Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Nature Reviews Clinical Oncology volume 10, pages 267–276 (2013)Cite this article

Subjects

Abstract

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

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chimeric antigen receptors.
Figure 2: Eradication of bone marrow lymphoma and normal B cells occurred after anti-CD19 CAR T cell infusion.
Figure 3: Eradication of bone marrow and blood CLL cells occurred in a patient treated with chemotherapy followed by anti-CD19 CAR T cells and IL-2.
Figure 4: Regression of adenopathy occurred in a patient with CLL after treatment with chemotherapy followed by an infusion of anti-CD19 CAR T cells and IL-2.
Figure 5: A schematic of our current approach to anti-CD19 CAR T cell therapy is shown.

References

  1. National Cancer Institute. Surveillance Epidemiology and End Results [online], (2013).

  2. Flowers, C. R. & Armitage, J. O. A decade of progress in lymphoma: Advances and continuing challenges. Clin. Lymphoma Myeloma Leuk. 10, 414–423 (2010).

    Article  PubMed  Google Scholar 

  3. Sinha, R., DeJoubner, N. & Flowers, C. Novel agents for diffuse large B-cell lymphoma. Expert Opin. Investig. Drugs 20, 669–680 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Sehn, L. H. 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).

    Article  CAS  PubMed  Google Scholar 

  5. Kenkre, V. P. & Smith, S. M. Management of relapsed diffuse large B-cell lymphoma. Curr. Oncol. Rep. 10, 393–403 (2008).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cortelazzo, S., Ponzoni, M., Ferreri, A. J. M. & Dreyling, M. Mantle cell lymphoma. Crit. Rev. Oncol. Hematol. 82, 78–101 (2012).

    Article  PubMed  Google Scholar 

  8. Gribben, J. G. & O'Brien, S. Update on therapy of chronic lymphocytic leukemia. J. Clin. Oncol. 29, 544–550 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Feugier, P. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Topp, M. S. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Van Oers, M. H. & Kersten, M. J. Treatment strategies in advanced stage follicular lymphoma. Best Pract. Res. Clin. Haematol. 24, 187–201 (2011).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  14. Khouri, I. F. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bacher, U., Klyuchnikov, E., Le-Rademacher, J., Carreras, J. & Armand, P. Conditioning regimens for allotransplants for diffuse large B-cell lymphoma myeloablative or reduced intensity? Blood 120, 4256–4262 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sorror, M. L. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  18. Hale, G. A. 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).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: Harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brenner, M. K. & Heslop, H. E. Adoptive T cell therapy of cancer. Curr. Opin. Immunol. 22, 251–257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Park, T. S., Rosenberg, S. A. & Morgan, R. A. Treating cancer with genetically engineered T cells. Trends Biotechnol. 29, 550–557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kershaw, M. H., Teng, M. W. L., Smyth, M. J. & Darcy, P. K. Supernatural T cells: Genetic modification of T cells for cancer therapy. Nat. Rev. Immunol. 5, 928–940 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Hoyos, V., Savoldo, B. & Dotti, G. Genetic modification of human T lymphocytes for the treatment of hematologic malignancies. Haematologica 97, 1622–1631 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Turtle, C. J., Hudecek, M., Jensen, M. C. & Riddell, S. R. Engineered T cells for anti-cancer therapy. Curr. Opin. Immunol. 24, 633–639 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brentjens, R. J. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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. 3, 95ra73 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Robbins, P. F. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kochenderfer, J. N. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sadelain, M., Brentjens, R. & Riviere, I. The promise and pitfalls of chimeric antigen receptors. Curr. Opin. Immunol. 21, 215–223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Irving, B. A. & Weiss, A. 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).

    Article  CAS  PubMed  Google Scholar 

  36. Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Curran, K. J., Pegram, H. J. & Brentjens, R. J. Chimeric antigen receptors for T cell immunotherapy: Current understanding and future directions. J. Gene Med. 14, 405–415 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pule, M. A. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hwu, P. 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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kochenderfer, J. N. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cheadle, E. J., Gilham, D. E., Thistlethwaite, F. C., Radford, J. A. & Hawkins, R. E. Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells. Br. J. Haematol. 129, 322–332 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  47. Brentjens, R. J. 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).

    Article  CAS  PubMed  Google Scholar 

  48. Savoldo, B. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Milone, M. C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, X. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cooper, L. J. 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).

    Article  CAS  PubMed  Google Scholar 

  54. 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. 23, 444–450 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Song, D. G. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Maher, J., Brentjens, R. J., Gunset, G., Rivière, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Zhao, Y. 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).

    Article  CAS  PubMed  Google Scholar 

  59. Guest, R. D. 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).

    Article  CAS  PubMed  Google Scholar 

  60. Rossig, C. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Cheadle, E. J. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Kochenderfer, J. N., Yu, Z., Frasheri, D., Restifo, N. P. & Rosenberg, S. A. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. Uckun, F. M. 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).

    CAS  PubMed  Google Scholar 

  65. Scheuermann, R. H. & Racila, E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk. Lymphoma 18, 385–397 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. Kowolik, C. M. 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).

    Article  CAS  PubMed  Google Scholar 

  68. Hsu, C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bollard, C. M., Rooney, C. M. & Heslop, H. E. T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat. Rev. Clin. Oncol. 9, 510–519 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Leen, A. M. 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).

    Article  CAS  PubMed  Google Scholar 

  72. Micklethwaite, K. P. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Terakura, S. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Klebanoff, C. A., Khong, H. T., Antony, P. A., Palmer, D. C. & Restifo, N. P. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 26, 111–117 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. Gattinoni, L. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lee, J. C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Porter, C. D. 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).

    Article  CAS  PubMed  Google Scholar 

  81. Jensen, M. C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Recchia, A. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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. 115, 1616–1626 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Brentjens, R. Y. R., Bernal, Y., Riviere, I. & Sadelain, M. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Caorsi, R., Federici, S. & Gattorno, M. Biologic drugs in autoinflammatory syndromes. Autoimmun. Rev. 12, 81–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Yanik, G. A. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  89. James, S. E. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Experimental Transplantation and Immunology Branch,

    James N. Kochenderfer

  2. Surgery Branch, National Cancer Institute, 10 Center Drive, Bethesda, 20892, MD, USA

    Steven A. Rosenberg

Authors
  1. James N. Kochenderfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven A. Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to James N. Kochenderfer.

Ethics declarations

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kochenderfer, J., Rosenberg, S. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10, 267–276 (2013). https://doi.org/10.1038/nrclinonc.2013.46

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2013.46

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer