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Immunotherapy pp 215–233Cite as

CAR T-Cells

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1244))

Abstract

CAR-T (chimeric antigens receptor-T) cell therapy is a breakthrough therapy of the twenty-first century for the management of different malignancies including lymphomas and leukemias. Numeral trials are underway to understand the optimal CAR-T cell design and dose to maximize efficacy and mitigate toxicity. Currently two CAR-T cell therapy products, axicabtagene ciloleucel and tisagenlecleucel, are approved by the US Food and Drug Administration, which have shown excellent responses in otherwise poor prognostic lymphomas and leukemias. The favorable outcomes achieved of this therapy were noted to be durable during long-term follow-up. Understanding the challenges associated with manufacturing and the reasons for T cell failure including poor T cell expansion, persistence, and tumor resistance are critical for its wide-scale application in order to attain the full potential of this novel therapy. Here we review the salient features of the different CAR-T products and discuss the pivotal trials that led to its approval.

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References

  1. Alabanza L, Pegues M, et al. Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol Ther. 2017;25(11):2452–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ali SA, Shi V, et al. T cells expressing an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128(13):1688–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Allen ES, Stroncek DF, et al. Autologous lymphapheresis for the production of chimeric antigen receptor T cells. Transfusion. 2017;57(5):1133–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Barber DL, Wherry EJ, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7.

    Article  CAS  PubMed  Google Scholar 

  5. Brentjens R, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Brudno JN, Maric I, et al. T cells genetically modified to express an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36(22):2267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Brudno JN, Somerville RPT, 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. 2016;34(10):1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ceppi F, Rivers J, et al. Lymphocyte apheresis for chimeric antigen receptor T-cell manufacturing in children and young adults with leukemia and neuroblastoma. Transfusion. 2018;58:1414–20.

    Article  CAS  PubMed  Google Scholar 

  9. Chen Y, Cheng Y, et al. Donor-derived CD 19-targeted T cell infusion induces minimal residual disease-negative remission in relapsed B-cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation. Br J Haematol. 2017;179(4):598–605.

    Article  CAS  PubMed  Google Scholar 

  10. Cherkassky L, Morello A, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126:3130–44.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chmielewski M, Hombach AA, et al. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev. 2014;257(1):83–90.

    Article  CAS  PubMed  Google Scholar 

  12. Crump M, Neelapu SS, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dudley ME, Yang JC, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gönen M, Sadelain M. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7.

    Google Scholar 

  15. Fielding AK, Richards SM, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50.

    Article  CAS  PubMed  Google Scholar 

  16. Flowers CS, et al. Improving outcomes for patients with diffuse large B-cell lymphoma. CA Cancer J Clin. 2010;60(6):393–408.

    PubMed  Google Scholar 

  17. Fraietta JA, Lacey SF, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gardner R, Wu D, 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):2406–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gill S, Frey NV, et al. CD19 CAR T-cells combined with ibrutinib to induce complete remission in CLL. J Clin Oncol. 2017;35:7509.

    Article  Google Scholar 

  20. Gross G, Waks T, et al. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci. 1989;86(24):10024–8.

    Article  CAS  PubMed  Google Scholar 

  21. Gust J, Hay KA, et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR T-cells. Cancer Discov. 2017;7(12):1404–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hegde M, Mukherjee M, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest. 2016;126(8):3036–52.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fraietta JA, Beckwith KA, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127:1117–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jacoby E, Nguyen SM, et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun. 2016;7:12320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abramson JS, Siddiqi T, et al. High durable CR rates and preliminary safety profile for JCAR017 in R/R aggressive b-NHL (TRANSCEND NHL 001 Study): a defined composition CD19-directed CAR T-cell product with potential for outpatient administration. J Clin Oncol. 2018;36:120.

    Article  Google Scholar 

  26. Jonnalagadda MM, et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid Fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther. 2015;23(4):757–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Klebanoff CA, Khong HT, et al. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Klebanoff CA, Scott CD, et al. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Invest. 2016;126(1):318–34.

    Article  PubMed  Google Scholar 

  29. Kochenderfer JN, Dudley ME, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122(25):4129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kochenderfer JN, Dudley ME, 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. 2012;119(12):2709–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kochenderfer JN, Wilson WH, 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. 2010;116:4099–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kochenderfer J, Dudley ME, 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.

    Article  CAS  PubMed  Google Scholar 

  33. Kochenderfer JS, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35:1803–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lacey SF, Xu. J, et al. Cars in leukemia: relapse with antigen-negative leukemia originating from a single B cell expressing the leukemia-targeting CAR. Blood. 2016;128:281.

    Article  Google Scholar 

  35. Laetsch TW, Maude SL, et al. CTL019 therapy appears safe and effective in pediatric patients with Down syndrome with relapsed/refractory (r/r) acute lymphoblastic leukemia. Blood. 2017;130:1280.

    Article  CAS  Google Scholar 

  36. Lanitis EM, et al. Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immun. 2013;1:43–53.

    Article  CAS  Google Scholar 

  37. Lee DW, Kochenderfer JN, 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):517–28.

    Article  CAS  PubMed  Google Scholar 

  38. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–38.

    Google Scholar 

  39. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31–42.

    Google Scholar 

  40. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR, Kaplan RN. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581–90.

    Google Scholar 

  41. Lee DW, Stetler-Stevenson M, et al. Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood. 2016;128:218.

    Article  Google Scholar 

  42. Prosser ME, Brown CE, Shami AF, Forman SJ, Jensen MC. Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol Immunol. 2012;51:263–72.

    Article  CAS  PubMed  Google Scholar 

  43. Maude SL, Frey N, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.

    Google Scholar 

  45. Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A. 2009;106(21):8623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Neelapu S, Tummala S, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47.

    Article  CAS  PubMed  Google Scholar 

  47. Neelapu SS, Locke FL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. O’Brien S, Thomas D, et al. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer Interdisciplinary Int J Am Cancer Soc. 2008;113(11):3186–91.

    Google Scholar 

  49. Park JH, Brentjens RJ, et al. Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells. Discov Med. 2010;9(47):277.

    PubMed  PubMed Central  Google Scholar 

  50. Perkins MR, Grande S, et al. Manufacturing an enhanced CAR T cell product by inhibition of the PI3K/Akt pathway during T cell expansion results in improved In vivo efficacy of anti-BCMA CAR T cells. Blood. 2015;126:1893.

    Article  Google Scholar 

  51. Porter DL, Levine BL, et al. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Porter DH, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukaemia. Sci Transl Med. 2015;7:303.

    Article  Google Scholar 

  53. Qin H, Ramakrishna S, et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol Ther Oncolytics. 2018;11:127–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Radinsky S, Bonagura VR. Subcutaneous immunoglobulin infusion as an alternative to intravenous immunoglobulin. J Allergy Clin Immunol. 2003;112:630–3.

    Article  CAS  PubMed  Google Scholar 

  55. Raje N, Berdeja J, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I studstudy. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–37.

    Article  PubMed  Google Scholar 

  56. Riddell SR, Sommermeyer D, et al. Adoptive therapy with chimeric antigen receptor modified T cells of defined subset composition. Cancer J (Sudbury, Mass). 2014;20:141.

    Article  CAS  Google Scholar 

  57. Ruella M, Kenderian SS, Shestova O, Klichinsky M, Melenhorst JJ, Wasik MA, Lacey SF, June CH, Gill S. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia. 2017;31(1):246–8.

    Google Scholar 

  58. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med. 1982;155(4):1063–74.

    Article  CAS  PubMed  Google Scholar 

  59. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348(6230):62–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sadelain M, Brentjens R, et al. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Santomasso BD, Park JH, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schuster SJ, Bishop MR, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45.

    Article  CAS  PubMed  Google Scholar 

  63. Schuster SJ, Svoboda J, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Smith JW. Apheresis techniques and cellular immunomodulation. Ther Apher. 1997;1:203–6.

    Article  CAS  PubMed  Google Scholar 

  65. Sotillo E, Barrett DM, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5:1282–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS. Cytokine release syndrome. Journal for immunotherapy of cancer. 2018;6(1):56.

    Google Scholar 

  67. Sterner RM, Sakemura R, Cox MJ, Yang N, Khadka RH, Forsman CL, Hansen MJ, Jin F, Ayasoufi K, Hefazi M, Schick KJ. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood, The Journal of the American Society of Hematology. 2019;133(7):697–709.

    Google Scholar 

  68. Tuazon SA, Li A, et al. Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies. Transfusion. 2019;59:1773–80.

    Article  CAS  PubMed  Google Scholar 

  69. Turtle CJ, Hanafi LA, et al. CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Vyas M, Müller R, et al. Antigen loss variants: catching hold of escaping foes. Front Immunol. 2017;8:175.

    PubMed  PubMed Central  Google Scholar 

  71. Wallen H, Thompson JA, et al. Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma. PLoS One. 2009;4(3):e4749.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ward E, DeSantis C, et al. Childhood and adolescent cancer statistics. CA Cancer J Clin. 2014;64(2):83–103.

    Article  PubMed  Google Scholar 

  73. Wrzesinski C, Paulos CM, et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cell. J Immunother. 2010;33(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Zhang E, Xu. H. A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy. J Hematol Oncol. 2017;10:1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Zhao WH, Liu J, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11(1):141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Lymphoma and Myeloma, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Ranjit Nair & Jason Westin

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  1. Ranjit Nair
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  2. Jason Westin
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Correspondence to Ranjit Nair .

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  1. MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    Aung Naing

  2. Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    Joud Hajjar

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Nair, R., Westin, J. (2020). CAR T-Cells. In: Naing, A., Hajjar, J. (eds) Immunotherapy. Advances in Experimental Medicine and Biology, vol 1244. Springer, Cham. https://doi.org/10.1007/978-3-030-41008-7_10

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