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Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors

Nature Reviews Clinical Oncology volume 10, pages 267276 (2013) | Download Citation


Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells. Additional patients have subsequently obtained long-term remissions of advanced-stage B-cell malignancies after infusions of anti-CD19 CAR T cells. Long-term eradication of normal CD19+ B cells from patients receiving infusions of anti-CD19 CAR T cells demonstrates the potent antigen-specific activity of these T cells. Some patients treated with anti-CD19 CAR T cells have experienced acute adverse effects, which were associated with increased levels of serum inflammatory cytokines. Although anti-CD19 CAR T cells are at an early stage of development, the potent antigen-specific activity observed in patients suggests that infusions of anti-CD19 CAR T cells might become a standard therapy for some B-cell malignancies.

Key points

  • T cells can be genetically modified to express chimeric antigen receptors (CARs), which are fusion proteins made up of antigen-recognition moieties and T-cell activation domains

  • CD19 is a suitable target for CAR T cells because it is expressed by B-cell malignancies, but not by normal essential tissues

  • Depleting endogenous lymphocytes by administering chemotherapy or radiotherapy before infusions of adoptively transferred T cells enhances the in vivo activity of the T cells

  • Patients have achieved complete remissions during clinical trials of anti-CD19 CAR T cells; however, acute toxicities associated with elevated serum levels of inflammatory cytokines were noted in trials

  • Evidence for biological activity is provided by long-term depletion of CD19+ normal B cells from several patients receiving infusions of anti-CD19 CAR T cells

  • Adoptive transfer of anti-CD19 CAR T cells is a potent new form of immunotherapy that has the potential to become an important therapy option for some advanced-stage B-cell malignancies

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  1. 1.

    National Cancer Institute. Surveillance Epidemiology and End Results , (2013).

  2. 2.

    & A decade of progress in lymphoma: Advances and continuing challenges. Clin. Lymphoma Myeloma Leuk. 10, 414–423 (2010).

  3. 3.

    , & Novel agents for diffuse large B-cell lymphoma. Expert Opin. Investig. Drugs 20, 669–680 (2011).

  4. 4.

    et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109, 1857–1861 (2007).

  5. 5.

    & Management of relapsed diffuse large B-cell lymphoma. Curr. Oncol. Rep. 10, 393–403 (2008).

  6. 6.

    et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J. Clin. Oncol. 28, 4184–4190 (2010).

  7. 7.

    , , & Mantle cell lymphoma. Crit. Rev. Oncol. Hematol. 82, 78–101 (2012).

  8. 8.

    & Update on therapy of chronic lymphocytic leukemia. J. Clin. Oncol. 29, 544–550 (2011).

  9. 9.

    et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J. Clin. Oncol. 23, 4117–4126 (2005).

  10. 10.

    et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 120, 5185–5187 (2012).

  11. 11.

    & Treatment strategies in advanced stage follicular lymphoma. Best Pract. Res. Clin. Haematol. 24, 187–201 (2011).

  12. 12.

    et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: The EBMT transplant consensus. Leukemia 21, 12–17 (2007).

  13. 13.

    Stem cell transplantation for indolent lymphoma. A reappraisal. Blood Rev. 25, 223–228 (2011).

  14. 14.

    et al. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood 119, 6373–6378 (2012).

  15. 15.

    , , , & Conditioning regimens for allotransplants for diffuse large B-cell lymphoma myeloablative or reduced intensity? Blood 120, 4256–4262 (2012).

  16. 16.

    et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA 306, 1874–1883 (2011).

  17. 17.

    & Allogeneic transplantation for lymphoma: Long-term outcome. Curr. Opin. Hematol. 17, 522–530 (2010).

  18. 18.

    et al. Alternate donor hematopoietic cell transplantation (HCT) in non-Hodgkin lymphoma using lower intensity conditioning: a report from the CIBMTR. Biol. Blood Marrow Transplant. 18, 1036–1043.e1 (2012).

  19. 19.

    Current status of allogeneic transplantation for aggressive non-Hodgkin lymphoma. Curr. Opin. Oncol. 23, 681–691 (2011).

  20. 20.

    et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

  21. 21.

    , & Adoptive immunotherapy for cancer: Harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

  22. 22.

    et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26, 5233–5239 (2008).

  23. 23.

    Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know. Nat. Rev. Clin. Oncol. 8, 577–585 (2011).

  24. 24.

    & Adoptive T cell therapy of cancer. Curr. Opin. Immunol. 22, 251–257 (2010).

  25. 25.

    , & Treating cancer with genetically engineered T cells. Trends Biotechnol. 29, 550–557 (2011).

  26. 26.

    et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

  27. 27.

    , , & Supernatural T cells: Genetic modification of T cells for cancer therapy. Nat. Rev. Immunol. 5, 928–940 (2005).

  28. 28.

    , & Genetic modification of human T lymphocytes for the treatment of hematologic malignancies. Haematologica 97, 1622–1631 (2012).

  29. 29.

    , , & Engineered T cells for anti-cancer therapy. Curr. Opin. Immunol. 24, 633–639 (2012).

  30. 30.

    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).

  31. 31.

    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).

  32. 32.

    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).

  33. 33.

    et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012).

  34. 34.

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

  35. 35.

    & 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).

  36. 36.

    , , & 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).

  37. 37.

    et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).

  38. 38.

    , & Chimeric antigen receptors for T cell immunotherapy: Current understanding and future directions. J. Gene Med. 14, 405–415 (2012).

  39. 39.

    et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14, 1264–1270 (2008).

  40. 40.

    et al. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J. Exp. Med. 178, 361–366 (1993).

  41. 41.

    et al. In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res. 55, 3369–3373 (1995).

  42. 42.

    et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

  43. 43.

    et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J. Immunother. 32, 689–702 (2009).

  44. 44.

    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).

  45. 45.

    , , , & Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells. Br. J. Haematol. 129, 322–332 (2005).

  46. 46.

    et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra53 (2012).

  47. 47.

    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).

  48. 48.

    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).

  49. 49.

    et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

  50. 50.

    et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 17, 1453–1464 (2009).

  51. 51.

    , , , & Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

  52. 52.

    et al. Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J. Immunother. 35, 689–701 (2012).

  53. 53.

    et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood 101, 1637–1644 (2003).

  54. 54.

    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. 23, 444–450 (2012).

  55. 55.

    et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J. Immunother. 32, 169–180 (2009).

  56. 56.

    et al. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res. 71, 4617–4627 (2011).

  57. 57.

    , , , & Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

  58. 58.

    et al. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J. Immunol. 183, 5563–5574 (2009).

  59. 59.

    et al. The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J. Immunother. 28, 203–211 (2005).

  60. 60.

    et al. Target antigen expression on a professional antigen-presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-cell receptors. J. Immunother. 29, 21–31 (2006).

  61. 61.

    et al. Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. J. Immunol. 184, 1885–1896 (2010).

  62. 62.

    , , , & 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).

  63. 63.

    et al. B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. J. Immunol. 131, 244–250 (1983).

  64. 64.

    et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood 71, 13–29 (1988).

  65. 65.

    & CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk. Lymphoma 18, 385–397 (1995).

  66. 66.

    et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin. Cancer Res. 13, 5426–5435 (2007).

  67. 67.

    et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 66, 10995–11004 (2006).

  68. 68.

    et al. Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene. Blood 109, 5168–5177 (2007).

  69. 69.

    et al. Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 110, 2838–2845 (2007).

  70. 70.

    , & T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat. Rev. Clin. Oncol. 9, 510–519 (2012).

  71. 71.

    et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat. Med. 12, 1160–1166 (2006).

  72. 72.

    et al. Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. Blood 115, 2695–2703 (2010).

  73. 73.

    et al. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Blood 119, 72–82 (2012).

  74. 74.

    et al. Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood 107, 2643–2652 (2006).

  75. 75.

    et al. Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat. Clin. Pract. Oncol. 3, 668–681 (2006).

  76. 76.

    , , , & Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 26, 111–117 (2005).

  77. 77.

    Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J. Exp. Med. 155, 1063–1074 (1982).

  78. 78.

    et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202, 907–912 (2005).

  79. 79.

    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).

  80. 80.

    et al. Comparison of efficiency of infection of human gene therapy target cells via four different retroviral receptors. Hum. Gene Ther. 7, 913–919 (1996).

  81. 81.

    et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol. Blood Marrow Transplant. 16, 1245–1256 (2010).

  82. 82.

    et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc. Natl Acad. Sci. USA 103, 1457–1462 (2006).

  83. 83.

    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).

  84. 84.

    , , & Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: a case report of an unforeseen adverse event in a phase I clinical trial. Mol. Ther. 18, 666–668 (2010).

  85. 85.

    , & Biologic drugs in autoinflammatory syndromes. Autoimmun. Rev. 12, 81–86 (2012).

  86. 86.

    et al. The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112, 3073–3081 (2008).

  87. 87.

    et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).

  88. 88.

    et al. Clinical impact of suicide gene therapy in allogeneic hematopoietic stem cell transplantation. Hum. Gene Ther. 21, 241–250 (2010).

  89. 89.

    et al. Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice. Blood 114, 5454–5463 (2009).

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This work was supported by intramural funding of the Center for Cancer Research, National Cancer Institute, NIH, USA.

Author information


  1. Experimental Transplantation and Immunology Branch,

    • James N. Kochenderfer
  2. Surgery Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.

    • Steven A. Rosenberg


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Both authors researched data for the article and made a substantial contribution to the discussion of the content. J. N. Kochenderfer wrote the article, and both authors revised and edited it before submission.

Competing interests

Kite Pharma has signed a Cooperative Research and Development Agreement with the National Cancer Institute (NCI) to support research in the Surgery Branch, NCI, to develop cell transfer therapies involving the genetic engineering of lymphocytes.

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Correspondence to James N. Kochenderfer.

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