Chimeric Antigen Receptor-T Cells for Leukemias in Adults: Methods, Data and Challenges

  • Mark B. Geyer
  • Jae H. Park
  • Renier J. BrentjensEmail author
Part of the Advances and Controversies in Hematopoietic Transplantation and Cell Therapy book series (ACHTCT)


Within the past several years, renewed interest in immunotherapy has been observed in multiple fields of oncology, including antibody-based therapeutics (e.g., checkpoint blockade) and adoptive cellular therapies. In the field of adult leukemias, such interest has been driven by the limitations of presently available therapies to induce durable remissions reliably in patients with relapsed and refractory leukemia. The adoptive transfer of genetically modified autologous T-cells aims to rapidly establish specific antitumor activity. This strategy requires targeting of autologous T-cells by means of a transgene-encoded antigen receptor, consisting of a chimeric antigen receptor (CAR), as will be discussed herein, or T-cell receptor (TCR) chains. CD19 is nearly universally expressed by B-ALL, CLL, and hairy cell leukemia, while not expressed on normal tissues other than B-cells, including multipotent hematopoietic progenitor cells. Multiple generations of CARs have been developed and investigated in clinical studies and will be discussed in this review. In this chapter, we review clinical outcomes of adults with leukemia treated with CAR T-cells, toxicities associated with CAR T-cell administration, present challenges limiting therapeutic efficacy, and future directions, including novel targets and enhancements to improve antileukemic activity.


Chimeric antigen receptor T-cell Leukemia Immunotherapy CD19 CD28 4-1BB 


  1. Bradbury LE, Goldmacher VS, Tedder TF (1993) The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13. J Immunol 151:2915–2927PubMedGoogle Scholar
  2. Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M (2010) Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 18:666–668CrossRefGoogle Scholar
  3. Brentjens RJ et al (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817–4828CrossRefGoogle Scholar
  4. Brentjens RJ et al (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra138CrossRefGoogle Scholar
  5. Brudno JN et al (2016) 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 34:1112–1121CrossRefGoogle Scholar
  6. Byrd JC et al (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369:32–42CrossRefGoogle Scholar
  7. Byrd JC et al (2015) Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125:2497–2506CrossRefGoogle Scholar
  8. Cruz CR et al (2013) 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 122:2965–2973CrossRefGoogle Scholar
  9. Davila ML et al (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra225CrossRefGoogle Scholar
  10. De Rossi G et al (1993) Immunophenotype of acute lymphoblastic leukemia cells: the experience of the Italian Cooperative Group (Gimema). Leuk Lymphoma 9:221–228CrossRefGoogle Scholar
  11. Fearon DT, Carter RH (1995) The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annu Rev Immunol 13:127–149CrossRefGoogle Scholar
  12. Fraietta JA et al (2016) Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127:1117–1127CrossRefGoogle Scholar
  13. Frey NV et al (2014) Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood 124:2296–2296Google Scholar
  14. Geyer MB et al (2016a) Implications of concurrent ibrutinib therapy on CAR T-cell manufacturing and phenotype and on clinical outcomes following CD19-targeted CAR T-cell administration in adults with relapsed/refractory CLL. Blood 128:58–58Google Scholar
  15. Geyer MB et al (2016b) Updated results: phase I trial of autologous CD19-targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy. J Clin Oncol 34:7526CrossRefGoogle Scholar
  16. Gill S et al (2014) Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood 123:2343–2354CrossRefGoogle Scholar
  17. Gokbuget N et al (2012) Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 120:2032–2041CrossRefGoogle Scholar
  18. Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG (2005) Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Investig 115:1797–1805CrossRefGoogle Scholar
  19. Grupp SA et al (2015) Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood 126:681Google Scholar
  20. John LB et al (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636–5646CrossRefGoogle Scholar
  21. Kantarjian HM et al (2010) Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer 116:5568–5574CrossRefGoogle Scholar
  22. Kay NE et al (2007) Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 109:405–411CrossRefGoogle Scholar
  23. Kenderian SS et al (2015) CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 29:1637–1647CrossRefGoogle Scholar
  24. Kochenderfer JN et al (2012) 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 119:2709–2720CrossRefGoogle Scholar
  25. Kochenderfer JN et al (2015) 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 33:540–549CrossRefGoogle Scholar
  26. Lee DW et al (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385:517–528CrossRefGoogle Scholar
  27. Mamonkin M, Rouce RH, Tashiro H, Brenner MK (2015) A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood 126:983–992CrossRefGoogle Scholar
  28. Matsumoto AK et al (1993) Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med 178:1407–1417CrossRefGoogle Scholar
  29. Maude SL et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507–1517CrossRefGoogle Scholar
  30. Maude SL et al (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378:439–448CrossRefGoogle Scholar
  31. McClanahan F et al (2015) PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood 126:203–211CrossRefGoogle Scholar
  32. Paggetti J et al (2015) Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood 126:1106–1117CrossRefGoogle Scholar
  33. Park JH, Brentjens RJ (2010) Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells. Discov Med 9:277–288PubMedPubMedCentralGoogle Scholar
  34. Park JH et al (2014) Phase I trial of autologous CD19-targeted CAR-modified t cells as consolidation after purine analog-based first-line therapy in patients with previously untreated CLL. J Clin Oncol 32:7020Google Scholar
  35. Park JH et al (2015) Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed, refractory B-cell ALL. Blood 126:682–682Google Scholar
  36. Park JH, Geyer MB, Brentjens RJ (2016) CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127:3312–3320CrossRefGoogle Scholar
  37. Park JH et al (2018) Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 378:449–459CrossRefGoogle Scholar
  38. Pegram HJ et al (2012) Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119:4133–4141CrossRefGoogle Scholar
  39. Pegram HJ et al (2015) IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29:415–422CrossRefGoogle Scholar
  40. Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733CrossRefGoogle Scholar
  41. Porter DL et al (2014) Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood 124:1982Google Scholar
  42. Porter DL et al (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139CrossRefGoogle Scholar
  43. Porter DL et al (2016) Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. J Clin Oncol 34:3009CrossRefGoogle Scholar
  44. Ramsay AG, Clear AJ, Fatah R, Gribben JG (2012) 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 120:1412–1421CrossRefGoogle Scholar
  45. Reiners KS et al (2013) Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 121:3658–3665CrossRefGoogle Scholar
  46. Riches JC et al (2013) T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121:1612–1621CrossRefGoogle Scholar
  47. Robbins BA et al (1993) Diagnostic application of two-color flow cytometry in 161 cases of hairy cell leukemia. Blood 82:1277–1287PubMedGoogle Scholar
  48. Sagiv-Barfi I et al (2015) Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A 112:E966–E972CrossRefGoogle Scholar
  49. Schwonzen M et al (1993) Immunophenotyping of low-grade B-cell lymphoma in blood and bone marrow: poor correlation between immunophenotype and cytological/histological classification. Br J Haematol 83:232–239CrossRefGoogle Scholar
  50. Sommermeyer D et al (2016) Chimeric antigen receptor-modified T cells derived from defined CD8(+) and CD4(+) subsets confer superior antitumor reactivity in vivo. Leukemia 30:492–500CrossRefGoogle Scholar
  51. Sotillo E et al (2015) Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov 5:1282–1295CrossRefGoogle Scholar
  52. Stamenkovic I, Seed B (1988) CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail. J Exp Med 168:1205–1210CrossRefGoogle Scholar
  53. Stephan MT et al (2007) T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13:1440–1449CrossRefGoogle Scholar
  54. Tam CS et al (2008) Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 112:975–980CrossRefGoogle Scholar
  55. Topp MS et al (2014) Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol 32:4134–4140CrossRefGoogle Scholar
  56. Turtle CJ et al (2015) Addition of fludarabine to cyclophosphamide lymphodepletion improves in vivo expansion of CD19 chimeric antigen receptor-modified T cells and clinical outcome in adults with B cell acute lymphoblastic leukemia. Blood 126:3773–3773Google Scholar
  57. Turtle CJ et al (2016) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Investig 126:2123–2138CrossRefGoogle Scholar
  58. Turtle CJ et al (2017) Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 35:3010–3020CrossRefGoogle Scholar
  59. U.S. Food and Drug Administration (2017) FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA, Silver SpringCrossRefGoogle Scholar
  60. Uckun FM et al (1988) Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti- CD19 immunotoxins. Blood 71:13–29PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mark B. Geyer
    • 1
    • 2
    • 3
    • 4
  • Jae H. Park
    • 1
    • 2
    • 3
    • 4
  • Renier J. Brentjens
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Leukemia Service and Cellular Therapeutics Center, Division of Hematologic Oncology, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Joan and Sanford I. Weill Department of MedicineWeill Cornell Medical CollegeNew YorkUSA
  4. 4.Center for Cell EngineeringMemorial Sloan Kettering Cancer CenterNew YorkUSA
  5. 5.Molecular Pharmacology and Chemistry ProgramMemorial Sloan Kettering Cancer CenterNew YorkUSA

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