Review Article | Published:

Therapeutic T cell engineering

Nature volume 545, pages 423431 (25 May 2017) | Download Citation

Abstract

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity.

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References

  1. 1.

    Immunological function of the thymus. Lancet 2, 748–749 (1961)

  2. 2.

    , , & Molecular components of T-cell recognition. Annu. Rev. Immunol. 10, 835–873 (1992)

  3. 3.

    Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer. J. Exp. Med. 102, 157–177 (1955)

  4. 4.

    , , & Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res. 20, 1561–1572 (1960)

  5. 5.

    Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv. Immunol. 49, 281–355 (1991)

  6. 6.

    Tumor eradication by adoptive transfer of cytotoxic T lymphocytes. Adv. Cancer Res. 58, 143–175 (1992)

  7. 7.

    Tumor immunology: the first century. Curr. Opin. Immunol. 4, 603–607 (1992)

  8. 8.

    & Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annu. Rev. Immunol. 4, 681–709 (1986)

  9. 9.

    , & A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233, 1318–1321 (1986)

  10. 10.

    et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N. Engl. J. Med. 300, 1068–1073 (1979)

  11. 11.

    & in Graft vs. Host Disease: Immunology, Pathophysiology, and Treatment (eds , , & ) 371–387 (Marcel Dekker, New York, 1990)

  12. 12.

    et al. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257, 238–241 (1992)

  13. 13.

    et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86, 2041–2050 (1995)

  14. 14.

    & Principles for adoptive T cell therapy of human viral diseases. Annu. Rev. Immunol. 13, 545–586 (1995)

  15. 15.

    et al. Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 330, 1185–1191 (1994)

  16. 16.

    , & Donor T cells to treat EBV-associated lymphoma. N. Engl. J. Med. 331, 679–680 (1994)

  17. 17.

    in Encyclopedia of Immunobiology (ed. ) Vol. 4 (Elsevier Academic Press, 2016)

  18. 18.

    Retrovirus packaging cells. Hum. Gene Ther. 1, 5–14 (1990)

  19. 19.

    & in 8th International Congress of Immunology (ed. International Congress of Immunology) (Springer-Verlag, Budapest; Hungary, 1992)

  20. 20.

    , & Targeting tumours with genetically enhanced T lymphocytes. Nat. Rev. Cancer 3, 35–45 (2003)

  21. 21.

    , , , & Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 3, 431–437 (2003)

  22. 22.

    et al. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320, 232–238 (1986)

  23. 23.

    et al. Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J. Immunol. 163, 507–513 (1999)

  24. 24.

    , & TCR affinity for p/MHC formed by tumor antigens that are self-proteins: impact on efficacy and toxicity. Curr. Opin. Immunol. 33, 16–22 (2015)

  25. 25.

    et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013)

  26. 26.

    et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci. Transl. Med. 5, 197ra103 (2013)

  27. 27.

    et al. Molecular design of the Cαβ interface favors specific pairing of introduced TCRαβ in human T cells. J. Immunol. 180, 391–401 (2008)

  28. 28.

    , , , & Selected murine residues endow human TCR with enhanced tumor recognition. J. Immunol. 184, 6232–6241 (2010)

  29. 29.

    et al. A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control. CII 63, 1163–1176 (2014)

  30. 30.

    et al. Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked antileukemia reactivity and safety. Blood 118, 1495–1503 (2011)

  31. 31.

    . et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).TCR-engineered T cells induce antigen-specific responses in patients with melanoma or sarcoma.

  32. 32.

    et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015)

  33. 33.

    , & The promise and potential pitfalls of chimeric antigen receptors. Curr. Opin. Immunol. 21, 215–223 (2009)

  34. 34.

    & The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64, 891–901 (1991)

  35. 35.

    & Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell 64, 1037–1046 (1991)

  36. 36.

    & T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc. Natl Acad. Sci. USA 88, 8905–8909 (1991)

  37. 37.

    , , & 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 90, 720–724 (1993)

  38. 38.

    , , & New simplified molecular design for functional T cell receptor. Eur. J. Immunol. 23, 1435–1439 (1993)

  39. 39.

    & Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J. Exp. Med. 181, 1653–1659 (1995)

  40. 40.

    et al. Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1, 123–127 (1999)

  41. 41.

    Chimeric Fv-zeta or Fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood 96, 1999–2001 (2000)

  42. 42.

    et al. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 188, 619–626 (1998)

  43. 43.

    et al. Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. J. Immunol. 167, 6123–6131 (2001)

  44. 44.

    ., ., ., & Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).Human T cells expressing a second-generation CAR expand and remain functional upon repeated exposure to antigen.

  45. 45.

    & Designing chimeric antigen receptors to effectively and safely target tumors. Curr. Opin. Immunol. 33, 9–15 (2015)

  46. 46.

    & Reassessing target antigens for adoptive T-cell therapy. Nat. Biotechnol. 31, 999–1008 (2013)

  47. 47.

    , & Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 6, 133–146 (2016)

  48. 48.

    , & The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015)

  49. 49.

    et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015)

  50. 50.

    et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016)

  51. 51.

    , , , & Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013)

  52. 52.

    , , , & Tumor PD-L1 co-stimulates primary human CD8+ cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol. Immunol. 51, 263–272 (2012)

  53. 53.

    et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016)

  54. 54.

    , & PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5, 215ra172 (2013)

  55. 55.

    . et al. Using CAR T Cells to Deliver Immune Modulating Agents Directly to the Tumor Microenvironment. (The New York Academy of Sciences, 2016)

  56. 56.

    et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood 125, 4103–4113 (2015)

  57. 57.

    et al. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J. Clin. Invest. 126, 4262–4272 (2016)

  58. 58.

    et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003).Human T cells engineered to express a CD19-specific CAR eradicate systemic B cell malignancies in mice.

  59. 59.

    et al. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3, 39–50 (1995)

  60. 60.

    , & Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376, 352–355 (1995)

  61. 61.

    , , , & Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116, 3875–3886 (2010)

  62. 62.

    et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012)

  63. 63.

    , , & 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 8, e61338 (2013)

  64. 64.

    et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 117, 72–82 (2011)

  65. 65.

    et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1, 26–31 (2013)

  66. 66.

    . et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116, 4099–4102 (2010).First report of a clinical response to CD19 CAR therapy in non-Hodgkin lymphoma.

  67. 67.

    . et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).First report of clinical response to CD19 in CAR therapy in chronic lymphocytic leukaemia.

  68. 68.

    . et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013).First report of clinical responses to CD19 CAR therapy in acute lymphoblastic leukaemia.

  69. 69.

    CAR therapy: the CD19 paradigm. J. Clin. Invest. 125, 3392–3400 (2015)

  70. 70.

    et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011)

  71. 71.

    et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2015)

  72. 72.

    et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014)

  73. 73.

    et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014)

  74. 74.

    et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015)

  75. 75.

    et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016)

  76. 76.

    et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011)

  77. 77.

    et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014)

  78. 78.

    Cancer immunotherapy. Science 342, 1432–1433 (2013)

  79. 79.

    et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015)

  80. 80.

    et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014)

  81. 81.

    , & Adoptive cellular therapy: a race to the finish line. Sci. Transl. Med. 7, 280ps7 (2015)

  82. 82.

    et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1174 (2013)

  83. 83.

    Anti-CD22 CAR therapy leads to ALL remissions. Cancer Discov. 7, 120 (2017)

  84. 84.

    et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048–2060 (2013)

  85. 85.

    . et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1700 (2016)

  86. 86.

    et al. 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 (2011)

  87. 87.

    & Targeting neoantigens for cancer immunotherapy. Int. Immunol. 28, 365–370 (2016)

  88. 88.

    et al. Rational development of high-affinity T-cell receptor-like antibodies. Proc. Natl Acad. Sci. USA 106, 5784–5788 (2009)

  89. 89.

    et al. Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor. Sci. Rep. 4, 3571 (2014)

  90. 90.

    et al. Functional comparison of engineered T cells carrying a native TCR versus TCR-like antibody-based chimeric antigen receptors indicates affinity/avidity thresholds. J. Immunol. 193, 5733–5743 (2014)

  91. 91.

    et al. Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H. Gene Ther. 21, 575–584 (2014)

  92. 92.

    et al. An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity. Mol. Ther. 3, 16023 (2017)

  93. 93.

    et al. Analysis of ROR1 protein expression in human cancer and normal tissues. Clin. Cancer Res. (2016)

  94. 94.

    , , , & Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin. Cancer Res. 3, 81–85 (1997)

  95. 95.

    et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J. Clin. Oncol. 24, e20–e22 (2006)

  96. 96.

    et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011)

  97. 97.

    et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7, 275ra22 (2015)

  98. 98.

    et al. Regression of glioblastoma after chimeric antigen receptor T-Cell Therapy. N. Engl. J. Med. 375, 2561–2569 (2016)

  99. 99.

    et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19, 3153–3164 (2013)

  100. 100.

    et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 75, 3505–3518 (2015)

  101. 101.

    et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 75, 3596–3607 (2015)

  102. 102.

    , , , & Enhancing the specificity of T-cell cultures for adoptive immunotherapy of cancer. Immunotherapy 3, 33–48 (2011)

  103. 103.

    et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J. Clin. Immunol. 32, 1059–1070 (2012)

  104. 104.

    , , , & ADDENDUM: T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 639–641 (2016)

  105. 105.

    et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016)

  106. 106.

    ., ., ., & Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077 (2015)

  107. 107.

    & The quest for spatio-temporal control of CAR T cells. Cell Res. 25, 1281–1282 (2015)

  108. 108.

    , & Cancer immunotherapy comes of age. Nature 480, 480–489 (2011)

  109. 109.

    et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J. Immunother. 33, 1–7 (2010)

  110. 110.

    Blocking IDO activity to enhance anti-tumor immunity. Front. Biosci. (Elite Ed.) 4, 734–745 (2012)

  111. 111.

    , , & Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 120, 1412–1421 (2012)

  112. 112.

    , , & Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 4, 879–888 (2014)

  113. 113.

    et al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia 31, 246–248 (2017)

  114. 114.

    et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016)

  115. 115.

    et al. PD-1 blockade modulates chimeric antigen receptor (CAR) modified T cells and induces tumor regression: refueling the CAR. Blood 129, 1039–1041 (2017)

  116. 116.

    et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013)

  117. 117.

    et al. Tumor-targeted human T cells expressing CD28-based chimeric antigen receptors circumvent CTLA-4 inhibition. PLoS One 10, e0130518 (2015)

  118. 118.

    et al. TALEN-mediated inactivation of PD-1 in tumor-reactive lymphocytes promotes intratumoral T-cell persistence and rejection of established tumors. Cancer Res. 76, 2087–2093 (2016)

  119. 119.

    et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24, 1160–1170 (2010)

  120. 120.

    & IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood 115, 3508–3519 (2010)

  121. 121.

    et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012)

  122. 122.

    et al. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 13, 1440–1449 (2007)

  123. 123.

    , & Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012)

  124. 124.

    , & Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014)

  125. 125.

    et al. Disparate individual fates compose robust CD8+ T cell immunity. Science 340, 630–635 (2013)

  126. 126.

    et al. Heterogeneous differentiation patterns of individual CD8+ T cells. Science 340, 635–639 (2013)

  127. 127.

    et al. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8+ central memory T cells. Immunity 41, 116–126 (2014)

  128. 128.

    , , , & Role of memory T cell subsets for adoptive immunotherapy. Semin. Immunol. 28, 28–34 (2016)

  129. 129.

    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. 115, 1616–1626 (2005)

  130. 130.

    et al. 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 (2008)

  131. 131.

    et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc. Natl Acad. Sci. USA 106, 17469–17474 (2009)

  132. 132.

    et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl. Med. 8, 355ra116 (2016)

  133. 133.

    et al. Novel serial positive enrichment technology enables clinical multiparameter cell sorting. PLoS One 7, e35798 (2012)

  134. 134.

    et al. Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy. Blood 124, 3490–3500 (2014)

  135. 135.

    et al. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J. Clin. Invest. 126, 3479–3494 (2016)

  136. 136.

    et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128, 519–528 (2016)

  137. 137.

    et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139 (2013)

  138. 138.

    et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34, 1112–1121 (2016)

  139. 139.

    et al. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD. Blood 127, 1361–1370 (2016)

  140. 140.

    et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat. Med. 23, 242–249 (2017)

  141. 141.

    & Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc. Natl Acad. Sci. USA 102, 4518–4523 (2005)

  142. 142.

    et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat. Biotechnol. 26, 453–461 (2008)

  143. 143.

    et al. Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. Blood 116, 4700–4702 (2010)

  144. 144.

    , , , & Virus-specific T-cell banks for ‘off the shelf’ adoptive therapy of refractory infections. Bone Marrow Transplant. 51, 1163–1172 (2016)

  145. 145.

    et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121, 5113–5123 (2013)

  146. 146.

    et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122, 2965–2973 (2013)

  147. 147.

    et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18, 807–815 (2012)

  148. 148.

    et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119, 5697–5705 (2012)

  149. 149.

    , , & TALEN-mediated editing of endogenous T-cell receptors facilitates efficient reprogramming of T lymphocytes by lentiviral gene transfer. Gene Ther. 21, 539–548 (2014)

  150. 150.

    . et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).Talen-mediated TCR deletion enables CD19 CAR therapy with donor T cells in allogeneic recipients.

  151. 151.

    et al. Generation of T cells from human embryonic stem cell-derived hematopoietic zones. J. Immunol. 182, 6879–6888 (2009)

  152. 152.

    et al. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. Cell Stem Cell 12, 31–36 (2013)

  153. 153.

    et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013)

  154. 154.

    . et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).Human CAR T cells generated in vitrofrom pluripotent stem cells induce tumour regression in mice.

  155. 155.

    , & New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell 16, 357–366 (2015)

  156. 156.

    , , & A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol. Rev. 257, 181–190 (2014)

  157. 157.

    et al. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol. Ther. 13, 151–159 (2006)

  158. 158.

    et al. Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer. Gene Ther. 16, 596–604 (2009)

  159. 159.

    . et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).CRISPR–Cas9-mediated CAR delivery to the TCR locus delays T cell differentiation and exhaustion of CAR T cells resulting in improved CAR T cell therapeutic efficacy.

  160. 160.

    & Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies. Cancer Gene Ther. 22, 85–94 (2015)

  161. 161.

    , & Massively parallel manipulation of single cells and microparticles using optical images. Nature 436, 370–372 (2005)

  162. 162.

    , , , , & The Concentration and separation of blood components using acoustic radiation force. Blood 122, 3665 (2013)

  163. 163.

    , , , & Separation of lymphocyte populations from peripheral blood progenitor cell products using affinity bead acoustophoresis. Blood 124, 315–315 (2014)

  164. 164.

    et al. A novel phase-change hydrogel substrate for t cell activation promotes increased expansion of CD8+ cells expressing central memory and naive phenotype markers. Blood 128, 3368–3368 (2016)

  165. 165.

    et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121, 573–584 (2013)

  166. 166.

    et al. T-cell therapy using interleukin-21-primed cytotoxic T-cell lymphocytes combined with cytotoxic T-cell lymphocyte antigen-4 blockade results in long-term cell persistence and durable tumor regression. J. Clin. Oncol. 34, 3787–3795 (2016)

  167. 167.

    et al. Towards a commercial process for the manufacture of genetically modified T cells for therapy. Cancer Gene Ther. 22, 72–78 (2015)

  168. 168.

    , & Biomanufacturing of therapeutic cells: state of the art, current challenges, and future perspectives. Annu. Rev. Chem. Biomol. Eng. 7, 455–478 (2016)

  169. 169.

    et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol. Ther. 5, 788–797 (2002)

  170. 170.

    & Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat. Rev. Immunol. 16, 149–163 (2016)

  171. 171.

    et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016).CAR T cells can treat autoimmunity in a murine model of pemphigus vulgaris.

  172. 172.

    et al. In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy. Cancer Res. 71, 2871–2881 (2011)

  173. 173.

    , , , & Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol. Ther. 22, 1018–1028 (2014)

  174. 174.

    et al. Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. Am. J. Transplant. 17, 931–943 (2017)

  175. 175.

    et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013)

  176. 176.

    et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013)

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Acknowledgements

The authors thank the National Cancer Institute for supporting their research via grants R01 CA114536; R01 CA136551; P01 CA59350 and P30 CA008748.

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Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Michel Sadelain
    •  & Isabelle Rivière
  2. Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA

    • Stanley Riddell

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Contributions

M.S., I.R. and S.R. co-authored the review.

Competing interests

S.R., I.R. and M.S. are consultants for Juno Therapeutics.

Corresponding author

Correspondence to Michel Sadelain.

Reviewer Information Nature thanks C. Melief, N. Restifo and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature22395

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