• 1
    Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 1986;233:13181321.
  • 2
    Rosenberg SA, et al. Gene transfer into humans–immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990;323:570578.
  • 3
    Kalos M, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011;3:95ra73.
  • 4
    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725733.
  • 5
    Grupp SA, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013;368:15091518.
  • 6
    Brentjens RJ, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra38.
  • 7
    Zhou Q, et al. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood 2010;116:24842493.
  • 8
    Ma C, et al. Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. Cancer Dis 2013;3:418429.
  • 9
    Gattinoni L, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 2005;115:16161626.
  • 10
    Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 2008;118:294305.
  • 11
    Gattinoni L, Restifo NP. Moving T memory stem cells to the clinic. Blood 2013;121:567568.
  • 12
    Scholler J, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 2012;4:132ra53.
  • 13
    Davila ML, Kloss CC, Gunset G, Sadelain M. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. PLoS ONE 2013;8:e61338.
  • 14
    Bendle GM, et al. Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med 2010;16:565570, 1p following 570.
  • 15
    Rosenberg SA. Of mice, not men: no evidence for graft-versus-host disease in humans receiving T-cell receptor-transduced autologous T cells. Mol Ther 2010;18:17441745.
  • 16
    Schodin BA, Tsomides TJ, Kranz DM. Correlation between the number of T cell receptors required for T cell activation and TCR-ligand affinity. Immunity 1996;5:137146.
  • 17
    Nauerth M, et al. TCR-ligand koff rate correlates with the protective capacity of antigen-specific CD8+ T cells for adoptive transfer. Sci Transl Med 2013;5:192ra87.
  • 18
    Schmitt TM, Ragnarsson GB, Greenberg P. T cell receptor gene therapy for cancer. Hum Gene Ther 2009;20:12401248.
  • 19
    Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 2011;333:218221.
  • 20
    Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell 2012;10:120136.
  • 21
    Kohn DB, Pai S-Y, Sadelain M. Gene therapy through autologous transplantation of gene-modified hematopoietic stem cells. Biol Blood Marrow Transplant 2013;19:S64S69.
  • 22
    Giannoni F, et al. Allelic exclusion and peripheral reconstitution by TCR transgenic T cells arising from transduced human hematopoietic stem/progenitor cells. Mol Ther 2013;21:10441054.
  • 23
    Dudley ME, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008;26:52335239.
  • 24
    Pogulis RJ, Hansen MJ, Pease LR. Retroviral-mediated expression of an MHC class I-restricted T cell receptor in the CD8 T cell compartment of bone marrow-reconstituted mice. Hum Gene Ther 1998;9:22852297.
  • 25
    Clay TM, Custer MC, Spiess PJ, Nishimura MI. Potential use of T cell receptor genes to modify hematopoietic stem cells for the gene therapy of cancer. Pathol Oncol Res 1999;5:315.
  • 26
    Yang L, Baltimore D. Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc Natl Acad Sci USA 2005;102:45184523.
  • 27
    Ha SP, et al. Transplantation of 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 2010;120:42734288.
  • 28
    Alajez NM, Schmielau J, Alter MD, Cascio M, Finn OJ. 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 2005;105:45834589.
  • 29
    Zhao Y, et al. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res 2007;67:24252429.
  • 30
    van Lent AU, et al. Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors. J Immunol 2007;179:49594968.
  • 31
    Kitchen SG, et al. Engineering antigen-specific T cells from genetically modified human hematopoietic stem cells in immunodeficient mice. PLoS ONE 2009;4:e8208.
  • 32
    Vatakis DN, et al. Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. Proc Natl Acad Sci USA 2011;108:E1408E1416.
  • 33
    Greenblatt MB, Vbranac V, Tivey T, Tsang K, Tager AM, Aliprantis AO. Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. PLoS ONE 2012;7:e44664.
  • 34
    Shultz LD, et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci USA 2010;107:1302213027.
  • 35
    Mostoslavsky R, Alt FW, Rajewsky K. The lingering enigma of the allelic exclusion mechanism. Cell 2004;118:539544.
  • 36
    Vatakis DN, Arumugam B, Kim SG, Bristol G, Yang O, Zack JA. Introduction of exogenous T-cell receptors into human hematopoietic progenitors results in exclusion of endogenous T-cell receptor expression. Mol Ther 2013;21:10551063.
  • 37
    Wargo JA, et al. Recognition of NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and epigenetic modulation of tumor antigen expression. Cancer Immunol Immunother 2009;58:383394.
  • 38
    Black ME, Kokoris MS, Sabo P. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Cancer Res 2001;61:30223026.
  • 39
    Cheever MA, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 2009;15:53235337.
  • 40
    Deng L, Mariuzza RA. Recognition of self-peptide-MHC complexes by autoimmune T-cell receptors. Trends Biochem Sci 2007;32:500508.
  • 41
    Papapetrou EP, Kovalovsky D, Beloeil L, Sant'angelo D, Sadelain M. Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras. J Clin Invest 2009;119:157168.
  • 42
    Hege KM, Cooke KS, Finer MH, Zsebo KM, Roberts MR. Systemic T cell-independent tumor immunity after transplantation of universal receptor-modified bone marrow into SCID mice. J Exp Med 1996;184:22612269.
  • 43
    Roberts MR, et al. Antigen-specific cytolysis by neutrophils and NK cells expressing chimeric immune receptors bearing zeta or gamma signaling domains. J Immunol 1998;161:375384.
  • 44
    Badowski MS, Zhang T, Tsang TC, Harris DT. Chimeric antigen receptors for stem cell based immunotherapy. J Exp Ther Oncol 2009;8:5363.
  • 45
    Doering CB, Archer D, Spencer HT. Delivery of nucleic acid therapeutics by genetically engineered hematopoietic stem cells. Adv Drug Delivery Rev 2010;62:12041212.
  • 46
    Tran AC, Zhang D, Byrn R, Roberts MR. Chimeric zeta-receptors direct human natural killer (NK) effector function to permit killing of NK-resistant tumor cells and HIV-infected T lymphocytes. J Immunol 1995;155:10001009.
  • 47
    Kebriaei P, et al. Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. Hum Gene Ther 2012;23:444450.
  • 48
    Walker RE, et al. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood 2000;96:467474.
  • 49
    Mitsuyasu RT, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 2000;96:785793.
  • 50
    Lin WY, Roberts MR. Developmental dissociation of T cells from B, NK, and myeloid cells revealed by MHC class II-specific chimeric immune receptors bearing TCR-zeta or FcR-gamma chain signaling domains. Blood 2002;100:30453048.
  • 51
    Letourneur F, Klausner RD. T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc Natl Acad Sci USA 1991;88:89058909.
  • 52
    Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 1993;90:720724.
  • 53
    Darcy PK, et al. Redirected perforin-dependent lysis of colon carcinoma by ex vivo genetically engineered CTL. J Immunol 2000;164:37053712.
  • 54
    Haynes NM, et al. Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma. J Immunol 2001;166:182187.
  • 55
    Chmielewski M, Rappl G, Hombach AA, Abken H. T cells redirected by a CD3ζ chimeric antigen receptor can establish self-antigen-specific tumour protection in the long term. Gene Ther 2013;20:177186.
  • 56
    Kohn DB, et al. CARs on track in the clinic. Mol Ther 2011;19:432438.
  • 57
    Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Disc 2013;3:388398.
  • 58
    Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE. The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol 2010;184:69386949.
  • 59
    Rappl G, et al. The CD3-zeta chimeric antigen receptor overcomes TCR Hypo-responsiveness of human terminal late-stage T cells. PLoS ONE 2012;7:e30713.
  • 60
    Romeo C, Amiot M, Seed B. Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor zeta chain. Cell 1992;68:889897.
  • 61
    Zhong X-S, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther 2010;18:413420.
  • 62
    Kochenderfer JN, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize Brief report Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells. Blood 2010;116:40994102.
  • 63
    Savoldo B, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 2011;121:18221826.
  • 64
    Shook DR, Campana D. Natural killer cell engineering for cellular therapy of cancer. Tissue Antigens 2011;78:409415.
  • 65
    Milone MC, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17:14531464.
  • 66
    Li L, et al. Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method. Cancer Gene Ther 2010;17:147154.
  • 67
    De Oliveira SN, et al. Modification of hematopoietic stem/progenitor cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy. Hum Gene Ther 2013;10:824839.
  • 68
    Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene 2013;525:174181.
  • 69
    Bonini C, et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997;276:17191724.
  • 70
    Riddell SR, et al. T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med 1996;2:216223.
  • 71
    Berger C, Flowers ME, Warren EH, Riddell SR. 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 2006;107:22942302.
  • 72
    Traversari C, et al. 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 2007;109:47084715.
  • 73
    Morris JC, Conerly M, Thomasson B, Storek J, Riddell SR, Kiem H-P. Induction of cytotoxic T-lymphocyte responses to enhanced green and yellow fluorescent proteins after myeloablative conditioning. Blood 2004;103:492499.
  • 74
    Arber C, et al. The immunogenicity of virus-derived 2A sequences in immunocot mpetent individuals. Gene Ther 2013;20:958962.
  • 75
    MacCorkle RA, Freeman KW, Spencer DM. Synthetic activation of caspases: artificial death switches. Proc Natl Acad Sci USA 1998;95:36553660.
  • 76
    Clackson T, et al. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci USA 1998;95:1043710442.
  • 77
    Thomis DC, et al. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 2001;97:12491257.
  • 78
    Straathof KC, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood 2005;105:42474254.
  • 79
    Benz C, et al. Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 2012;10:273283.
  • 80
    Mackall CL, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995;332:143149.
  • 81
    Weinberg K, Annett G, Kashyap A, Lenarsky C, Forman SJ, Parkman R. The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant 1995;1:1823.