How (specific) would you like your T-cells today? Generating T-cell therapeutic function through TCR-gene transfer

Frontiers in Immunology

Volumn 3, Issue JUL, 2012, Pages

  Daniel Meshulam, Inbal ^a   Ya'akobi, Shlomo ^a   Ankri, Chen ^a   Cohen, Cyrille J ^a  

^a BAR ILAN UNIVERSITY   (Israel)

Author keywords

Autoimmunity; Cancer; Immunotherapy; Infectious diseases; T cell receptor; T cells; TCR gene transfer

Indexed keywords

EID: 84874272015     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00186     Document Type: Review

References (169)

1. Aarnoudse, C. A., Kruse, M., Kono-pitzky, R., Brouwenstijn, N., and Schrier, P. I. (2002). TCR reconsti-tution in Jurkat reporter cells facilitates the identification of novel tumor antigens by cDNA expression cloning. Int. J. Cancer 99, 7-13.
2. Aggen, D. H., Chervin, A. S., Schmitt, T. M., Engels, B., Stone, J. D., Richman, S. A., Piepenbrink, K.H., Baker, B. M., Greenberg, P. D., Schreiber, H., and Kranz, D. M. (2012). Single-chain ValphaVbeta T-cell receptors function without mispairing with endogenous TCR chains. Gene Ther. 19, 365-374.
3. Ahmadi, M., King, J. W., Xue, S. A., Voisine, C., Holler, A., Wright, G. P., Waxman, J., Morris, E., and Stauss, H. J. (2011). CD3 limits the efficacy of TCR gene therapy in vivo. Blood 118, 3528-3537.
4. Alajez, N. M., Schmielau, J., Alter, M. D., Cascio, M., and Finn, O. J. (2005). Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution. Blood 105, 4583-4589.
5. Alli, R., Zhang, Z. M., Nguyen, P., Zheng, J. J., and Geiger, T. L. (2011). Rational design of T cell receptors with enhanced sensitivity for antigen. PLoS ONE 6, e18027. doi: 10.1371/journal.pone.0018027
6. Almasbak, H., Rian, E., Hoel, H. J., Pule, M., Walchli, S., Kvalheim, G., Gaud-ernack, G., and Rasmussen, A. M. (2011). Transiently redirected T cells for adoptive transfer. Cytotherapy 13, 629-640.
7. Amir, A. L., van der Steen, D. M., van Loenen, M. M., Hagedoorn, R. S., de Boer, R., Kester, M. D., de Ru, A. H., Lugthart, G. J., van Kooten, C., Hiemstra, P. S., Jedema, I., Grif-fioen, M., van Veelen, P. A., Falken-burg, J. H., and Heemskerk, M. H. (2011). PRAME-specific Allo-HLA-restricted T cells with potent antitu-mor reactivity useful for therapeutic T-cell receptor gene transfer. Clin. Cancer Res. 17, 5615-5625.
8. Amos, S. M., Duong, C. P., West-wood, J. A., Ritchie, D. S., Junghans, R. P., Darcy, P. K., and Kershaw, M. H. (2011). Autoimmunity associated with immunotherapy of cancer. Blood 118, 499-509.
9. Andersen, R. S., Thrue, C. A., Junker, N., Lyngaa, R., Donia, M., Ellebaek, E., Svane, I. M., Schumacher, T. N., Thor, S. P., and Hadrup, S. R. (2012). Dissection of T-cell antigen specificity in human melanoma. Cancer Res. 72, 1642-1650.
10. Bear, A. S., Morgan, R. A., Cornetta, K., June, C. H., Binder-Scholl, G., Dudley, M. E., Feldman, S. A., Rosenberg, S. A., Shurtleff, S. A., Rooney, C. M., Heslop, H. E., and Dotti, G. (2012). Replication-competent retro-viruses in gene-modified T cells used in clinical trials: is it time to revise the testing requirements? Mol. Ther. 20, 246-249.
11. Bendle, G. M., Linnemann, C., Hooi-jkaas, A. I., Bies, L., de Witte, M. A., Jorritsma, A., Kaiser, A. D., Pouw, N., Debets, R., Kieback, E., Uckert, W., Song, J. Y., Haanen, J. B., and Schumacher, T. N. (2010). Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat. Med. 16, 565-570.
12. Berger, C., Jensen, M. C., Lansdorp, P. M., Gough, M., Elliott, C., and Rid-dell, S. R. (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.
13. Berger, C., Turtle, C. J., Jensen, M. C., and Riddell, S. R. (2009). Adoptive transfer of virus-specific and tumor-specific T cell immunity. Curr. Opin. Immunol. 21, 224-232.
14. Bialer, G., Horovitz-Fried, M., Ya'acobi, S., Morgan, R. A., and Cohen, C. J. (2010). Selected murine residues endow human TCR with enhanced tumor recognition. J. Immunol. 184, 6232-6241.
15. Birkholz, K., Hofmann, C., Hoyer, S., Schulz, B., Harrer, T., Kampgen, E., Schuler, G., Dorrie, J., and Schaft, N. (2009). A fast and robust method to clone and functionally validate T-cell receptors. J. Immunol. Methods 346, 45-54.
16. Bonini, C., Ferrari, G., Verzeletti, S., Servida, P., Zappone, E., Ruggieri, L., Ponzoni, M., Rossini, S., Mav-ilio, F., Traversari, C., and Bordignon, C. (1997). HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276, 1719-1724.
17. Borbulevych, O. Y., Santhanagopolan, S. M., Hossain, M., and Baker, B. M. (2011). TCRs used in cancer gene therapy cross-react with MART-1/Melan-A tumor antigens via distinct mechanisms. J. Immunol. 187, 2453-2463.
18. Boria, I., Cotella, D., Dianzani, I., San-toro, C., and Sblattero, D. (2008). Primer sets for cloning the human repertoire of T cell receptor variable regions. BMC Immunol. 9, 50. doi: 10.1186/1471-2172-9-50
19. Burns, W. R., Zheng, Z., Rosenberg, S. A., and Morgan, R. A. (2009). Lack of specific gamma-retroviral vector long terminal repeat promoter silencing in patients receiving genetically engineered lymphocytes and activation upon lymphocyte restimulation. Blood 114, 2888-2899.
20. Cavalieri, S., Cazzaniga, S., Geuna, M., Magnani, Z., Bordignon, C., Naldini, L., and Bonini, C. (2003). Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence. Blood 102, 497-505.
21. Chinnasamy, N., Wargo, J. A., Yu, Z., Rao, M., Frankel, T. L., Riley, J. P., Hong, J. J., Parkhurst, M. R., Feldman, S. A., Schrump, D. S., Restifo, N. P., Robbins, P. F., Rosenberg, S. A., and Morgan, R. A. (2011). A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J. Immunol. 186, 685-696.
22. Chlewicki, L. K., Holler, P. D., Monti, B. C., Clutter, M. R., and Kranz, D. M. (2005). High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. J. Mol. Biol. 346, 223-239.
23. Chung, S., Wucherpfennig, K. W., Friedman, S. M., Hafler, D. A., and Stro-minger, J.L. (1994). Functional three-domain single-chain T-cell receptors. Proc. Natl. Acad. Sci. U.S.A. 91, 12654-12658.
24. Circosta, P., Granziero, L., Follenzi, A., Vigna, E., Stella, S., Vallario, A., Elia, A. R., Gammaitoni, L., Vitaggio, K., Orso, F., Geuna, M., Sangiolo, D., Todorovic, M., Giachino, C., and Cignetti, A. (2009). T cell receptor (TCR) gene transfer with lentiviral vectors allows efficient redirection of tumor specificity in naive and memory T cells without prior stimulation of endogenous TCR. Hum. Gene Ther. 20, 1576-1588.
25. Clay, T. M., Custer, M. C., Sachs, J., Hwu, P., Rosenberg, S. A., and Nishimura, M. I. (1999). Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J. Immunol. 163, 507-513.
26. Cohen, C. J., Li, Y. F., El Gamil, M., Robbins, P. F., Rosenberg, S. A., and Morgan, R. A. (2007). Enhanced anti-tumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res. 67, 3898-3903.
27. Cohen, C. J., Zhao, Y., Zheng, Z., Rosenberg, S. A., and Morgan, R. A. (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.
28. Cohen, C. J., Zheng, Z., Bray, R., Zhao, Y., Sherman, L. A., Rosenberg, S. A., and Morgan, R. A. (2005). Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR. J. Immunol. 175, 5799-5808.
29. Cooper, L. J., Kalos, M., Lewinsohn, D. A., Riddell, S. R., and Greenberg, P. D. (2000). Transfer of specificity for human immunodeficiency virus type 1 intoprimaryhumanTlymphocytes by introduction of T-cell receptor genes. J. Virol. 74, 8207-8212.
30. Daniels, M. A., Hogquist, K. A., and Jameson, S. C. (2002). Sweet 'n' sour: the impact of differential gly-cosylation on T cell responses. Nat. Immunol. 3, 903-910.
31. Davis, J. L., Theoret, M. R., Zheng, Z., Lamers, C. H., Rosenberg, S. A., and Morgan, R. A. (2010). Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. Clin. Cancer Res. 16, 5852-5861.
32. Dembic, Z., Haas, W., Weiss, S., McCubrey, J., Kiefer, H., von Boehmer, H., and Steinmetz, M. (1986). Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320, 232-238.
33. de Witte, M. A., Jorritsma, A., Swart, E., Straathof, K. C., de Punder, K., Haa-nen, J. B., Rooney, C. M., and Schumacher, T. N. (2008). An inducible caspase 9 safety switch can halt cell therapy-induced autoimmune disease. J. Immunol. 180, 6365-6373.
34. Di Stasi, A., Tey, S. K., Dotti, G., Fujita, Y., Kennedy-Nasser, A., Martinez, C., Straathof, K., Liu, E., Durett, A. G., Grilley, B., Liu, H., Cruz, C. R., Savoldo, B., Gee, A. P., Schindler, J., Krance, R. A., Heslop, H. E., Spencer, D. M., Rooney, C. M., and Brenner, M. K. (2011). Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673-1683.
35. Duffy, D., Dawoodji, A., Agger, E. M., Andersen, P., Westermann, J., and Bell, E. B. (2009). Immunolog-ical memory transferred with CD4 T cells specific for tuberculosis antigens Ag85B-TB10.4: persisting antigen enhances protection. PLoS ONE 4, e8272. doi: 10.1371/journal.pone. 0008272
36. Feuchtinger, T., Matthes-Martin, S., Richard, C., Lion, T., Fuhrer, M., Hamprecht, K., Handgretinger, R., Peters, C., Schuster, F. R., Beck, R., Schumm, M., Lotfi, R., Jahn, G., and Lang, P. (2006). Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic aden-ovirus infection after allogeneic stem cell transplantation. Br. J. Haematol. 134, 64-76.
37. Frankel, T. L., Zhang, L., Burns, W. R., Zheng, Z., and Morgan, R. A. (2011). The position of the AUG start codon in MFG-based gamma-retroviral vectors has a dramatic effect on translation-dependent protein expression. J. Gene Med. 13 478-486.
38. Frecha, C., Levy, C., Cosset, F. L., and Verhoeyen, E. (2010). Advancesin the field of lentivector-based trans-duction of T and B lymphocytes for gene therapy. Mol. Ther. 18 1748-1757.
39. Fujio, K., Okamoto, A., Araki, Y. Shoda, H., Tahara, H., Tsuno, N. H., Takahashi, K., Kitamura, T., and Yamamoto, K. (2006). Gene therapy of arthritis with TCR isolated from the inflamed paw. J. Immunol. 177 8140-8147.
40. Fujio, K., Okamoto, A., Tahara, H. Abe, M., Jiang, Y., Kitamura, T. Hirose, S., and Yamamoto, K. (2004). Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease. J. Immunol. 173 2118-2125.
41. Fujita, Y., Rooney, C. M., and Heslop, H. E. (2008). Adoptive cellularimmunotherapy for viral diseases. Bone Marrow Transplant. 41 193-198.
42. Gattinoni, L., Klebanoff, C. A., Palmer, D. C., Wrzesinski, C., Kerstann, K., Yu, Z., Finkelstein, S. E., Theoret, M. R., Rosenberg, S. A., and Res-tifo, N. P. (2005). Acquisition of full effector function in vitro paradoxically impairs the in vivo antitu-mor efficacy of adoptively transferred CD8+ T cells. J Clin. Invest. 115 1616-1626.
43. Gattinoni, L., Lugli, E., Ji, Y., Pos Z., Paulos, C. M., Quigley, M. F. Almeida, J. R., Gostick, E., Yu, Z., Carpenito, C., Wang, E., Douek, D. C., Price, D. A., June, C. H., Marin-cola, F. M., Roederer, M., and Restifo, N. P. (2011). A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290-1297.
44. Gattinoni, L., Zhong, X. S., Palmer, D. C., Ji, Y., Hinrichs, C. S., Yu Z., Wrzesinski, C., Boni, A., Cas-sard, L., Garvin, L. M., Paulos, C. M., Muranski, P., and Restifo, N. P. (2009). Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808-813.
45. Gehring, A. J., Xue, S. A., Ho, Z. Z., Teoh, D., Ruedl, C., Chia, A., Koh, S., Lim, S. G., Maini, M. K., Stauss, H., and Bertoletti, A. (2011). Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocel-lular carcinoma cell lines. J. Hepatol. 55, 103-110.
46. Ghattas, I. R., Sanes, J. R., and Majors, J. E. (1991). The encephalomyocardi-tis 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.
47. Govers, C., Sebestyen, Z., Berrevoets, C., Venselaar, H., and Debets, R. (2011). T cell receptor fused to CD3zeta: transmembrane domain of CD3zeta prevents TCR mis-pairing, whereas complete CD3zeta directs functional TCR expression. Open Gene Ther. J. 4, 11-22.
48. Govers, C., Sebestyen, Z., Coccoris, M., Willemsen, R. A., and Debets, R. (2010). T cell receptor gene therapy: strategies for optimizing transgenic TCR pairing. Trends Mol. Med. 16, 77-87.
49. Ha, S. P., Klemen, N. D., Kinnebrew, G. H., Brandmaier, A. G., Marsh, J., Hangoc, G., Palmer, D. C., Restifo, N. P., Cornetta, K., Broxmeyer, H. E., and Touloukian, C. E. (2010). Trans-plantationof mouse HSCs genetically modified to express a CD4-restricted TCR results in long-term immunity that destroys tumors and initiates spontaneous autoimmunity. J. Clin. Invest 120, 4273-4288.
50. Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., McIntyre, E., Radford, I., Villeval, J. L., Fraser, C. C., Cavazzana-Calvo, M., and Fischer, A. (2003). A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255-256.
51. Haga-Friedman, A., Horovitz-Fried, M., and Cohen, C. J. (2012). Incorporation of transmembrane hydropho-bic mutations in the TCR enhance its surface expression and T cell functional avidity. J. Immunol. 188, 5538-5546.
52. Hart, D. P., Xue, S. A., Thomas, S., Cesco-Gaspere, M., Tranter, A., Will-cox, B., Lee, S. P., Steven, N., Morris, E. C., and Stauss, H. J. (2008). Retro-viral 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.
53. Hawkins, R. E., Gilham, D. E., Debets, R., Eshhar, Z., Taylor, N., Abken, H., Schumacher, T. N., and ATTACK Consortium (2010). Development of adoptive cell therapy for cancer: a clinical perspective. Hum. Gene Ther. 21, 665-672.
54. Heemskerk, M. H., Hagedoorn, R. S., van der Hoorn, M. A., van der Veken, L. T., Hoogeboom, M., Kester, M. G., Willemze, R., and Falkenburg, J. H. (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.
55. Heemskerk, M. H., Hoogeboom, M., de Paus, R. A., Kester, M. G., van der Hoorn, M. A., Goulmy, E., Willemze, R., and Falkenburg, J. H. (2003). Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompat-ibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102, 3530-3540.
56. Heslop, H. E., Ng, C. Y., Li, C., Smith, C. A., Loftin, S. K., Krance, R. A., Brenner, M. K., and Rooney, C. M. (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.
57. Hinrichs, C. S., Borman, Z. A., Cas-sard, L., Gattinoni, L., Spolski, R., Yu, Z., Sanchez-Perez, L., Muran-ski, P., Kern, S. J., Logun, C., Palmer, D. C., Ji, Y., Reger, R. N., Leonard, W. J., Danner, R. L., Rosenberg, S. A., and Restifo, N. P. (2009). Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc. Natl. Acad. Sci. U.S.A. 106, 17469-17474.
58. Hinrichs, C. S., Borman, Z. A., Gat-tinoni, L., Yu, Z., Burns, W. R., Huang, J., Klebanoff, C. A., Johnson, L. A., Kerkar, S. P., Yang, S., Muranski, P., Palmer, D. C., Scott, C. D., Morgan, R. A., Robbins, P. F., Rosenberg, S. A., and Restifo, N. P. (2011). Human effector CD8+Tcells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood 117, 808-814.
59. Holler, P. D., Holman, P. O., Shusta, E. V., O'Herrin, S., Wittrup, K. D., and Kranz, D. M. (2000). In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc. Natl. Acad. Sci. U.S.A. 97, 5387-5392.
60. Huang, X., Wilber, A. C., Bao, L., Tuong, D., Tolar, J., Orchard, P. J., Levine, B. L., June, C. H., McIvor, R. S., Blazar, B. R., and Zhou, X. (2006). Stable gene transfer and expression in human primary T cells by the Sleep ing Beauty transposon system. Blood 107, 483-491.
61. Ivics, Z., Hackett, P. B., Plasterk, R. H., and Izsvak, Z. (1997). Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon fromfish, and its transposition in human cells. Cell 91, 501-510.
62. Jena, B., Dotti, G., and Cooper, L. J. (2010). Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood 116, 1035-1044.
63. Jin, Z., Maiti, S., Huls, H., Singh, H., Olivares, S., Mates, L., Izsvak, Z., Ivics, Z., Lee, D. A., Champlin, R. E., and Cooper, L. J. (2011). The hyperactive Sleeping Beauty transposase SB100X improves the genetic modification of T cells to express a chimeric antigen receptor. Gene Ther. 18, 849-856.
64. Johnson, L. A., Heemskerk, B., Powell, D. J. Jr., Cohen, C. J., Morgan, R. A., Dudley, M. E., Robbins, P. F., and Rosenberg, S. A. (2006). Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J. Immunol. 177, 6548-6559.
65. Johnson, L. A., Morgan, R. A., Dudley, M. E., Cassard, L., Yang, J. C., Hughes, M. S., Kammula, U. S., Royal, R. E., Sherry, R. M., Wunderlich, J. R., Lee, C. C., Restifo, N. P., Schwarz, S. L., Cogdill, A. P., Bishop, R. J., Kim, H., Brewer, C. C., Rudy, S. F., Vanwaes, C., Davis, J. L., Mathur, A., Ripley, R. T., Nathan, D. A., Laurencot, C. M., and Rosenberg, S. A. (2009). Gene ther apy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues express ing cognate antigen. Blood 114, 535-546
66. Jones, S., Peng, P. D., Yang, S., Hsu, C., Cohen, C. J., Zhao, Y., Abad, J., Zheng, Z., Rosenberg, S. A., and Morgan, R. A. (2009). Lentiviral vector design for optimal T cell receptor gene expression in the transduction of peripheral blood lymphocytes and tumor-infiltrating lymphocytes. Hum. Gene Ther. 20, 630-640.
67. Jorritsma, A., Gomez-Eerland, R., Dok-ter, M., van de, K. W., Zoet, Y. M., Doxiadis, I. I., Rufer, N., Romero, P., Morgan, R. A., Schumacher, T. N., and Haanen, J. B. (2007). Selecting highly affine and well-expressed TCRs for gene therapy of melanoma. Blood 110, 3564-3572.
68. Kay, M. A. (2011). State-of-the-art gene-based therapies: the road ahead. Nat. Rev. Genet. 12, 316-328.
69. Kerkar, S. P., Sanchez-Perez, L., Yang, S., Borman, Z. A., Muranski, P., Ji, Y., Chinnasamy, D., Kaiser, A. D., Hinrichs, C. S., Klebanoff, C. A., Scott, C. D., Gattinoni, L., Morgan, R. A., Rosenberg, S. A., and Restifo, N. P. (2011). Genetic engineering of murine CD8(+) and CD4(+) T cells for preclinical adoptive immunother-apy studies. J. Immunother. 34, 343-352.
70. Kershaw, M. H., Teng, M. W., Smyth, M. J., and Darcy, P. K. (2005). Supernatural T cells: genetic modification of T cells for cancer therapy. Nat. Rev. Immunol. 5, 928-940.
71. Kessels, H. W., Wolkers, M. C., van den Boom, M. D., van der Valk, M. A., and Schumacher, T. N. (2001). Immunotherapy through TCR gene transfer. Nat. Immunol. 2, 957-961.
72. Kieback, E., Charo, J., Sommermeyer, D., Blankenstein, T., and Uckert, W. (2008). A safeguard eliminates T cell receptor gene-modified autore-active T cells after adoptive transfer. Proc. Natl. Acad. Sci. U.S.A. 105, 623-628.
73. Kohn, D. B., Dotti, G., Brentjens, R., Savoldo, B., Jensen, M., Cooper, L. J., June, C. H., Rosenberg, S., Sadelain, M., and Heslop, H. E. (2011). CARs on track in the clinic. Mol. Ther. 19, 432-438.
74. Kuball, J., Dossett, M. L., Wolfl, M., Ho, W. Y., Voss, R. H., Fowler, C., and Greenberg, P. D. (2007). Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109, 2331-2338.
75. Kuball, J., Hauptrock, B., Malina, V., Antunes, E., Voss, R. H., Wolfl, M., Strong, R., Theobald, M., and Greenberg, P. D. (2009). Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain. J. Exp. Med. 206, 463-475.
76. Kuball, J., Schmitz, F. W., Voss, R. H., Ferreira, E. A., Engel, R., Guil-laume, P., Strand, S., Romero, P., Huber, C., Sherman, L. A., and Theobald, M. (2005). Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity 22, 117-129.
77. Leen, A. M., Myers, G. D., Sili, U., Huls, M. H., Weiss, H., Leung, K. S., Car-rum, G., Krance, R. A., Chang, C. C., Molldrem, J. J., Gee, A. P., Brenner, M. K., Heslop, H. E., Rooney, C. M., and Bollard, C. M. (2006). Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immuno-compromised individuals. Nat. Med. 12, 1160-1166.
78. Lei, F., Zhao, B., Haque, R., Xiong, X., Budgeon, L., Christensen, N. D., Wu, Y., and Song, J. (2011). In vivo programming of tumor antigen-specific T lymphocytes from pluripo-tent stem cells to promote cancer immunosurveillance. Cancer Res. 71, 4742-4747.
79. Leisegang, M., Engels, B., Meyerhuber, P., Kieback, E., Sommermeyer, D., Xue, S. A., Reuss, S., Stauss, H., and Uckert, W. (2008). Enhanced functionality of T cell receptor-redirected T cells is defined by the trans-gene cassette. J. Mol. Med. 86, 573-583.
80. Levine, B. L., Humeau, L. M., Boyer, J., MacGregor, R. R., Rebello, T., Lu, X., Binder, G. K., Slepushkin, V., Lemi-ale, F., Mascola, J. R., Bushman, F. D., Dropulic, B., and June, C. H. (2006). Gene transfer in humans using a conditionally replicating lentiviral vector. Proc. Natl. Acad. Sci. U.S.A. 103, 17372-17377.
81. Li, L. P., Lampert, J. C., Chen, X., Leitao, C., Popovic, J., Muller, W., and Blankenstein, T. (2010). Trans-genic mice with a diverse human T cell antigen receptor repertoire. Nat. Med. 16, 1029-1034.
82. Li, Y., Moysey, R., Molloy, P. E., Vuide-pot, A. L., Mahon, T., Baston, E., Dunn, S., Liddy, N., Jacob, J., Jakob-sen, B. K., and Boulter, J. M. (2005). Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat. Biotechnol. 23, 349-354.
83. Liddy, N., Bossi, G., Adams, K. J., Lissina, A., Mahon, T. M., Hassan, N. J., Gavarret, J., Bianchi, F. C., Pumphrey, N. J., Ladell, K., Gostick, E., Sewell, A. K., Lissin, N. M., Har-wood, N. E., Molloy, P. E., Li, Y., Cameron, B. J., Sami, M., Baston, E. E., Todorov, P. T., Paston, S. J., Dennis, R. E., Harper, J. V., Dunn, S. M., Ashfield, R., Johnson, A., McGrath, Y., Plesa, G., June, C. H., Kalos, M., Price, D. A., Vuidepot, A., Williams, D. D., Sutton, D. H., and Jakobsen, B. K. (2012). Monoclonal TCR-redirected tumor cell killing. Nat. Med. 18, 980-987.
84. Luo, W., Zhang, X. B., Huang, Y. T., Hao, P. P., Jiang, Z. M., Wen, Q., Zhou, M. Q., Jin, Q., and Ma, L. (2011). Development of genetically engineered CD4+ and CD8+ T cells expressing TCRs specific for a M. tuberculosis 38-kDa antigen. J. Mol. Med. (Berl) 89, 903-913.
85. Marcu-Malina, V., Heijhuurs, S., van Buuren, M., Hartkamp, L., Strand, S., Sebestyen, Z., Scholten, K., Martens, A., and Kuball, J. (2011). Redirecting alphabeta T cells against cancer cells by transfer of a broadly tumor-reactive gammadeltaT-cell receptor. Blood 118, 50-59.
86. Marr, L. A., Gilham, D. E., Campbell, J. D., and Fraser, A. R. (2012). Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies. Clin. Exp. Immunol. 167, 216-225.
87. Mellman, I., Coukos, G., and Dra-noff, G. (2011). Cancer immunother-apy comes of age. Nature 480, 480-489.
88. Merhavi-Shoham, E., Haga-Friedman, A., and Cohen, C. J. (2012). Genetically modulating T-cell function to target cancer. Semin. Cancer Biol. 22, 14-22.
89. Mizuguchi, H., Xu, Z., Ishii-Watabe, A., Uchida, E., and Hayakawa, T. (2000). IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol. Ther. 1, 376-382.
90. Mommaas, B., van Halteren, A. G., Pool, J., van der Veken, L., Wieles, B., Heemskerk, M. H., and Goulmy, E. (2005). Adult and cord blood T cells can acquire HA-1 specificity through HA-1 T-cell receptor gene transfer. Haematologica 90, 1415-1421.
91. Morgan, R. A. (2012). Live and let die: a new suicide gene therapy moves to the clinic. Mol. Ther. 20, 11-13.
92. Morgan, R. A., Dudley, M. E., Wun-derlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., Royal, R. E., Topalian, S. L., Kammula, U. S., Res-tifo, N. P., Zheng, Z., Nahvi, A., de Vries, C. R., Rogers-Freezer, L. J., Mavroukakis, S. A., and Rosenberg, S. A. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126-129.
93. Morris, G. P., and Allen, P. M. (2012). How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat. Immunol. 13, 121-128.
94. Muranski, P., Borman, Z. A., Kerkar, S. P., Klebanoff, C. A., Ji, Y., Sanchez-Perez, L., Sukumar, M., Reger, R. N., Yu, Z., Kern, S. J., Roychoudhuri, R., Ferreyra, G. A., Shen, W., Durum, S. K., Feigenbaum, L., Palmer, D. C., Antony, P. A., Chan, C. C., Laurence, A., Danner, R. L., Gattinoni, L., and Restifo, N. P. (2011). Th17 cells are long lived and retain a stem celllike molecular signature. Immunity 35, 972-985.
95. Murphy, A., Westwood, J. A., Brown, L. E., Teng, M. W., Moeller, M., Xu, Y., Smyth, M. J., Hwu, P., Darcy, P. K., and Kershaw, M. H. (2007). Antitumor activity of dual-specific T cells and influenza virus. Cancer Gene Ther. 14, 499-508.
96. Novellino, L., Castelli, C., and Parmi-ani, G. (2005). A listing of human tumor antigens recognized by T cells: March 2004update. Cancer Immunol. Immunother. 54, 187-207.
97. Okamoto, S., Mineno, J., Ikeda, H., Fujiwara, H., Yasukawa, M., Shiku, H., and Kato, I. (2009). Improved expression and reactivity of transduced tumor-specificTCRsinhuman lymphocytes by specific silencing of endogenous TCR. Cancer Res. 69, 9003-9011.
98. Palmer, D. C., Chan, C. C., Gattinoni, L., Wrzesinski, C., Paulos, C. M., Hin-richs, C. S., Powell, D. J. Jr., Klebanoff, C. A., Finkelstein, S. E., Fariss, R. N., Yu, Z., Nussenblatt, R. B., Rosenberg, S. A., and Restifo, N. P. (2008). Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoim-munity. Proc. Natl. Acad. Sci. U.S.A. 105, 8061-8066.
99. Park, T. S., Rosenberg, S. A., and Morgan, R. A. (2011). Treating cancer with genetically engineered T cells. Trends Biotechnol. 29, 550-557.
100. Parkhurst, M. R., Yang, J. C., Langan, R. C., Dudley, M. E., Nathan, D. A., Feld-man, S. A., Davis, J. L., Morgan, R. A., Merino, M. J., Sherry, R. M., Hughes, M. S., Kammula, U. S., Phan, G. Q., Lim, R. M., Wank, S. A., Restifo, N. P., Robbins, P. F., Laurencot, C. M., and Rosenberg, S. A. (2011a). T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620-626.
101. Parkhurst, M. R., Yang, J. C., Langan, R. C., Dudley, M. E., Nathan, D. A., Feldman, S. A., Davis, J. L., Morgan, R. A., Merino, M. J., Sherry, R. M., Hughes, M. S., Kammula, U. S., Phan, G. Q., Lim, R. M., Wank, S. A., Restifo, N. P., Robbins, P. F., Laurencot, C. M., and Rosenberg, S. A. (2011b). T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620-626.
102. Peng, P. D., Cohen, C. J., Yang, S., Hsu, C., Jones, S., Zhao, Y., Zheng, Z., Rosenberg, S. A., and Morgan, R. A. (2009). Efficient nonviral Sleeping Beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity. Gene Ther. 16, 1042-1049.
103. Perro, M., Tsang, J., Xue, S. A., Escors, D., Cesco-Gaspere, M., Pospori, C., Gao, L., Hart, D., Collins, M., Stauss, H., and Morris, E. C. (2010). Generation of multi-functional antigen-specific human T-cells by lentiviral TCR gene transfer. Gene Ther. 17, 721-732.
104. Provasi, E., Genovese, P., Lombardo, A., Magnani, Z., Liu, P. Q., Reik, A., Chu, V., Paschon, D. E., Zhang, L., Kuball, J., Camisa, B., Bondanza, A., Casorati, G., Ponzoni, M., Ciceri, F., Bordignon, C., Greenberg, P. D., Holmes, M. C., Gregory, P. D., Nal-dini, L., and Bonini, C. (2012). Editing T cell specificity towards leukemia by zinc finger nucleases and lentivi-ral gene transfer. Nat. Med. 18, 807-815.
105. Pule, M. A., Savoldo, B., Myers, G. D., Rossig, C., Russell, H. V., Dotti, G., Huls, M. H., Liu, E., Gee, A. P., Mei, Z., Yvon, E., Weiss, H. L., Liu, H., Rooney, C. M., Heslop, H. E., and Brenner, M. K. (2008). Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14, 1264-1270.
106. Pulido, J., Kottke, T., Thompson, J., Galivo, F., Wongthida, P., Diaz, R. M., Rommelfanger, D., Ilett, E., Pease, L., Pandha, H., Harrington, K., Selby, P., Melcher, A., and Vile, R. (2012). Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat. Biotechnol. 30, 337-344.
107. Recchia, A., Bonini, C., Magnani, Z., Urbinati, F., Sartori, D., Muraro, S., Tagliafico, E., Bondanza, A., Stanghellini, M. T., Bernardi, M., Pescarollo, A., Ciceri, F., Bordignon, C., and Mavilio, F. (2006). Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc. Natl. Acad. Sci. U.S.A. 103, 1457-1462.
108. Restifo, N. P., Dudley, M. E., and Rosenberg, S. A. (2012). Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269-281.
109. Robbins, P. F., Dudley, M. E., Wun-derlich, J., El Gamil, M., Li, Y. F., Zhou, J., Huang, J., Powell, D. J. Jr., and Rosenberg, S. A. (2004). Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J. Immunol. 173, 7125-7130.
110. Robbins, P. F., Li, Y. F., El Gamil, M., Zhao, Y., Wargo, J. A., Zheng, Z., Xu, H., Morgan, R. A., Feldman, S. A., Johnson, L. A., Bennett, A. D., Dunn, S. M., Mahon, T. M., Jakobsen, B. K., and Rosenberg, S. A. (2008). Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J. Immunol. 180, 6116-6131.
111. Robbins, P. F., Morgan, R. A., Feld-man, S. A., Yang, J. C., Sherry, R. M., Dudley, M. E., Wunderlich, J. R., Nahvi, A. V., Helman, L. J., Mackall, C. L., Kammula, U. S., Hughes, M. S., Restifo, N. P., Raffeld, M., Lee, C. C., Levy, C. L., Li, Y. F., El Gamil, M., Schwarz, S. L., Laurencot, C., and Rosenberg, S. A. (2011). Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917-924.
112. Rosenberg, S. A., Packard, B. S., Aeber-sold, P. M., Solomon, D., Topalian, S. L., Toy, S. T., Simon, P., Lotze, M. T., Yang, J. C., Seipp, C. A., Einhorn, J. H., and White, D. E. (1988). Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319, 1676-1680.
113. Rosenberg, S. A., Yang, J. C., Sherry, R. M., Kammula, U. S., Hughes, M. S., Phan, G. Q., Citrin, D. E., Restifo, N. P., Robbins, P. F., Wunderlich, J. R., Morton, K. E., Laurencot, C. M., Steinberg, S. M., White, D. E., and Dudley, M. E. (2011). Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immuno-therapy. Clin. Cancer Res. 17, 4550-4557.
114. Rossig, C., Bollard, C. M., Nuchtern, J. G., Rooney, C. M., and Brenner, M. K. (2002). Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunother-apy. Blood 99, 2009-2016.
115. Sadovnikova, E., and Stauss, H. J. (1996). Peptide-specific cytotoxic T lymphocytes restricted by non-self major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc. Natl. Acad. Sci. U.S.A. 93, 13114-13118.
116. Saito, T., Hochstenbach, F., Marusic-Galesic, S., Kruisbeek, A. M., Brenner, M., and Germain, R. N. (1988). Surface expression of only gamma delta and/or alpha beta T cell receptor heterodimers by cells with four (alpha, beta, gamma, delta) functional receptor chains. J. Exp. Med. 168, 1003-1020.
117. Savage, P., Gao, L., Vento, K., Cow-burn, P., Man, S., Steven, N., Ogg, G., McMichael, A., Epene-tos, A., Goulmy, E., and Stauss, H. J. (2004). Use of B cell-bound HLA-A2 class I monomers to generate high-avidity, allo-restricted CTLs against the leukemia-associated protein Wilms tumor antigen. Blood 103, 4613-4615.
118. Schaft, N., Dorrie, J., Muller, I., Beck, V., Baumann, S., Schunder, T., Kampgen, E., and Schuler, G. (2006a). A new way to generate cytolytic tumor-specific T cells: elec-troporation of RNA coding for a T cell receptor into T lymphocytes. Cancer Immunol. Immunother. 55, 1132-1141.
119. Schaft, N., Lankiewicz, B., Drexhage, J., Berrevoets, C., Moss, D. J., Lev-itsky, V., Bonneville, M., Lee, S. P., McMichael, A. J., Gratama, J. W., Bolhuis, R. L., Willemsen, R., and Debets, R. (2006b). T cell retargeting to EBV antigens following TCR gene transfer: CD28-containing receptors mediate enhanced antigen-specific IFNgamma production. Int. Immunol. 18, 591-601.
120. Schmitt, T. M., Ragnarsson, G. B., and Greenberg, P. D. (2009). T cell receptor gene therapy for cancer. Hum. Gene Ther. 20, 1240-1248.
121. Schodin, B. A., Tsomides, T. J., and Kranz, D. M. (1996). Correlation between the number of T cell receptors required for T cell activation and TCR-ligand affinity. Immunity 5, 137-146.
122. Scholten, K. B., Kramer, D., Kueter, E. W., Graf, M., Schoedl, T., Meijer, C. J., Schreurs, M. W., and Hooi-jberg, E. (2006). Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells. Clin. Immunol. 119, 135-145.
123. Scholten, K. B., Schreurs, M. W., Ruizendaal, J. J., Kueter, E. W., Kramer, D., Veenbergen, S., Mei-jer, C. J., and Hooijberg, E. (2005). Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer. Clin. Immunol. 114, 119-129.
124. Scholten, K. B., Turksma, A. W., Ruizen-daal, J. J., van den, H. M., van der Burg, S. H., Heemskerk, M. H., Meijer, C. J., and Hooijberg, E. (2011). Generating HPV specific T helper cells for the treatment of HPV induced malignancies using TCR gene transfer. J. Transl. Med. 9, 147.
125. Schub, A., Schuster, I. G., Ham-merschmidt, W., and Moosmann, A. (2009). CMV-specific TCR-transgenic T cells for immunother-apy. J. Immunol. 183, 6819-6830.
126. Sebestyen, Z., Schooten, E., Sals, T., Zal-divar, I., San Jose, E., Alarcon, B., Bobisse, S., Rosato, A., Szollosi, J., Gratama, J. W., Willemsen, R. A., and 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.
127. Sheridan, C. (2011). Gene therapy finds its niche. Nat. Biotechnol. 29, 121-128.
128. Sherman, L. A., Hesse, S. V., Irwin, M. J., La Face, D., and Peterson, P. (1992). Selecting T cell receptors with high affinity for self-MHC by decreasing the contribution of CD8. Science 258, 815-818.
129. Soetandyo, N., Wang, Q., Ye, Y., and Li, L. (2010). Role of intramem-brane charged residues in the quality control of unassembled T-cell receptor alpha-chains at the endo-plasmic reticulum. J. Cell Sci. 123, 1031-1038.
130. Sommermeyer, D., Neudorfer, J., Wein-hold, M., Leisegang, M., Engels, B., Noessner, E., Heemskerk, M. H., Charo, J., Schendel, D. J., Blanken-stein, T., Bernhard, H., and Uck-ert, W. (2006). Designer T cells by T cell receptor replacement. Eur. J. Immunol. 36, 3052-3059.
131. Sommermeyer, D. and Uckert, W. (2010). Minimal amino acid exchange in human TCR constant regions fosters improved function of TCR gene-modified T cells. J. Immunol. 184, 6223-6231.
132. Stanislawski, T., Voss, R. H., Lotz, C., Sadovnikova, E., Willemsen, R. A., Kuball, J., Ruppert, T., Bolhuis, R. L., Melief, C. J., Huber, C., Stauss, H. J., and Theobald, M. (2001). Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat. Immunol. 2, 962-970.
133. Straathof, K. C., Pule, M. A., Yotnda, P., Dotti, G., Vanin, E. F., Brenner, M. K., Heslop, H. E., Spencer, D. M., and Rooney, C. M. (2005). An inducible caspase 9 safety switch for T-cell therapy. Blood 105, 4247-4254.
134. Straetemans, T., van Brakel, M., van Steenbergen, S., Broertjes, M., Drex-hage, J., Hegmans, J., Lambrecht, B. N., Lamers, C., Bruggen, P. D., Coulie, P. G., and Debets, R. (2012). TCR gene transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 epi-topes as melanoma-specific immune targets. Clin. Dev. Immunol. 2012, 586314.
135. Szymczak, A. L., and Vignali, D. A. (2005). Development of 2A peptide-based strategies in the design of mul-ticistronic vectors. Expert. Opin. Biol. Ther. 5, 627-638.
136. Theobald, M., Biggs, J., Dittmer, D., Levine, A. J., and Sherman, L .A. (1995). Targeting p53 as a general tumor antigen. Proc. Natl. Acad. Sci. U.S.A. 92, 11993-11997.
137. Thomas, S., Stauss, H. J., and Morris, E. C. (2010). Molecular immunology lessons from therapeutic T-cell receptor gene transfer. Immunology 129, 170-177.
138. Thomas, S., Xue, S. A., Bangham, C. R., Jakobsen, B. K., Morris, E. C., and Stauss, H. J. (2011). Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen. Blood 118, 319-329.
139. Thomas, S., Xue, S. A., Cesco-Gaspere, M., San Jose, E., Hart, D. P., Wong, V., Debets, R., Alarcon, B., Morris, E., and Stauss, H. J. (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.
140. Till, B. G., Jensen, M. C., Wang, J., Chen, E. Y., Wood, B. L., Greis-man, H. A., Qian, X., James, S. E., Raubitschek, A., Forman, S. J., Gopal, A. K., Pagel, J. M., Lindgren, C. G., Greenberg, P. D., Riddell, S. R., and Press, O. W. (2008). Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112, 2261-2271.
141. 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., and 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.
142. Uckert, W., and Schumacher, T. N. (2009). TCR transgenes and transgene cassettes for TCR gene therapy: status in 2008. Cancer Immunol. Immunother. 58, 809-822.
143. Udyavar, A., Alli, R., Nguyen, P., Baker, L., and Geiger, T. L. (2009). Subtle affinity-enhancing mutations in a myelin oligoden-drocyte glycoprotein-specific TCR alter specificity and generate new self-reactivity. J. Immunol. 182, 4439-4447.
144. Udyavar, A., and Geiger, T. L. (2010). Rebalancing immune specificity and function in cancer by T-cell receptor gene therapy. Arch. Immunol. Ther. Exp. (Warsz.) 58, 335-346.
145. Ueno, T., Tomiyama, H., Fujiwara, M., Oka, S., and Takiguchi, M. (2004). Functionally impaired HIV-specific CD8 T cells show high affinity TCR-ligand interactions. J. Immunol. 173, 5451-5457.
146. van der Veken, L. T., Coccoris, M., Swart, E., Falkenburg, J. H., Schumacher, T. N., and Heemskerk, M. H. (2009). Alpha beta T cell receptor transfer to gamma delta T cells generates functional effector cells without mixed TCR dimers in vivo. J. Immunol. 182, 164-170.
147. van der Veken, L. T., Hagedoorn, R. S., van Loenen, M. M., Willemze, R., Falkenburg, J. H., and Heemskerk, M. H. (2006). Alphabeta T-cell receptor engineered gammadelta T cells mediate effective antileukemic reactivity. Cancer Res. 66, 3331-3337.
148. van Lent, A. U., Nagasawa, M., van Loe-nen, M. M., Schotte, R., Schumacher, T. N., Heemskerk, M. H., Spits, H., and Legrand, N. (2007). Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoi-etic progenitors. J. Immunol. 179, 4959-4968.
149. van Loenen, M. M., de Boer, R., Amir, A. L., Hagedoorn, R. S., Volbeda, G. L., Willemze, R., van Rood, J. J., Falken-burg, J. H., and Heemskerk, M. H. (2010). Mixed T cell receptor dimers harbor potentially harmful neoreac-tivity. Proc. Natl. Acad. Sci. U.S.A. 107, 10972-10977.
150. van Loenen, M. M., Hagedoorn, R. S., de Boer, R., van Egmond, E. H., Falkenburg, J. H., and Heemskerk, M. H. (2011). Rapid re-expression of retrovirally introduced versus endogenous TCRs in engineered T cells after antigen-specific stimulation. J. Immunother. 34, 165-174.
151. Varela-Rohena, A., Molloy, P. E., Dunn, S. M., Li, Y., Suhoski, M. M., Carroll, R. G., Milicic, A., Mahon, T., Sutton, D. H., Laugel, B., Moysey, R., Cameron, B. J., Vuidepot, A., Purb-hoo, M. A., Cole, D. K., Phillips, R. E., June, C. H., Jakobsen, B. K., Sewell, A. K., and Riley, J. L. (2008). Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat. Med. 14, 1390-1395.
152. Voss, R. H., Kuball, J., Engel, R., Guil-laume, P., Romero, P., Huber, C., and Theobald, M. (2006). Redirection of T cells by delivering a trans-genic 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.
153. Voss, R. H., Thomas, S., Pfirschke, C., Hauptrock, B., Klobuch, S., Kuball, J., Grabowski, M., Engel, R., Guillaume, P., Romero, P., Huber, C., Beck-hove, P., and Theobald, M. (2010). Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells. Blood 115, 5154-5163.
154. Voss, R. H., Willemsen, R. A., Kuball, J., Grabowski, M., Engel, R., Intan, R. S., Guillaume, P., Romero, P., Huber, C., and Theobald, M. (2008). Molecular design of the Calpha-beta interface favors specific pairing of introduced TCRalphabeta in human T cells. J. Immunol. 180, 391-401.
155. Vyas, J. M., van der Veen, A. G., and Ploegh, H. L. (2008). The known unknowns of antigen processing and presentation. Nat. Rev. Immunol. 8, 607-618.
156. Walchli, S., Loset, G. A., Kumari, S., Johansen, J. N., Yang, W., San-dlie, I., and Olweus, J. (2011). A practical approach to T-cell receptor cloning and expression. PLoS ONE 6, e27930. doi: 10.1371/journal.pone. 0027930
157. Walter, E. A., Greenberg, P. D., Gilbert, M. J., Finch, R. J., Watanabe, K. S., Thomas, E. D., and Riddell, S. R. (1995). Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl. J. Med. 333, 1038-1044.
158. Wang, X., Berger, C., Wong, C. W., Forman, S. J., Riddell, S. R., and Jensen, M. C. (2011). Engraftment of human central memory-derived effector CD8+ T cells in immunode-ficient mice. Blood 117, 1888-1898.
159. Woodworth, J. S., Wu, Y., and Behar, S. M. (2008). Mycobacterium tuberculosis-specific CD8+ T cells require perforin to kill target cells and provide protection in vivo. J. Immunol. 181, 8595-8603.
160. Wright, G. P., Notley, C. A., Xue, S. A., Bendle, G.M., Holler, A., Schumacher, T. N., Ehrenstein, M. R., and Stauss, H. J. (2009). Adop tive therapy with redirected primary regulatory T cells results in antigen- specific suppression of arthritis. Proc. Natl. Acad. Sci. U.S.A. 106, 19078-19083.
161. Yang, L., and Baltimore, D. (2005). Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc. Natl. Acad. Sci. U.S.A. 102, 4518-4523.
162. Yang, S., Cohen, C. J., Peng, P. D., Zhao, Y., Cassard, L., Yu, Z., Zheng, Z., Jones, S., Restifo, N. P., Rosenberg, S. A., and Morgan, R. A. (2008). Development of optimal bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell recognition. Gene Ther. 15, 1411-1423.
163. Yang, S., Luca, G., Liu, F., Ji, Y., Yu, Z., Restifo, N. P., Rosenberg, S. A., and Morgan, R. A. (2011). In vitro generated anti-tumor T lymphocytes exhibit distinct subsets mimicking in vivo antigen-experienced cells. Cancer Immunol. Immunother. 60, 739-749.
164. Zhang, Y., Liu, Y., Moxley, K. M., Golden-Mason, L., Hughes, M. G., Liu, T., Heemskerk, M. H., Rosen, H. R., and Nishimura, M. I. (2010). Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity. PLoS Pathog. 6, e1001018. doi: 10.1371/journal. ppat.1001018
165. Zhao, Y., Bennett, A. D., Zheng, Z., Wang, Q. J., Robbins, P. F., Yu, L. Y., Li, Y., Molloy, P. E., Dunn, S. M., Jakobsen, B. K., Rosenberg, S. A., and Morgan, R. A. (2007a). 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.
166. Zhao, Y., Moon, E., Carpenito, C., Pau-los, C. M., Liu, X., Brennan, A. L., Chew, A., Carroll, R. G., Scholler, J., Levine, B. L., Albelda, S. M., and June, C. H. (2010). Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70, 9053-9061.
167. Zhao, Y., Parkhurst, M. R., Zheng, Z., Cohen, C. J., Riley, J. P., Gattinoni, L., Restifo, N. P., Rosenberg, S. A., and Morgan, R. A. (2007b). Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res. 67, 2425-2429.
168. Zhao, Y., Zheng, Z., Cohen, C. J., Gat-tinoni, L., Palmer, D. C., Restifo, N. P., Rosenberg, S. A., and Morgan, R. A. (2006a). High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol. Ther. 13, 151-159.
169. Zhao, Y., Zheng, Z., Khong, H. T., Rosenberg, S. A., and Morgan, R. A. (2006b). Transduction of an HLA-DP4-restricted NY-ESO-1-specific TCR into primary human CD4+ lymphocytes. J. Immunother. 29, 398-406.