graf M, Schoedl T, Meijer CJ, Schreurs MW, Hooijberg E (2006) Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells. Clin Immunol 119:135–145

    Article  PubMed  CAS  Google Scholar 

  49. de Felipe P, Martin V, Cortes ML, Ryan M, Izquierdo M (1999) Use of the 2A sequence from foot-and-mouth disease virus in the generation of retroviral vectors for gene therapy. Gene Ther 6:198–208

    Article  PubMed  CAS  Google Scholar 

  50. Klump H, Schiedlmeier B, Vogt B, Ryan M, Ostertag W, Baum C (2001) Retroviral vector-mediated expression of HoxB4 in hematopoietic cells using a novel coexpression strategy. Gene Ther 8:811–817

    Article  PubMed  CAS  Google Scholar 

  51. Leisegang M, Engels B, Meyerhuber P, Kieback E, Sommermeyer D, Xue SA, Reuss S, Stauss H, Uckert W (2008) Enhanced functionality of T cell receptor-redirected T cells is defined by the transgene cassette. J Mol Med 86:573–583

    Article  PubMed  CAS  Google Scholar 

  52. Theoret MR, Cohen CJ, Nahvi AV, Ngo LT, Suri KB, Powell DJ, Dudley ME, Morgan RA, Rosenberg SA (2008) Relationship of p53 overexpression on cancers and recognition by anti-p53 TCR transduced T cells. Hum Gene Ther (epub ahead of print). doi:10.1089/hgt.2008.083

  53. Li Y, Moysey R, Molloy PE, Vuidepot AL, Mahon T, Baston E, Dunn S, Liddy N, Jacob J, Jakobsen BK, Boulter JM (2005) Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol 23:349–354

    Article  PubMed  CAS  Google Scholar 

  54. Heemskerk MH, Hoogeboom M, de Paus RA, Kester MG, van der Hoorn MA, Goulmy E, Willemze R, Falkenburg JH (2003) Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102:3530–3540

    Article  PubMed  CAS  Google Scholar 

  55. Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J, Ruppert T, Bolhuis RL, Melief CJ, Huber C, Stauss HJ, Theobald M (2001) Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2:962–970

    Article  PubMed  CAS  Google Scholar 

  56. Sandberg JK, Karre K, Glas R (1999) Recognition of the major histocompatibility complex restriction element modulates CD8(+) T cell specificity and compensates for loss of T cell receptor contacts with the specific peptide. J Exp Med 189:883–894

    Article  PubMed  CAS  Google Scholar 

  57. Sadovnikova E, Stauss HJ (1996) Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc Natl Acad Sci USA 93:13114–13118

    Article  PubMed  CAS  Google Scholar 

  58. Holler PD, Holman PO, Shusta EV, O’Herrin S, Wittrup KD, Kranz DM (2000) In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc Natl Acad Sci USA 97:5387–5392

    Article  PubMed  CAS  Google Scholar 

  59. Kessels HW, n Boom MD, Spits H, Hooijberg E, Schumacher TN (2000) Changing T cell specificity by retroviral T cell receptor display. Proc Natl Acad Sci USA 97:14578–14583

    Article  PubMed  CAS  Google Scholar 

  60. Richman SA, Kranz DM (2007) Display, engineering, and applications of antigen-specific T cell receptors. Biomol Eng 24:361–373

    Article  PubMed  CAS  Google Scholar 

  61. Zhao Y, Bennett AD, Zheng Z, Wang QJ, Robbins PF, Yu LY, Li Y, Molloy PE, Dunn SM, Jakobsen BK, Rosenberg SA, Morgan RA (2007) High-affinity TCRs generated by phage display provide CD4 + T cells with the ability to recognize and kill tumor cell lines. J Immunol 179:5845–5854

    PubMed  CAS  Google Scholar 

  62. Robbins PF, Li YF, El-Gamil M, Zhao Y, Wargo JA, Zheng Z, Xu H, Morgan RA, Feldman SA, Johnson LA, Bennett AD, Dunn SM, Mahon TM, Jakobsen BK, Rosenberg SA (2008) Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol 180:6116–6131

    PubMed  CAS  Google Scholar 

  63. Holler PD, Chlewicki LK, Kranz DM (2003) TCRs with high affinity for foreign pMHC show self-reactivity. Nat Immunol 4:55–62

    Article  PubMed  CAS  Google Scholar 

  64. Weber KS, Donermeyer DL, Allen PM, Kranz DM (2005) Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci USA 102:19033–19038

    Article  PubMed  CAS  Google Scholar 

  65. Donermeyer DL, Weber KS, Kranz DM, Allen PM (2006) The study of high-affinity TCRs reveals duality in T cell recognition of antigen: specificity and degeneracy. J Immunol 177:6911–6919

    PubMed  CAS  Google Scholar 

  66. Sommermeyer D, Neudorfer J, Weinhold M, Leisegang M, Engels B, Noessner E, Heemskerk MH, Charo J, Schendel DJ, Blankenstein T, Bernhard H, Uckert W (2006) Designer T cells by T cell receptor replacement. Eur J Immunol 36:3052–3059

    Article  PubMed  CAS  Google Scholar 

  67. Voss RH, Kuball J, Engel R, Guillaume P, Romero P, Huber C, Theobald M (2006) Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression. Immunol Res 34:67–87

    Article  PubMed  CAS  Google Scholar 

  68. Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA (2006) Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res 66:8878–8886

    Article  PubMed  CAS  Google Scholar 

  69. Hart DP, Xue SA, Thomas S, Cesco-Gaspere M, Tranter A, Willcox B, Lee SP, Steven N, Morris EC, Stauss HJ (2008) Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells. Gene Ther 15:625–631

    Article  PubMed  CAS  Google Scholar 

  70. Kuball J, Dossett ML, Wolfl M, Ho WY, Voss RH, Fowler C, Greenberg PD (2007) Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109:2331–2338

    Article  PubMed  CAS  Google Scholar 

  71. Cohen CJ, Li YF, El-Gamil M, Robbins PF, Rosenberg SA, Morgan RA (2007) Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res 67:3898–3903

    Article  PubMed  CAS  Google Scholar 

  72. Thomas S, Xue SA, Cesco-Gaspere M, San Jose E, Hart DP, Wong V, Debets R, Alarcon B, Morris E, Stauss HJ (2007) Targeting the Wilms tumor antigen 1 by TCR gene transfer: TCR variants improve tetramer binding but not the function of gene modified human T cells. J Immunol 179:5803–5810

    PubMed  CAS  Google Scholar 

  73. Heemskerk MH, Hagedoorn RS, van der Hoorn MA, van der Veken LT, Hoogeboom M, Kester MG, Willemze R, Falkenburg JH (2007) Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex. Blood 109:235–243

    Article  PubMed  CAS  Google Scholar 

  74. Voss RH, Willemsen RA, Kuball J, Grabowski M, Engel R, Intan RS, Guillaume P, Romero P, Huber C, Theobald M (2008) Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells. J Immunol 180:391–401

    PubMed  CAS  Google Scholar 

  75. Sebestyen Z, Schooten E, Sals T, Zaldivar I, San Jose E, Alarcon B, Bobisse S, Rosato A, Szollosi J, Gratama JW, Willemsen RA, Debets R (2008) Human TCR that incorporate CD3zeta induce highly preferred pairing between TCRalpha and beta chains following gene transfer. J Immunol 180:7736–7746

    PubMed  CAS  Google Scholar 

  76. Zhang T, He X, Tsang TC, Harris DT (2004) Transgenic TCR expression: comparison of single chain with full-length receptor constructs for T-cell function. Cancer Gene Ther 11:487–496

    Article  PubMed  CAS  Google Scholar 

  77. Lamers CH, Langeveld SC, Groot-van Ruijven CM, Debets R, Sleijfer S, Gratama JW (2007) Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo. Cancer Immunol Immunother 56:1875–1883

    Article  PubMed  Google Scholar 

  78. Ciceri F, Bonini C, Gallo-Stampino C, Bordignon C (2005) Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation. Cytotherapy 7:144–149

    Article  PubMed  CAS  Google Scholar 

  79. Bonini C, Bondanza A, Perna SK, Kaneko S, Traversari C, Ciceri F, Bordignon C (2007) The suicide gene therapy challenge: how to improve a successful gene therapy approach. Mol Ther 15:1248–1252

    Article  PubMed  CAS  Google Scholar 

  80. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724

    Article  PubMed  CAS  Google Scholar 

  81. Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, Deconinck E, Certoux JM, Robinet E, Saas P, Petracca B, Juttner C, Reynolds CW, Longo DL, Herve P, Cahn JY (2001) Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 97:63–72

    Article  PubMed  CAS  Google Scholar 

  82. Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L, Manley SA, Lupton SD, Overell RW, Reynolds TC, Corey L, Greenberg PD (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med 2:216–223

    Article  PubMed  CAS  Google Scholar 

  83. Berger C, Flowers ME, Warren EH, Riddell SR (2006) Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 107:2294–2302

    Article  PubMed  CAS  Google Scholar 

  84. Traversari C, Marktel S, Magnani Z, Mangia P, Russo V, Ciceri F, Bonini C, Bordignon C (2007) The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood 109:4708–4715

    Article  PubMed  CAS  Google Scholar 

  85. Frank O, Rudolph C, Heberlein C, von Neuhoff N, Schrock E, Schambach A, Schlegelberger B, Fehse B, Ostertag W, Stocking C, Baum C (2004) Tumor cells escape suicide gene therapy by genetic and epigenetic instability. Blood 104:3543–3549

    Article  PubMed  CAS  Google Scholar 

  86. Deschamps M, Mercier-Lethondal P, Certoux JM, Henry C, Lioure B, Pagneux C, Cahn JY, Deconinck E, Robinet E, Tiberghien P, Ferrand C (2007) Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft. Blood 110:3842–3852

    Article  PubMed  CAS  Google Scholar 

  87. Introna M, Barbui AM, Bambacioni F, Casati C, Gaipa G, Borleri G, Bernasconi S, Barbui T, Golay J, Biondi A, Rambaldi A (2000) Genetic modification of human T cells with CD20: a strategy to purify and lyse transduced cells with anti-CD20 antibodies. Hum Gene Ther 11:611–620

    Article  PubMed  CAS  Google Scholar 

  88. Serafini M, Bonamino M, Golay J, Introna M (2004) Elongation factor 1 (EF1alpha) promoter in a lentiviral backbone improves expression of the CD20 suicide gene in primary T lymphocytes allowing efficient rituximab-mediated lysis. Haematologica 89:86–95

    PubMed  CAS  Google Scholar 

  89. van Meerten T, Claessen MJ, Hagenbeek A, Ebeling SB (2006) The CD20/alphaCD20 ‘suicide’ system: novel vectors with improved safety and expression profiles and efficient elimination of CD20-transgenic T cells. Gene Ther 13:789–797

    Article  PubMed  CAS  Google Scholar 

  90. Serafini M, Manganini M, Borleri G, Bonamino M, Imberti L, Biondi A, Golay J, Rambaldi A, Introna M (2004) Characterization of CD20-transduced T lymphocytes as an alternative suicide gene therapy approach for the treatment of graft-versus-host disease. Hum Gene Ther 15:63–76

    Article  PubMed  CAS  Google Scholar 

  91. Casares S, Stan AC, Bona CA, Brumeanu TD (2001) Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II-peptide chimera. Nat Biotechnol 19:142–147

    Article  PubMed  CAS  Google Scholar 

  92. Yuan RR, Wong P, McDevitt MR, Doubrovina E, Leiner I, Bornmann W, O’Reilly R, Pamer EG, Scheinberg DA (2004) Targeted deletion of T-cell clones using alpha-emitting suicide MHC tetramers. Blood 104:2397–2402

    Article  PubMed  CAS  Google Scholar 

  93. Hess PR, Barnes C, Woolard MD, Johnson MD, Cullen JM, Collins EJ, Frelinger JA (2007) Selective deletion of antigen-specific CD8 + T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin. Blood 109:3300–3307

    Article  PubMed  CAS  Google Scholar 

  94. de Witte MA, Jorritsma A, Swart E, Straathof KC, de Punder K, Haanen JB, Rooney CM, Schumacher TN (2008) An inducible caspase 9 safety switch can halt cell therapy-induced autoimmune disease. J Immunol 180:6365–6373

    PubMed  Google Scholar 

  95. Kieback E, Charo J, Sommermeyer D, Blankenstein T, Uckert W (2008) A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer. Proc Natl Acad Sci USA 105:623–628

    Article  PubMed  CAS  Google Scholar 

  96. Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM (2005) An inducible caspase 9 safety switch for T-cell therapy. Blood 105:4247–4254

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the EU FP6 Integrated Project ATTACK, ZON-MW grant 431-00-005 and DFG grant SFB-TR36. We would like to thank members from our labs for fruitful discussions and suggestions.

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Gene Therapy, Max-Delbrück-Center of Molecular Medicine, Robert-Rössle-Strasse 10, 13092, Berlin, Germany

    Wolfgang Uckert

  2. Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Ton N. M. Schumacher

Authors
  1. Wolfgang Uckert
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  2. Ton N. M. Schumacher
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Correspondence to Wolfgang Uckert or Ton N. M. Schumacher.

Additional information

This paper is a focussed research review based on a presentation given at the sixth annual meeting of the Association for Immunotherapy of Cancer (CIMT), held in Mainz, Germany,15–16 May 2008.

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Uckert, W., Schumacher, T.N.M. TCR transgenes and transgene cassettes for TCR gene therapy: status in 2008. Cancer Immunol Immunother 58, 809–822 (2009). https://doi.org/10.1007/s00262-008-0649-4

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  • DOI: https://doi.org/10.1007/s00262-008-0649-4

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