CAR T Cell Therapy for Hematological Malignancies

An Erratum to this article was published on 13 February 2021

This article has been updated

Summary

As a rapidly progressing field in oncology, the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors (CARs) has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials. Of note, CAR T cell therapy has shown extraordinary potential, especially in relapsed/refractory patients. However, there are still challenges regarding the further development of this strategy, spanning from engineering and manufacturing issues, to limited applications, to accompanying toxicities. In this review, we will summarize the general knowledge of this novel method, including receptor composition, applications, adverse events and challenges. Additionally, we will propose several comprehensive recommendations.

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References

  1. 1

    Ritchie DS, Neeson PJ, Khot A, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther, 2013,21(11):2122–2129

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol, 2016,13:370–383

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3

    Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer, 2016,16:566–581

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Heuser C, Hombach A, Losch C, et al. T-cell activation by recombinant immunoreceptors: impact of the intracellular signalling domain on the stability of receptor expression and antigen-specific activation of grafted T cells. Gene Ther, 2003,10(17):1408–1419

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5

    Song DG, Ye Q, Poussin M, et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood, 2012,119(3):696–706

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6

    Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther, 2009,17(8):1453–1464

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    Till BG, Jensen MC, Wang J, et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood, 2012,119(17):3940–3950

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Hombach AA, Heiders J, Foppe M, et al. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4(+) T cells. Oncormmunology, 2012,1(4):458–466

    Article  Google Scholar 

  9. 9

    Pegram HJ, Lee JC, Hayman EG, et al. Tumor-targeted T-cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood, 2012,119(18):4133–4141

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther, 2015,15(8):1145–1154

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11

    Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev, 2016,30:157–167

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12

    Jain N, O’Brien S. Targeted therapies for CLL: practical issues with the changing treatment paradigm. Blood Rev, 2016,30:233–244

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13

    Fujiwara H. Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors. Pharmaceuticals (Basel), 2014,7(12):1049–1068

    CAS  Article  Google Scholar 

  14. 14

    Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissio ns in leukemia. N Engl J Med, 2014,371(16):1507–1517

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15

    Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood, 2016,128:221–221

    Article  Google Scholar 

  16. 16

    Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 2018,378(5):439–448

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Mamonkin M, Rouce RH, Tashiro H, et al. A T-cell directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood, 2015,126(8):983–992

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Pinz K, Liu H, Golightly M, et al. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia, 2016,30(3):701–707

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19

    Huang L, Wang N, Cao Y. CAR22/19 Cocktail Therapy for Patients with Refractory/Relapsed B-Cell Malignancies. Blood, 2018,132:(abstract1408)

  20. 20

    Wang QS, Wang Y, Lv HY, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther, 2005,23(1):184–191

    Article  CAS  Google Scholar 

  21. 21

    Tettamanti S, Biondi A, Biagi E, et al. CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics?. Oncoimmunology, 2014,3:e28835

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Morsink LM, Walter RB, Ossenkoppele GJ. Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia. Blood Rev, 2019,34:26–33

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23

    Kenderian SS, Ruella M, Shestova O, et al. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia, 2015,29(8):1637–1647

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Mewawalla P, Nathan S. Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review. Ther Adv Hematol, 2014,5(5):139–152

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor modified T cells in chronic lymphoid leukemia. N Engl J Med, 2011,365(8):725–733

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med, 2015,7(303):303ra139

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Kochenderfer JN, Dudley ME, Kassim SH, 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, 2015,33(6):540–549

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28

    Norelli M, Casucci M, Bonini C, et al. Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects. Biochim Biophys Acta, 2016,1865(1):90–100

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Mueller KT, Maude SL, Porter DL, et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood, 2017,130(21):2317–2325

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med, 2018,24(5):563–571

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med, 2017(26),377:2531–2544

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Abramson JS, Chen YB. More on antiCD19 CAR T cells in CNS diffuse large-B-cell lymphoma. N Engl J Med, 2017,377(21):2102

    PubMed  Google Scholar 

  33. 33

    Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med, 2017,377(26):2545–2554

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Neelapu SS. An interim analysis of the ZUMA-1 study of KTE-C19 in refractory, aggressive non-Hodgkin lymphoma. Clin Adv Hematol Oncol, 2017,15(2):117–120

    PubMed  Google Scholar 

  35. 35

    Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther, 2017,25(1):285–295

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Fry TJ, Stetler-Stevenson M, Shah NN, et al. Clinical activity and persistence of anti-CD22 chimeric antigen receptor in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood, 2015,126(23):(abstract1324)

    Google Scholar 

  37. 37

    Teo EC, Chew Y, Phipps C. A review of monoclonal antibody therapies in lymphoma. Crit Rev Oncol Hematol, 2016,97:72–84

    PubMed  Article  Google Scholar 

  38. 38

    Till BG, Jensen MC, Wang J, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood, 2008,112(6):2261–2271

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest, 2017,127(9):3462–3471

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Wang CM, Wu ZQ, Wang Y, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory hodgkin lymphoma: An open-label phase I trial. Clin Cancer Res, 2017,23(5):1156–1166

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Heffner LT, Jagannath S, Zimmerman TM, et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week cycle: safety and further evidence of clinical activity. Blood, 2015,120(21):4042

    Article  Google Scholar 

  42. 42

    Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation-antigen chimeric antigen receptor causes remission of multiple myeloma. Blood, 2016,128(13):1688–1700

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Xu J, Wang Q, Xu H, et al. Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma. J Hematol Oncol, 2018,11(1):128

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med, 2015,373(11):1040–1047

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Garfall AL, Stadtmauer EA, Maus MV, et al. Pilot study of anti-CD19 chimeric antigen receptor T cells (CTL019) in conjunction with salvage autologous stem cell transplantation for advanced multiple myeloma. Blood, 2016,128(22):(abstract974)

    Google Scholar 

  46. 46

    Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov, 2017,7(12):1404–1419

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Brentjens R, Yeh R, Bernal Y, et al. 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, 2010,18(4):666–668

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 2014,6(224):224ra25

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49

    Lee DW, Kochenderfer JN, Stetler-Stevenson M, 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, 2015,385(9967):517–528

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50

    Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol, 2018,15(1):47–62

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51

    Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): update to the interim analysis. Haematological, 2017,102:178:(abstract S476)

    Google Scholar 

  52. 52

    Mei H, Jiang H, Wu Y, et al. Neurological toxicities and coagulation disorders in the cytokine release syndrome during CAR-T therapy. Br J Haematol, 2017,181(5):689–692

    PubMed  Article  PubMed Central  Google Scholar 

  53. 53

    Xu XJ, Tang YM, Liao C, et al. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med, 2013,39(2):319–326

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54

    Ishii K, Shalabi H, Yates B, et al. Tocilizumab refractory cytokine release syndrome (CRS) triggered by chimeric antigen receptor (CAR)-transduced T cells may have distinct cytokine profiles compared to typical CRS. Blood, 2016,128(22):3358

    Article  Google Scholar 

  55. 55

    Prudent V, Breitbart WS. Chimeric antigen receptor T-cell neuropsychiatric toxicity in acute lymphoblastic leukemia. Palliat Support Care, 2017,15(4):499–503

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Wang Z, Guo Y, Han W. Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment. Protein Cell, 2017,8(12):896–925

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Hu Y, Sun J, Wu Z, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol, 2016,9(1):70

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Pehlivan KC, Duncan BB, Lee DW. CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: Transforming the Treatment of Relapsed and Refractory Disease. Curr Hematol Malig Rep, 2018,13(5):396–406

    PubMed  Article  PubMed Central  Google Scholar 

  59. 59

    Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr, 2012,24(1):9–15

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60

    Bonifant CL, Jackson HJ, Brentjens RJ, et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics, 2016,3:16011

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Vairy S, Garcia JL, Teira PB, et al. CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Drug Des Devel Ther, 2018,12:3885–3898

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Dai H, Zhang W, Li X, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology, 2015,4(11):e1027469

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63

    Turtle CJ, Riddell SR, Maloney DG. CD19-Targeted chimeric antigen receptor-modified T-cell immunotherapy for B-cell malignancies. Clin Pharmacol Ther, 2016,100(3):252–258

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64

    Ninomiya S, Narala N, Huye L, et al. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood, 2015,125(25):3905–3916

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Pegram HJ, Purdon TJ, van Leeuwen DG, et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia, 2015,29(2):415–422

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66

    Curran KJ, Seinstra BA, Nikhamin Y, et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther, 2015,23(4):769–778

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19 negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T cell therapy. Blood, 2016,127(20):2406–2410

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov, 2015,5(12):1282–1295

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Park J, Riviere I, Wang X, et al. Impact of disease burden on longterm outcome of 19–28z CAR modified T cells in adult patients with relapsed B-ALL. J Clin Oncol, 2016,34:(abstract7003)

    Article  Google Scholar 

  70. 70

    Hamieh M, Dobrin A, Cabriolu A, et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature, 2019,568(7750):112–116

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Wei G, Ding L, Wang J, et al. Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia. Exp Hematol Oncol, 2017,6:10

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72

    Haso W, Lee DW, Shah NN, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood, 2013,121(7):1165–1174

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73

    Ruella M, Maus MV. Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies. Comput Struct Biotechnol J, 2016,14:357–362

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Dufort F, Su L, Wu L, et al. Activity of CAR19 T cells secreting impact fusion proteins against hematopoietic and solid tumors. Am Soc Clin Oncol, 2018,36(15):e15046

    Article  Google Scholar 

  75. 75

    Cho JH, Collins JJ, Wong WW. Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses. Cell, 2018,173(6):1426–1438

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Zhao J, Lin Q, Song Y. Universal CARs, universal T cells, and universal CAR T cells. J Hematol Oncol, 2018,11(1):132

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Correspondence to Jian-feng Zhou.

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The authors have declared that they have no conflicts of interest.

This project was supported by the Key Program of the National Natural Science Foundation (NNSF) of China (No. 81230052 and No. 81630006).

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Yang, X., Wang, Gx. & Zhou, Jf. CAR T Cell Therapy for Hematological Malignancies. CURR MED SCI 39, 874–882 (2019). https://doi.org/10.1007/s11596-019-2118-z

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Key words

  • immune therapy
  • chimeric antigen receptor T cells
  • hematological malignancies