Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities

BioDrugs

Volumn 33, Issue 1, 2019, Pages 45-60

  Dholaria, Bhagirathbhai R ^a   Bachmeier, Christina A ^a   Locke, Frederick ^a  

^a H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICONVULSIVE AGENT; CHIMERIC ANTIGEN RECEPTOR; CYTOKINE; GLUCOCORTICOID; INTERLEUKIN 6 ANTIBODY; MONOCLONAL ANTIBODY; TOCILIZUMAB;

CHIMERIC ANTIGEN RECEPTOR T-CELL IMMUNOTHERAPY; CLINICAL FEATURE; CYTOKINE RELEASE SYNDROME; CYTOTOXICITY; DRUG SAFETY; ELECTROENCEPHALOGRAPHY; HUMAN; INCIDENCE; NEUROTOXICITY; PATHOGENESIS; PATHOPHYSIOLOGY; PATIENT CARE; PRIORITY JOURNAL; PROPHYLAXIS; REVIEW; ADOPTIVE IMMUNOTHERAPY; DRUG EFFECT; IMMUNOLOGY; INFLAMMATION; METABOLISM; T LYMPHOCYTE; TOXICITY AND INTOXICATION;

ANTIBODIES, MONOCLONAL, HUMANIZED; CYTOKINES; CYTOTOXICITY, IMMUNOLOGIC; GLUCOCORTICOIDS; HUMANS; IMMUNOTHERAPY, ADOPTIVE; INFLAMMATION; NEUROTOXICITY SYNDROMES; T-LYMPHOCYTES;

EID: 85058804860     PISSN: 11738804     EISSN: 1179190X     Source Type: Journal    
DOI: 10.1007/s40259-018-0324-z     Document Type: Review

References (79)

1. Lamers CH, Klaver Y, Gratama JW, Sleijfer S, Debets R. Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells-a completed study overview. Biochem Soc Trans. 2016;44(3):951–9
2. Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181(5):1653–9
3. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Investig. 2011;121(5):1822–6
4. Wang X, Riviere I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolyt. 2016;3:16015
5. June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: a race to the finish line. Sci Transl Med. 2015;7(280):280ps7
6. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44
7. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54
8. Borchmann P, Tam C, Jäger U, McGuirk J, Holte H, Waller E, et al. An updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory diffuse large B-cell lymphoma. European Hematology Association, abstract S799; June 2018
9. FDA approves second CAR T-cell therapy. Cancer Discov. 2018;8(1):5–6. http://cancerdiscovery.aacrjournals.org/content/8/1/5.full
10. Heymach J, Krilov L, Alberg A, Baxter N, Chang SM, Corcoran R, et al. Clinical Cancer advances 2018: annual report on progress against cancer from the american society of clinical oncology. J Clin Oncol. 2018;36(10):1020–44
11. First two CAR-T cell medicines recommended for approval in the European Union 2018. https://www.ema.europa.eu/en/news/first-two-car-t-cell-medicines-recommended-approval-european-union. Accessed 19 Oct 2018
12. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2017;Sep:19
13. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30
14. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95
15. Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24(6):731–8
16. Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24(6):739–48
17. Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood. 2017;Sep:18
18. van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14(7):499–509
19. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48
20. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17
21. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4 +:CD8 + composition in adult B cell ALL patients. J Clin Investig. 2016;126(6):2123–38
22. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;19;6(224):224ra25
23. NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data file. 2009; 4.0:[NCI]. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 13 Sept 2014
24. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017; https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed 22 Apr 2018
25. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Locke FL, Lin Y, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat Rev Clin Oncol. 2018;15(4):218
26. Porter DL, Hwang W-T, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139–303ra139
27. Porter D, Frey N, Wood PA, Weng Y, Grupp SA. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol. 2018;11(1):35
28. CAR-T toxicity rating system to be finalized by ASBMT by year-end—Drug Development Technology. https://www.drugdevelopment-technology.com/comment/car-t-toxicity-rating-system-finalized-asbmt-year-end/. Accessed 11 Sept 2018
29. Schuster SJBM, Tam CS. Primary analysis of JULIET: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017;130(suppl 1)
30. Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol. 2016;104(1):6–17
31. Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2017;Aug:31
32. Center for Drug Evaluation and Research. Approved Drugs—FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm574154.htm. Accessed 21 Nov 2018
33. Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Jacobson CA, Braunschweig I, et al. Preliminary results of prophylactic tocilizumab after axicabtageneciloleucel (axi-cel; KTE-C19) treatment for patients with refractory, aggressive non-hodgkin lymphoma (NHL). Blood. 2017;130(Suppl 1):1547
34. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664–79
35. van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966–74
36. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–64
37. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;20(177):177ra38
38. Teachey DT, Bishop MR, Maloney DG, Grupp SA. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat Rev Clin Oncol. 2018;15(4):218
39. Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, 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
40. DeAngelo D, Ghobadi A, Park J, Dinner S, Mannis G, Lunning M, et al. Clinical outcomes for the phase 2, single-arm, multicenter trial of JCAR015 in adult B-ALL (ROCKET Study). 32nd annual meeting and pre-conference programs of the Society for Immunotherapy of Cancer (SITC 2017): part one. J Immunother Cancer. 2017;5(2):86
41. Santomasso B, Park JH, Riviere I, Mead E, Halton E, Diamonte C, et al. Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells. J Clin Oncol. 2017;35(15_suppl):3019
42. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62
43. Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59
44. Package insert—KYMRIAH. 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf. Accessed 1 May 2018
45. Abramson JS, Gordon LI, Palomba ML, Lunning MA, Arnason JE, Forero-Torres A, et al. 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. 2018;36(15_suppl):7505
46. Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biologic correlates of neurotoxicity associated with CAR T cell therapy in patients with B-cell Acute lymphoblastic leukemia (B-ALL). Cancer Discov. 2018;8(8):958–71
47. Taraseviciute A, Tkachev V, Ponce R, Turtle CJ, Snyder JM, Liggitt HD, et al. Chimeric antigen receptor T cell-mediated neurotoxicity in nonhuman primates. Cancer Discov. 2018;8(6):750–63
48. Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–306
49. Higgins SJ, Purcell LA, Silver KL, Tran V, Crowley V, Hawkes M, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci Transl Med. 2016;28;8(358):358ra128
50. Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, 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(16):1803–13
51. Turtle CJ, Hay KA, Juliane G, Hanafi L-A, Li D, Chaney C, et al. Biomarkers of Cytokine Release Syndrome and Neurotoxicity after CD19 CAR-T cells and mitigation of toxicity by cell dose. Blood. 2016;128(22):1852
52. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, 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 (London, England). 2015;385(9967):517–28
53. Hu Y, Sun J, Wu Z, Yu J, Cui Q, Pu C, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol Engl. 2016;9(1):70
54. Prudent V, Breitbart WS. Chimeric antigen receptor T-cell neuropsychiatric toxicity in acute lymphoblastic leukemia. Palliat Support Care. 2017;15(4):499–503
55. Raje NS, Berdeja JG, Lin Y, Munshi N, Siegel BA, Liedtke M, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007)
56. Pangman VC, Sloan J, Guse L. An examination of psychometric properties of the mini-mental state examination and the standardized mini-mental state examination: implications for clinical practice. ANR. 2000;13(4):209–13
57. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet (London, England). 1974;2(7872):81–4
58. Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood. 2017;130(Suppl 1):505
59. Locke F, Ghobadi A, Lekakis LJ, Miklos DB, Jacobson CA, Jacobsen ED, et al. Outcomes by prior lines of therapy (LoT) in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B cell lymphoma. J Clin Oncol. 2018;36(no. 15_suppl):3039
60. Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, 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):285–95
61. Gardner R, Leger KJ, Annesley CE, Summers C, Rivers J, Gust J, et al. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. Blood. 2016;128(22):586
62. Chen F, Teachey DT, Pequignot E, Frey N, Porter D, Maude SL, et al. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods. 2016;434:1–8
63. Park JH, Santomasso B, Riviere I, Senechal B, Wang X, Purdon T, et al. Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with relapsed B-ALL. J Clin Oncol. 2017;35(15_suppl):7024
64. Ghorashian S, Kramer AM, Albon SJ, Wright G, Castro F, Popova B, et al. A Novel Low affinity CD19CAR results in durable disease remissions and prolonged CAR T cell persistence without severe CRS or neurotoxicity in patients with paediatric ALL. Blood. 2017;130(Suppl 1):806
65. Watanabe K, Terakura S, Uchiyama S, Martens AC, Meerten TV, Kiyoi H, et al. Excessively high-affinity single-chain fragment variable region in a chimeric antigen receptor can counteract T-cell proliferation. Blood. 2014;124(21):4799
66. Park S, Shevlin E, Vedvyas Y, Zaman M, Hsu YS, Min IM, et al. Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep. 2017;7(1):14366
67. Schmid DA, Irving MB, Posevitz V, Hebeisen M, Posevitz-Fejfar A, Sarria JC, et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol. 2010;184(9):4936–46
68. Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent anti-tumor activity. Cancer Res. 2015;75(17):3505–18
69. Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7
70. Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018;24(7):939–46
71. Zhou X, Brenner MK. Improving the safety of T-Cell therapies using an inducible caspase-9 gene. Exp Hematol. 2016;44(11):1013–9
72. Casucci M, Falcone L, Camisa B, Norelli M, Porcellini S, Stornaiuolo A, et al. Extracellular NGFR spacers allow efficient tracking and enrichment of fully functional CAR-T cells co-expressing a suicide gene. Front Immunol. 2018;9:507
73. Minagawa K, Jamil MO, Al-Obaidi M, Pereboeva L, Salzman D, Erba HP, et al. In vitro pre-clinical validation of suicide gene modified anti-CD33 redirected chimeric antigen receptor T-cells for acute myeloid leukemia. PLoS One. 2016;11(12):e0166891
74. Tasian SK, Kenderian SS, Shen F, Ruella M, Shestova O, Kozlowski M, et al. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood. 2017;129(17):2395–407
75. Qasim W, Ciocarlie O, Adams S, Inglott S, Murphy C, Rivat C, et al. Preliminary results of UCART19, an allogeneic anti-CD19 CAR T-cell product in a first-in-human trial (PALL) in pediatric patients with CD19 + relapsed/refractory B-cell acute lymphoblastic leukemia. Blood. 2017;130(Suppl 1):1271
76. Sakemura R, Terakura S, Watanabe K, Julamanee J, Takagi E, Miyao K, et al. A tet-on inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol Res. 2016;4(8):658–68
77. Ma JS, Kim JY, Kazane SA, Choi SH, Yun HY, Kim MS, et al. Versatile strategy for controlling the specificity and activity of engineered T cells. Proc Natl Acad Sci USA. 2016;113(4):E450–8
78. Juillerat A, Marechal A, Filhol JM, Valogne Y, Valton J, Duclert A, et al. An oxygen sensitive self-decision making engineered CAR T-cell. Sci Rep. 2017;20(7):39833
79. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell. 2016;164(4):770–9