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Annual Review of Medicine

Volume 72, 2021

Toward Better Understanding and Management of CAR-T Cell–Associated Toxicity

Abstract

Adoptive transfer of T cells modified with chimeric antigen receptors (CAR-T cells) has changed the therapeutic landscape of hematological malignancies, particularly for acute lymphoblastic leukemia and large B cell lymphoma, where two different CAR-T products are now considered standard of care. Furthermore, intense research efforts are under way to expand the clinical application of CAR-T cell therapy for the benefit of patients suffering from other types of cancers. Nevertheless, CAR-T cell treatment is associated with toxicities such as cytokine release syndrome, which can range in severity from mild flu-like symptoms to life-threatening vasodilatory shock, and a neurological syndrome termed ICANS (immune effector cell–associated neurotoxicity syndrome), which can also range in severity from a temporary cognitive deficit lasting only a few hours to lethal cerebral edema. In this review, we provide an in-depth discussion of different types of CAR-T cell–associated toxicities, including an overview of clinical presentation and grading, pathophysiology, and treatment options. We also address future perspectives and opportunities, with a special focus on hematological malignancies.

Keyword(s): adoptive cell therapy, chimeric antigen receptor, cytokine release syndrome, ICANS, neurotoxicity, T cells, tocilizumab, toxicity
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2021-01-27
2025-04-24
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Literature Cited

  1. 1. 
    Mullard A. 2017. FDA approves first CAR T therapy. Nat. Rev. Drug Discov. 16:669
     [Google Scholar]
  2. 2. 
    Raje N, Berdeja J, Lin Y et al. 2019. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl. J. Med. 380:1726–37
     [Google Scholar]
  3. 3. 
    Neelapu SS, Tummala S, Kebriaei P et al. 2018. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15:47–62
     [Google Scholar]
  4. 4. 
    Zhu Y, Tan Y, Ou R et al. 2016. Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. Eur. J. Haematol. 96:389–96
     [Google Scholar]
  5. 5. 
    Yao X, Ahmadzadeh M, Lu YC et al. 2012. Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood 119:5688–96
     [Google Scholar]
  6. 6. 
    Gattinoni L, Finkelstein SE, Klebanoff CA et al. 2005. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202:907–12
     [Google Scholar]
  7. 7. 
    Thiant S, Yakoub-Agha I, Magro L et al. 2010. Plasma levels of IL-7 and IL-15 in the first month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. Bone Marrow Transplant 45:1546–52
     [Google Scholar]
  8. 8. 
    Jensen MC, Popplewell L, Cooper LJ et al. 2010. 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. 16:1245–56
     [Google Scholar]
  9. 9. 
    Turtle CJ, Hay KA, Hanafi LA 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. 35:3010–20
     [Google Scholar]
  10. 10. 
    Turtle CJ, Hanafi LA, Berger C et al. 2016. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 126:2123–38
     [Google Scholar]
  11. 11. 
    Turtle CJ, Hanafi LA, Berger C et al. 2016. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl. Med. 8:355ra116
     [Google Scholar]
  12. 12. 
    Kansagra AJ, Frey NV, Bar M et al. 2019. Clinical utilization of chimeric antigen receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)—an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT). Bone Marrow Transplant 54:1868–80
     [Google Scholar]
  13. 13. 
    Cameron BJ, Gerry AB, Dukes J et al. 2013. Identification of a titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci. Transl. Med. 5:197ra03
     [Google Scholar]
  14. 14. 
    Linette GP, Stadtmauer EA, Maus MV et al. 2013. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122:863–71
     [Google Scholar]
  15. 15. 
    Lamers CH, Sleijfer S, van Steenbergen S et al. 2013. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21:904–12
     [Google Scholar]
  16. 16. 
    Morgan RA, Yang JC, Kitano M et al. 2010. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18:843–51
     [Google Scholar]
  17. 17. 
    Lee DW, Kochenderfer JN, Stetler-Stevenson M 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 385:517–28
     [Google Scholar]
  18. 18. 
    Davila ML, Riviere I, Wang X et al. 2014. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6:224ra25
     [Google Scholar]
  19. 19. 
    Park JH, Riviere I, Gonen M et al. 2018. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378:449–59
     [Google Scholar]
  20. 20. 
    Kochenderfer JN, Dudley ME, Kassim SH 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. 33:540–49
     [Google Scholar]
  21. 21. 
    Maude SL, Laetsch TW, Buechner J et al. 2018. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378:439–48
     [Google Scholar]
  22. 22. 
    Mueller KT, Waldron E, Grupp SA et al. 2018. Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Clin. Cancer Res. 24:6175–84
     [Google Scholar]
  23. 23. 
    Majzner RG, Mackall CL. 2019. Clinical lessons learned from the first leg of the CAR T cell journey. Nat. Med. 25:1341–55
     [Google Scholar]
  24. 24. 
    Halliley JL, Tipton CM, Liesveld J et al. 2015. Long-lived plasma cells are contained within the CD19−CD38hiCD138+ subset in human bone marrow. Immunity 43:132–45
     [Google Scholar]
  25. 25. 
    Bhella S, Majhail NS, Betcher J et al. 2018. Choosing wisely BMT: American Society for Blood and Marrow Transplantation and Canadian Blood and Marrow Transplant Group's list of 5 tests and treatments to question in blood and marrow transplantation. Biol. Blood Marrow Transplant. 24:909–13
     [Google Scholar]
  26. 26. 
    Mahadeo KM, Khazal SJ, Abdel-Azim H et al. 2019. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat. Rev. Clin. Oncol. 16:45–63
     [Google Scholar]
  27. 27. 
    Porter DL, Levine BL, Kalos M et al. 2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365:725–33
     [Google Scholar]
  28. 28. 
    Kochenderfer JN, Dudley ME, Carpenter RO et al. 2013. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129–39
     [Google Scholar]
  29. 29. 
    Maude SL, Frey N, Shaw PA et al. 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371:1507–17
     [Google Scholar]
  30. 30. 
    Maus MV, Haas AR, Beatty GL et al. 2013. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1:26–31
     [Google Scholar]
  31. 31. 
    Kershaw MH, Westwood JA, Parker LL et al. 2006. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12:6106–15
     [Google Scholar]
  32. 32. 
    Till BG, Jensen MC, Wang J et al. 2008. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112:2261–71
     [Google Scholar]
  33. 33. 
    Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al. 2003. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–19
     [Google Scholar]
  34. 34. 
    Stein S, Ott MG, Schultze-Strasser S et al. 2010. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat. Med. 16:198–204
     [Google Scholar]
  35. 35. 
    Scholler J, Brady TL, Binder-Scholl G et al. 2012. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4:132ra53
     [Google Scholar]
  36. 36. 
    Fraietta JA, Nobles CL, Sammons MA et al. 2018. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558:307–12
     [Google Scholar]
  37. 37. 
    Kenderian SS, Ruella M, Shestova O et al. 2015. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 29:1637–47
     [Google Scholar]
  38. 38. 
    Beatty GL, Haas AR, Maus MV et al. 2014. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2:112–20
     [Google Scholar]
  39. 39. 
    Eyquem J, Mansilla-Soto J, Giavridis T et al. 2017. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543:113–17
     [Google Scholar]
  40. 40. 
    Suntharalingam G, Perry MR, Ward S et al. 2006. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355:1018–28
     [Google Scholar]
  41. 41. 
    Chatenoud L, Ferran C, Reuter A et al. 1989. Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma [corrected]. N. Engl. J. Med. 320:1420–21
     [Google Scholar]
  42. 42. 
    von Stackelberg A, Locatelli F, Zugmaier G et al. 2016. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J. Clin. Oncol. 34:4381–89
     [Google Scholar]
  43. 43. 
    Frey N. 2017. Cytokine release syndrome: Who is at risk and how to treat. Best Pract. Res. Clin. Haematol. 30:336–40
     [Google Scholar]
  44. 44. 
    Gauthier J, Turtle CJ. 2018. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr. Res. Transl. Med. 66:50–52
     [Google Scholar]
  45. 45. 
    Gardner RL, Leger KJ, Annesley CE et al. 2016. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. Blood 128:586
     [Google Scholar]
  46. 46. 
    Frey NV, Shaw PA, Hexner EO et al. 2016. Optimizing chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). J. Clin. Oncol. 34:7002
     [Google Scholar]
  47. 47. 
    Neelapu SS, Locke FL, Bartlett NL et al. 2017. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377:2531–44
     [Google Scholar]
  48. 48. 
    Gardner RA, Finney O, Annesley C et al. 2017. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129:3322–31
     [Google Scholar]
  49. 49. 
    Schuster SJ, Svoboda J, Chong EA et al. 2017. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377:2545–54
     [Google Scholar]
  50. 50. 
    Abramson JS, Gordon LI, Palomba ML et al. 2018. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J. Clin. Oncol. 36:7505
     [Google Scholar]
  51. 51. 
    Schuster SJ, Bishop MR, Tam CS et al. 2019. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380:45–56
     [Google Scholar]
  52. 52. 
    Maloney DG, Abramson JS, Palomba ML et al. 2017. Preliminary safety profile of the CD19-directed defined composition CAR T cell product JCAR017 in relapsed/refractory aggressive B-NHL patients: potential for outpatient administration. Blood 130:Suppl. 11552
     [Google Scholar]
  53. 53. 
    Abramson JS, Siddiqi T, Palomba ML et al. 2018. 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. 36:120
     [Google Scholar]
  54. 54. 
    Lee DW, Gardner R, Porter DL et al. 2014. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–95
     [Google Scholar]
  55. 55. 
    Norelli M, Camisa B, Barbiera G et al. 2018. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24:739–48
     [Google Scholar]
  56. 56. 
    Giavridis T, van der Stegen SJC, Eyquem J et al. 2018. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24:731–38
     [Google Scholar]
  57. 57. 
    Porter D, Frey N, Wood PA et al. 2018. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J. Hematol. Oncol. 11:35
     [Google Scholar]
  58. 58. 
    Lee DW, Santomasso BD, Locke FL et al. 2019. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25:625–38
     [Google Scholar]
  59. 59. 
    Fishman JA, Hogan JI, Maus MV 2019. Inflammatory and infectious syndromes associated with cancer immunotherapies. Clin. Infect. Dis. 69:909–20
     [Google Scholar]
  60. 60. 
    Yakoub-Agha I, Chabannon C, Bader P et al. 2020. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica 105:297–316
     [Google Scholar]
  61. 61. 
    Brentjens RJ, Davila ML, Riviere I et al. 2013. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5:177ra38
     [Google Scholar]
  62. 62. 
    Gardner RA, Ceppi F, Rivers J et al. 2019. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood 134:2149–58
     [Google Scholar]
  63. 63. 
    Shah BD, Bishop MR, Oluwole OO et al. 2019. End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). J. Clin. Oncol. 37:7006
     [Google Scholar]
  64. 64. 
    Schuster SJ, Maziarz RT, Rusch ES et al. 2020. Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv 4:1432–39
     [Google Scholar]
  65. 65. 
    Locke FL, Ghobadi A, Jacobson CA et al. 2019. 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 20:31–42
     [Google Scholar]
  66. 66. 
    Reuters 2017. Juno ends development of high-profile leukemia drug after deaths. Reuters http://www.reuters.com/article/us-juno-leukemia-idUSKBN1685QQ
    [Google Scholar]
  67. 67. 
    Turtle CJ, Hay KA, Gust J et al. 2017. Cytokine release syndrome (CRS) and neurotoxicity (NT) after CD19-specific chimeric antigen receptor- (CAR-) modified T cells. J. Clin. Oncol. 35:15 Suppl.3020
     [Google Scholar]
  68. 68. 
    Gust J, Hay KA, Hanafi LA et al. 2017. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 7:1404–19
     [Google Scholar]
  69. 69. 
    Cancer Discovery 2018. JCAR015 in ALL: a root-cause investigation. News in brief. Cancer Discov 8:4–5
     [Google Scholar]
  70. 70. 
    Wang M, Munoz J, Goy A et al. 2020. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 382:1331–42
     [Google Scholar]
  71. 71. 
    Hunter BD, Jacobson CA. 2019. CAR T-cell associated neurotoxicity: mechanisms, clinicopathologic correlates, and future directions. J. Natl. Cancer Inst. 111:646–54
     [Google Scholar]
  72. 72. 
    Santomasso BD, Park JH, Salloum D et al. 2018. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov 8:958–71
     [Google Scholar]
  73. 73. 
    Karschnia P, Jordan JT, Forst DA et al. 2019. Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood 133:2212–21
     [Google Scholar]
  74. 74. 
    Teachey DT, Bishop MR, Maloney DG, Grupp SA 2018. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat. Rev. Clin. Oncol. 15:218
     [Google Scholar]
  75. 75. 
    Cohen AD, Garfall AL, Stadtmauer EA et al. 2019. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Investig. 129:2210–21
     [Google Scholar]
  76. 76. 
    Di Stasi A, Tey SK, Dotti G et al. 2011. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365:1673–83
     [Google Scholar]
  77. 77. 
    Straathof KC, Pule MA, Yotnda P et al. 2005. An inducible caspase 9 safety switch for T-cell therapy. Blood 105:4247–54
     [Google Scholar]
  78. 78. 
    Hoyos V, Savoldo B, Quintarelli C et al. 2010. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24:1160–70
     [Google Scholar]
  79. 79. 
    Sato T, Neschadim A, Konrad M et al. 2007. Engineered human tmpk/AZT as a novel enzyme/prodrug axis for suicide gene therapy. Mol. Ther. 15:962–70
     [Google Scholar]
  80. 80. 
    Philip B, Kokalaki E, Mekkaoui L et al. 2014. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 124:1277–87
     [Google Scholar]
  81. 81. 
    Vogler I, Newrzela S, Hartmann S et al. 2010. An improved bicistronic CD20/tCD34 vector for efficient purification and in vivo depletion of gene-modified T cells for adoptive immunotherapy. Mol. Ther. 18:1330–38
     [Google Scholar]
  82. 82. 
    Paszkiewicz PJ, Frassle SP, Srivastava S et al. 2016. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J. Clin. Investig. 126:4262–72
     [Google Scholar]
  83. 83. 
    Wang X, Chang WC, Wong CW et al. 2011. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118:1255–63
     [Google Scholar]
  84. 84. 
    Mestermann K, Giavridis T, Weber J et al. 2019. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci. Transl. Med. 11:eaau5907
     [Google Scholar]
  85. 85. 
    Weber EW, Lynn RC, Sotillo E et al. 2019. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv 3:711–17
     [Google Scholar]
  86. 86. 
    Wu CY, Roybal KT, Puchner EM et al. 2015. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:aab4077
     [Google Scholar]
  87. 87. 
    Mata M, Gerken C, Nguyen P et al. 2017. Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models. Cancer Discov 7:1306–19
     [Google Scholar]
  88. 88. 
    Giordano-Attianese G, Gainza P, Gray-Gaillard E et al. 2020. A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy. Nat. Biotechnol. 38:426–32
     [Google Scholar]
/content/journals/10.1146/annurev-med-061119-015600
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Toward Better Understanding and Management of CAR-T Cell–Associated Toxicity
Annual Review of Medicine 72, 365 (2021); https://doi.org/10.1146/annurev-med-061119-015600
/content/journals/10.1146/annurev-med-061119-015600
/content/journals/10.1146/annurev-med-061119-015600
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