Adoptive immunotherapy using TCR gene modified T cells may allow separation of beneficial Graft versus tumour responses from harmful GvHD. Improvements to this include methods to generate high avidity or high affinity TCR, improvements in vector design and reduction in mispairing. Following adoptive transfer, TCR transduced T cells must be able to survive and persist in vivo to give most effective antitumour responses. Central memory or naive T cells have both been shown to be more effective than effector cells at expanding and persisting in vivo. Lymphodepletion may enhance persistence of transferred T cell populations. TCR gene transfer can be used to redirect CD4 helper T cells, and these could be used in combination with CD8+ tumour specific T cells to provide help for the antitumour response. Antigen specific T regulatory T cells can also be generated by TCR gene transfer and could be used to suppress unwanted alloresponses. 1. Introduction Allogeneic haematopoietic stem cell transplantation (HSCT) is an effective treatment for many haematological malignancies. In addition, unselected donor lymphocyte infusions (DLIs) can be utilized to successfully treat relapsed leukaemia after HSCT [1]. Depending on the degree of HLA mismatch, donor T cells recognize alloantigens derived from allogeneic MHC or from polymorphic minor histocompatibility antigens (mHags) expressed by the host. Whilst able to deliver beneficial Graft versus Tumour effects (GvT), alloreactive T cells may also direct their response against normal tissues resulting in Graft versus Host Disease (GvHD), and this is one of the leading causes of transplant-related morbidity and mortality. The incidence of GvHD can be reduced by utilizing T-cell-depleted transplants-but this also leads to an increase in disease relapse rate [2–4]. How best to deliver effective GvT responses whilst minimizing harmful GvHD remains a significant challenge. Refining the concept of donor lymphocyte infusions by isolating donor lymphocytes that have known tumour reactivity may result in more effective GvT. Falkenburg et al. have utilized donor-derived leukaemia reactive cytotoxic T lymphocytes (CTLs) to treat a patient with relapsed accelerated phase CML after HSCT [5]. The patient, who had previously been resistant to DLI, went on to achieve a complete remission as a result of this therapy. A phase I/II study looking at generating leukaemia reactive CTLs for patients with relapsed leukaemia after HSCT found that whilst this strategy was feasible, it was complex and time consuming requiring improvements before
References
[1]
H. J. Kolb, A. Schattenberg, J. M. Goldman et al., “Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients,” Blood, vol. 86, no. 5, pp. 2041–2050, 1995.
[2]
A. M. Marmont, M. M. Horowitz, R. P. Gale et al., “T-cell depletion of HLA-identical transplants in leukemia,” Blood, vol. 78, no. 8, pp. 2120–2130, 1991.
[3]
M. M. Horowitz, R. P. Gale, P. M. Sondel et al., “Graft-versus-leukemia reactions after bone marrow transplantation,” Blood, vol. 75, no. 3, pp. 555–562, 1990.
[4]
J. M. Goldman, R. P. Gale, M. M. Horowitz et al., “Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion,” Annals of Internal Medicine, vol. 108, no. 6, pp. 806–814, 1988.
[5]
J. H. F. Falkenburg, A. R. Wafelman, P. Joosten et al., “Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes,” Blood, vol. 94, no. 4, pp. 1201–1208, 1999.
[6]
E. Marijt, A. Wafelman, M. Van Der Hoorn et al., “Phase I/II feasibility study evaluating the generation of leukemia-reactive cytotoxic T lymphocyte lines for treatment of patients with relapsed leukemia after allogeneic stem cell transplantation,” Haematologica, vol. 92, no. 1, pp. 72–80, 2007.
[7]
T. M. Clay, M. C. Custer, J. Sachs, P. Hwu, S. A. Rosenberg, and M. I. Nishimura, “Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity,” Journal of Immunology, vol. 163, no. 1, pp. 507–513, 1999.
[8]
S. A. Xue, L. Gao, D. Hart et al., “Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene-transduced human T cells,” Blood, vol. 106, no. 9, pp. 3062–3067, 2005.
[9]
E. C. Morris, A. Tsallios, G. M. Bendle, S. A. Xue, and H. J. Stauss, “A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 22, pp. 7934–7939, 2005.
[10]
Y. Zhao, Z. Zheng, P. F. Robbins, H. T. Khong, S. A. Rosenberg, and R. A. Morgan, “Primary human lymphocytes transduced with NY-ESO-1 antigen-specific TCR genes recognize and kill diverse human tumor cell lines,” Journal of Immunology, vol. 174, no. 7, pp. 4415–4423, 2005.
[11]
M. S. Hughes, Y. Y. L. Yu, M. E. Dudley et al., “Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions,” Human Gene Therapy, vol. 16, no. 4, pp. 457–472, 2005.
[12]
M. H. M. Heemskerk, M. Hoogeboom, R. Hagedoorn, M. G. D. Kester, R. Willemze, and J. H. F. Falkenburg, “Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer,” Journal of Experimental Medicine, vol. 199, no. 7, pp. 885–894, 2004.
[13]
R. A. Morgan, M. E. Dudley, J. R. Wunderlich et al., “Cancer regression in patients after transfer of genetically engineered lymphocytes,” Science, vol. 314, no. 5796, pp. 126–129, 2006.
[14]
L. A. Johnson, R. A. Morgan, M. E. Dudley et al., “Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen,” Blood, vol. 114, no. 3, pp. 535–546, 2009.
[15]
P. F. Robbins, R. A. Morgan, S. A. Feldman et al., “Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1,” Journal of Clinical Oncology, vol. 29, no. 7, pp. 917–924, 2011.
[16]
M. E. Dudley, J. C. Yang, R. Sherry et al., “Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens,” Journal of Clinical Oncology, vol. 26, no. 32, pp. 5233–5239, 2008.
[17]
M. A. Alexander-Miller, G. R. Leggatt, and J. A. Berzofsky, “Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 9, pp. 4102–4107, 1996.
[18]
T. Stanislawski, R. H. Voss, C. Lotz et al., “Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer,” Nature Immunology, vol. 2, no. 10, pp. 962–970, 2001.
[19]
J. Kuball, F. W. Schmitz, R. H. Voss et al., “Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR,” Immunity, vol. 22, no. 1, pp. 117–129, 2005.
[20]
E. Sadovnikova and H. J. Stauss, “Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 23, pp. 13114–13118, 1996.
[21]
E. Sadovnikova, L. A. Jopling, K. S. Soo, and H. J. Stauss, “Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules,” European Journal of Immunology, vol. 28, no. 1, pp. 193–200, 1998.
[22]
A. W. Goldrath and M. J. Bevan, “Selecting and maintaining a diverse T-cell repertoire,” Nature, vol. 402, no. 6759, pp. 255–262, 1999.
[23]
P. G. Ashton-Rickardt, A. Bandeira, J. R. Delaney et al., “Evidence for a differential avidity model of T cell selection in the thymus,” Cell, vol. 76, no. 4, pp. 651–663, 1994.
[24]
Y. Li, R. Moysey, P. E. Molloy et al., “Directed evolution of human T-cell receptors with picomolar affinities by phage display,” Nature Biotechnology, vol. 23, no. 3, pp. 349–354, 2005.
[25]
P. D. Holler, L. K. Chlewicki, and D. M. Kranz, “TCRs with high affinity for foreign pMHC show self-reactivity,” Nature Immunology, vol. 4, no. 1, pp. 55–62, 2003.
[26]
P. D. Holler, A. R. Lim, B. K. Cho, L. A. Rund, and D. M. Kranz, “CD8-T cell transfectants that express a high affinity T cell receptor exhibit enhanced peptide-dependent activation,” Journal of Experimental Medicine, vol. 194, no. 8, pp. 1043–1052, 2001.
[27]
Y. Zhao, A. D. Bennett, Z. Zheng et al., “High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines,” Journal of Immunology, vol. 179, no. 9, pp. 5845–5854, 2007.
[28]
S. Thomas, S.-A. Xue, C. Bangham, B. K. Jakobsen, E. C. Morris, and H. J. Stauss, “Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen,” Blood, vol. 118, no. 2, pp. 319–329, 2011.
[29]
D. T. Kim, J. B. Rothbard, D. D. Bloom, and C. G. Fathman, “Quantitative analysis of T cell activation: role of TCR/ligand density and TCR affinity,” Journal of Immunology, vol. 156, no. 8, pp. 2737–2742, 1996.
[30]
A. Jorritsma, R. Gomez-Eerland, M. Dokter et al., “Selecting highly affine and well-expressed TCRs for gene therapy of melanoma,” Blood, vol. 110, no. 10, pp. 3564–3572, 2007.
[31]
M. A. De Witte, A. Jorritsma, A. Kaiser et al., “Requirements for effective antitumor responses of TCR transduced T cells,” Journal of Immunology, vol. 181, no. 7, pp. 5128–5136, 2008.
[32]
H. Mizuguchi, Z. Xu, A. Ishii-Watabe, E. Uchida, and T. Hayakawa, “IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector,” Molecular Therapy, vol. 1, no. 4, pp. 376–382, 2000.
[33]
M. L. L. Donnelly, L. E. Hughes, G. Luke et al., “The “cleavage” activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring “2A-like” sequences,” Journal of General Virology, vol. 82, no. 5, pp. 1027–1041, 2001.
[34]
A. L. Szymczak, C. J. Workman, Y. Wang et al., “Correction of multi-gene deficiency in vivo using a single “self-cleaving” 2A peptide-based retroviral vector,” Nature Biotechnology, vol. 22, no. 5, pp. 589–594, 2004.
[35]
M. Leisegang, B. Engels, P. Meyerhuber et al., “Enhanced functionality of T cell receptor-redirected T cells is defined by the transgene cassette,” Journal of Molecular Medicine, vol. 86, no. 5, pp. 573–583, 2008.
[36]
S. Thomas, S. A. Xue, M. Cesco-Gaspere et al., “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,” Journal of Immunology, vol. 179, no. 9, pp. 5803–5810, 2007.
[37]
C. J. Cohen, Y. F. Li, M. El-Gamil, P. F. Robbins, S. A. Rosenberg, and R. A. Morgan, “Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond,” Cancer Research, vol. 67, no. 8, pp. 3898–3903, 2007.
[38]
J. Kuball, M. L. Dossett, M. Wolfl et al., “Facilitating matched pairing and expression of TCR chains introduced into human T cells,” Blood, vol. 109, no. 6, pp. 2331–2338, 2007.
[39]
S. Okamoto, J. Mineno, H. Ikeda et al., “Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR,” Cancer Research, vol. 69, no. 23, pp. 9003–9011, 2009.
[40]
M. H. M. Heemskerk, R. S. Hagedoorn, M. A. W. G. Van Der Hoorn et al., “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, vol. 109, no. 1, pp. 235–243, 2007.
[41]
P. F. Robbins, M. E. Dudley, J. Wunderlich et al., “Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy,” Journal of Immunology, vol. 173, no. 12, pp. 7125–7130, 2004.
[42]
L. Gattinoni, C. A. Klebanoff, D. C. Palmer et al., “Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells,” Journal of Clinical Investigation, vol. 115, no. 6, pp. 1616–1626, 2005.
[43]
C. A. Klebanoff, L. Gattinoni, P. Torabi-Parizi et al., “Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 27, pp. 9571–9576, 2005.
[44]
D. J. Powell, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg, “Transition of late-stage effector T cells to CD27+ CD28 + tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy,” Blood, vol. 105, no. 1, pp. 241–250, 2005.
[45]
X. Shen, J. Zhou, K. S. Hathcock et al., “Persistence of tumor infiltrating lymphocytes in adoptive immunotherapy correlates with telomere length,” Journal of Immunotherapy, vol. 30, no. 1, pp. 123–129, 2007.
[46]
A. D. Roberts, K. H. Ely, and D. L. Woodland, “Differential contributions of central and effector memory T cells to recall responses,” Journal of Experimental Medicine, vol. 202, no. 1, pp. 123–133, 2005.
[47]
C. Berger, M. C. Jensen, P. M. Lansdorp, M. Gough, C. Elliott, and S. R. Riddell, “Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates,” Journal of Clinical Investigation, vol. 118, no. 1, pp. 294–305, 2008.
[48]
C. S. Hinrichs, Z. A. Borman, L. Cassard et al., “Adoptively transferred effector cells derived from na？ve rather than central memory CD8+ T cells mediate superior antitumor immunity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 41, pp. 17469–17474, 2009.
[49]
L. Gattinoni, Y. Ji, and N. P. Restifo, “Wnt/β-catenin signaling in T-cell immunity and cancer immunotherapy,” Clinical Cancer Research, vol. 16, no. 19, pp. 4695–4701, 2010.
[50]
L. Gattinoni, X. S. Zhong, D. C. Palmer et al., “Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells,” Nature Medicine, vol. 15, no. 7, pp. 808–813, 2009.
[51]
Y. Zhang, G. Joe, E. Hexner, J. Zhu, and S. G. Emerson, “Host-reactive CD8+ memory stem cells in graft-versus-host disease,” Nature Medicine, vol. 11, no. 12, pp. 1299–1305, 2005.
[52]
M. E. Dudley, J. R. Wunderlich, J. C. Yang et al., “Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma,” Journal of Clinical Oncology, vol. 23, no. 10, pp. 2346–2357, 2005.
[53]
C. Wrzesinski, C. M. Paulos, L. Gattinoni et al., “Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells,” Journal of Clinical Investigation, vol. 117, no. 2, pp. 492–501, 2007.
[54]
E. B. Bell, S. M. Sparshott, M. T. Drayson, and W. L. Ford, “The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells,” Journal of Immunology, vol. 139, no. 5, pp. 1379–1384, 1987.
[55]
B. Rocha, N. Dautigny, and P. Pereira, “Peripheral T lymphocytes: expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo,” European Journal of Immunology, vol. 19, no. 5, pp. 905–911, 1989.
[56]
S. Oehen and K. Brduscha-Riem, “Naive cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: a pitfall for T cell memory studies?” European Journal of Immunology, vol. 29, no. 2, pp. 608–614, 1999.
[57]
W. C. Kieper and S. C. Jameson, “Homeostatic expansion and phenotypic conversion of na？ve T cells in response to self peptide/MHC ligands,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 23, pp. 13306–13311, 1999.
[58]
C. Viret, F. S. Wong, and C. A. Janeway, “Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition,” Immunity, vol. 10, no. 5, pp. 559–568, 1999.
[59]
R. M. Kondrack, J. Harbertson, J. T. Tan, M. E. McBreen, C. D. Surh, and L. M. Bradley, “Interleukin 7 Regulates the Survival and Generation of Memory CD4 Cells,” Journal of Experimental Medicine, vol. 198, no. 12, pp. 1797–1806, 2003.
[60]
J. T. Tan, B. Ernst, W. C. Kieper, E. LeRoy, J. Sprent, and C. D. Surh, “Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells,” Journal of Experimental Medicine, vol. 195, no. 12, pp. 1523–1532, 2002.
[61]
C. L. Mackall, C. V. Bare, L. A. Granger, S. O. Sharrow, J. A. Titus, and R. E. Gress, “Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing,” Journal of Immunology, vol. 156, no. 12, pp. 4609–4616, 1996.
[62]
C. T. Moses, K. M. Thorstenson, S. C. Jamesont, and A. Khoruts, “Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 1185–1190, 2003.
[63]
A. E. Troy and H. Shen, “Cutting edge: homeostatic proliferation of peripheral T lymphocytes is regulated by clonal competition,” Journal of Immunology, vol. 170, no. 2, pp. 672–676, 2003.
[64]
L. X. Wang, R. Li, G. Yang et al., “Interleukin-7-dependent expansion and persistence of melanoma-specific T cells in lymphodepleted mice lead to tumor regression and editing,” Cancer Research, vol. 65, no. 22, pp. 10569–10577, 2005.
[65]
M. A. Gavin, S. R. Clarke, E. Negrou, A. Gallegos, and A. Rudensky, “Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo,” Nature Immunology, vol. 3, no. 1, pp. 33–41, 2002.
[66]
J. C. Sun and M. J. Bevan, “Defective CD8 T cell memory following acute infection without CD4 T cell help,” Science, vol. 300, no. 5617, pp. 339–342, 2003.
[67]
E. M. Janssen, E. E. Lemmens, T. Wolfe, U. Christen, M. G. Von Herrath, and S. P. Schoenberger, “CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes,” Nature, vol. 421, no. 6925, pp. 852–856, 2003.
[68]
D. J. Shedlock and H. Shen, “Requirement for CD4 T cell help in generating functional CD8 T cell memory,” Science, vol. 300, no. 5617, pp. 337–339, 2003.
[69]
S. A. Quezada, T. R. Simpson, K. S. Peggs et al., “Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts,” Journal of Experimental Medicine, vol. 207, no. 3, pp. 637–650, 2010.
[70]
H. W. H. G. Kessels, K. Schepers, M. D. Van Den Boom, D. J. Topham, and T. N. M. Schumacher, “Generation of T cell help through a MHC class I-restricted TCR,” Journal of Immunology, vol. 177, no. 2, pp. 976–982, 2006.
[71]
P. A. Taylor, C. J. Lees, and B. R. Blazar, “The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality,” Blood, vol. 99, no. 10, pp. 3493–3499, 2002.
[72]
J. L. Cohen, A. Trenado, D. Vasey, D. Klatzmann, and B. L. Salomon, “CD4+CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease,” Journal of Experimental Medicine, vol. 196, no. 3, pp. 401–406, 2002.
[73]
P. Hoffmann, J. Ermann, M. Edinger, C. Garrison Fathman, and S. Strober, “Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation,” Journal of Experimental Medicine, vol. 196, no. 3, pp. 389–399, 2002.
[74]
A. Trenado, F. Charlotte, S. Fisson et al., “Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia,” Journal of Clinical Investigation, vol. 112, no. 11, pp. 1688–1696, 2003.
[75]
M. Edinger, P. Hoffmann, J. Ermann et al., “CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation,” Nature Medicine, vol. 9, no. 9, pp. 1144–1150, 2003.
[76]
S. C. Jones, G. F. Murphy, and R. Korngold, “Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+25+ T cells to allow an effective graft-versus-leukemia response,” Biology of Blood and Marrow Transplantation, vol. 9, no. 4, pp. 243–256, 2003.
[77]
M. H. Albert, Y. Liu, C. Anasetti, and X. Z. Yu, “Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation,” European Journal of Immunology, vol. 35, no. 9, pp. 2598–2607, 2005.
[78]
C. A. Wysocki, A. Panoskaltsis-Mortari, B. R. Blazar, and J. S. Serody, “Leukocyte migration and graft-versus-host disease,” Blood, vol. 105, no. 11, pp. 4191–4199, 2005.
[79]
G. P. Wright, C. A. Notley, S. A. Xue et al., “Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 45, pp. 19078–19083, 2009.
[80]
H. J. P. M. Koenen, R. L. Smeets, P. M. Vink, E. Van Rijssen, A. M. H. Boots, and I. Joosten, “Human CD25highFoxp3pos regulatory T cells differentiate into IL-17 producing cells,” Blood, vol. 112, no. 6, pp. 2340–2352, 2008.
[81]
H. T. Khong and N. P. Restifo, “Natural selection of tumor variants in the generation of "tumor escape" phenotypes,” Nature Immunology, vol. 3, no. 11, pp. 999–1005, 2002.
[82]
N. P. Restifo, F. Esquivel, Y. Kawakami et al., “Identification of human cancers deficient in antigen processing,” Journal of Experimental Medicine, vol. 177, no. 2, pp. 265–272, 1993.
[83]
R. D. Schreiber, L. J. Old, and M. J. Smyth, “Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion,” Science, vol. 331, no. 6024, pp. 1565–1570, 2011.
[84]
M. R. Parkhurst, J. C. Yang, R. C. Langan et al., “T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis,” Molecular Therapy, vol. 19, no. 3, pp. 620–625, 2011.
[85]
M. A. Cheever, J. P. Allison, A. S. Ferris et al., “The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research,” Clinical Cancer Research, vol. 15, no. 17, pp. 5323–5337, 2009.
[86]
G. M. Bendle, C. Linnemann, A. I. Hooijkaas et al., “Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy,” Nature Medicine, vol. 16, no. 5, pp. 565–570, 2010.
[87]
F. Ciceri, C. Bonini, S. Marktel et al., “Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation,” Blood, vol. 109, no. 11, pp. 4698–4707, 2007.
[88]
P. Tiberghien, C. Ferrand, B. Lioure et al., “Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft,” Blood, vol. 97, no. 1, pp. 63–72, 2001.
[89]
F. Ciceri, C. Bonini, M. T. L. Stanghellini et al., “Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study,” The Lancet Oncology, vol. 10, no. 5, pp. 489–500, 2009.
[90]
C. Berger, M. E. Flowers, E. H. Warren, and S. R. Riddell, “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, vol. 107, no. 6, pp. 2294–2302, 2006.
[91]
K. C. Straathof, M. A. Pulè, P. Yotnda et al., “An inducible caspase 9 safety switch for T-cell therapy,” Blood, vol. 105, no. 11, pp. 4247–4254, 2005.
[92]
S. Hacein-Bey-Abina, C. Von Kalle, M. Schmidt et al., “LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1,” Science, vol. 302, no. 5644, pp. 415–419, 2003.
[93]
S. Hacein-Bey-Abina, A. Garrigue, G. P. Wang et al., “Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1,” Journal of Clinical Investigation, vol. 118, no. 9, pp. 3132–3142, 2008.
[94]
S. J. Howe, M. R. Mansour, K. Schwarzwaelder et al., “Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients,” Journal of Clinical Investigation, vol. 118, no. 9, pp. 3143–3150, 2008.
[95]
U. P. Davé, N. A. Jenkins, and N. G. Copeland, “Gene therapy insertional mutagenesis insights,” Science, vol. 303, no. 5656, p. 333, 2004.
[96]
N. B. Woods, V. Bottero, M. Schmidt, C. Von Kalle, and I. M. Verma, “Gene therapy: therapeutic gene causing lymphoma,” Nature, vol. 440, no. 7088, p. 1123, 2006.
[97]
K. Pike-Overzet, D. de Ridder, F. Weerkamp et al., “Ectopic retroviral expression of LMO2, but not IL2Rγ, blocks human T-cell development from CD34+ cells: implications for leukemogenesis in gene therapy,” Leukemia, vol. 21, no. 4, pp. 754–763, 2007.
[98]
U. Modlich, A. Schambach, M. H. Brugman et al., “Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16,” Leukemia, vol. 22, no. 8, pp. 1519–1528, 2008.
[99]
S. F. Yu, T. Von Ruden, and P. W. Kantoff, “Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 10, pp. 3194–3198, 1986.
[100]
U. Modlich, J. Bohne, M. Schmidt et al., “Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity,” Blood, vol. 108, no. 8, pp. 2545–2553, 2006.
[101]
E. Montini, D. Cesana, M. Schmidt et al., “The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy,” Journal of Clinical Investigation, vol. 119, no. 4, pp. 964–975, 2009.
[102]
D. Zychlinski, A. Schambach, U. Modlich et al., “Physiological promoters reduce the genotoxic risk of integrating gene vectors,” Molecular Therapy, vol. 16, no. 4, pp. 718–725, 2008.
[103]
S. I. Thornhill, A. Schambach, S. J. Howe et al., “Self-inactivating gammaretroviral vectors for gene therapy of x-linked severe combined immunodeficiency,” Molecular Therapy, vol. 16, no. 3, pp. 590–598, 2008.
[104]
F. Bushman, M. Lewinski, A. Ciuffi et al., “Genome-wide analysis of retroviral DNA integration,” Nature Reviews Microbiology, vol. 3, no. 11, pp. 848–858, 2005.
[105]
X. Wu, Y. Li, B. Crise, and S. M. Burgess, “Transcription start regions in the human genome are favored targets for MLV integration,” Science, vol. 300, no. 5626, pp. 1749–1751, 2003.
[106]
A. R. W. Schr？der, P. Shinn, H. Chen, C. Berry, J. R. Ecker, and F. Bushman, “HIV-1 integration in the human genome favors active genes and local hotspots,” Cell, vol. 110, no. 4, pp. 521–529, 2002.
[107]
R. S. Mitchell, B. F. Beitzel, A. R. W. Schroder et al., “Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences,” PLoS Biology, vol. 2, no. 8, Article ID E234, 2004.
[108]
C. Cattoglio, G. Facchini, D. Sartori et al., “Hot spots of retroviral integration in human CD34+ hematopoietic cells,” Blood, vol. 110, no. 6, pp. 1770–1778, 2007.
[109]
A. Recchia, C. Bonini, Z. Magnani et al., “Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 5, pp. 1457–1462, 2006.
