Cytokine release syndrome after CAR T-cell therapy: a review of the literature and our experience

Česká verzia

Authors: B. Čemusová
Authors place of work: Ústav hematologie a krevní transfuze, Praha
Published in the journal: Anest. intenziv. Med., 33, 2022, č. 2, s. 90-96
Category: Review Article

Summary

Cytokine release syndrome is an acute systemic inflammatory response triggered by overactivation of the immune system that may be initiated by a variety of factors. The incidence of cytokine release syndrome is high, especially after immunotherapy with chimeric antigen receptor T-cells, which is effective for refractory or recurrent B cell hematological malignancies. Cytokine release syndrome occurs due to a high level of immune activation of lymphocytes, macrophages, or myeloid cells with a subsequent massive release of inflammatory cytokines.

After chimeric antigen receptor T-cell therapy, symptoms appear within days of infusion, which correlates with the maximum T-cells expansion. The monocyte-macrophage system, which is the main source of the most important cytokines, plays a key role in pathophysiology. The central mediator of toxicity is interleukin 6.

Cytokine release syndrome is presented by fever, hypotension, and hypoxia, severe forms are clinically indistinguishable from sepsis and may lead to multiorgan failure.

Because chimeric antigen receptor T-cell immunotherapy is a potentially curative treatment, patients should be provided with full resuscitation care after administration of this therapy. In severe cytokine release syndrome, treatment with tocilizumab is indicated, after which symptoms usually resolve rapidly. The challenge in clinical practice is to differentiate cytokine release syndrome from other serious conditions, which may be concomitant and may require a different therapeutic approach.

Keywords:

immunotherapy – cytokine release syndrome – multiple organ failures

Zdroje

1. Tonini G, Santini D, Vincenzi B, Borzomati D, Dicuonzo G, La Cesa A,et al. Oxaliplatin may induce cytokine‑release syndrome in colorectal cancer patients.J Biol Regul Homeost Agents. 2002 Apr‑Jun; 16(2):105-9.

2. Aue G, Njuguna N, Tian X, Soto S, Hughes T, Vire B, et al. Lenalidomide‑induced upregulation of CD80 on tumor cells correlates with T‑cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia. Haematologica. 2009 Sep;94(9):1266-73.

3. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006 Oct;12(10):1203-7.

4. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32

5. Picchianti Diamanti A, Rosado MM, Pioli C, Sesti G, Laganà B. Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern: The Fragile Balance between Infections and Autoimmunity. Int J Mol Sci. 2020 May 8;21(9):3330.

6. Kang L, Tang X, Zhang J, Li M, Xu N, Qi W, et al. Interleukin-6-knockdown of chimeric antigen receptor‑modified T cells significantly reduces IL-6 release from monocytes. Exp Hematol Oncol. 2020 Jun 8;9:11.

7. 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;377:2531-2544.

8. 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 Feb 1;378(5):439-448.

9. 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 Jul 10;124(2):188- 95. doi: 10.1182/blood-2014-05-552729. Epub 2014 May 29. Erratum in: Blood. 2015 Aug 20;126(8):1048.

10. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, 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 Mar 22;119(12):2709-20.

11. Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y, et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020 May 29;368(6494).

12. Liu Y, Fang Y, Chen X, Wang Z, Liang X, Zhang T, et al. Gasdermin E‑mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. 2020 Jan 17;5(43).

13. Hao Z, Li R, Meng L, Han Z, Hong Z. Macrophage, the potential key mediator in CAR‑T related CRS. Exp Hematol Oncol. 2020 Jul 10;9:15. doi: 10.1186/s40164-020-00171-5. PMID: 32665874; PMCID: PMC7349474.

14. 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 Jun;24(6):739-748.

15. Gong T, Liu L, Jiang W, Zhou R. DAMP‑sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020 Feb;20(2):95-112. doi: 10.1038/s41577-019- 0215-7. Epub 2019 Sep 26. PMID: 31558839.

16. 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 Jun;24(6):731-738.

17. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor‑modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-1518.

18. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. N Engl J Med. 2014 Oct 16;371(16):1507-17.

19. Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X, et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T‑ cell therapy and associated prevention and management strategies. J Exp Clin Cancer Res. 2021 Nov 18;40(1):367. doi: 10.1186/s13046-021- 02148-6. PMID: 34794490; PMCID: PMC8600921.

20. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell‑engaging therapies. Cancer J. 2014;20(2):119-122.

21. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321-3330.

22. Murthy H, Iqbal M, Chavez JC, Kharfan‑Dabaja MA. Cytokine Release Syndrome: Current Perspectives. Immunotargets Ther. 2019 Oct 29;8:43-52. doi: 10.2147/ITT.S202015. PMID: 31754614; PMCID: PMC6825470.

23. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j. bbmt.2018. 12. 758. Epub 2018 Dec 25. PMID: 30592986.

24. Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell‑induced cytokine release syndrome. Expert Rev Clin Immunol. 2019;15(8):1-10.

25. Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handb Exp Pharmacol. 2008;181:151-160.

26. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‑ Induced Severe or Life‑Threatening Cytokine Release Syndrome. Oncologist. 2018 Aug;23(8):943-947. doi: 10.1634/theoncologist.2018-0028. Epub 2018 Apr 5. PMID: 29622697; PMCID: PMC6156173.

27. Gardner RA, Ceppi F, Rivers J, Annesley C, Summers C, Taraseviciute A, et al. Preemptive mitigation of CD19 CAR T‑ cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019 Dec 12;134(24):2149-2158.

28. Barrett DM, Singh N, Hofmann TJ, Gershenson Z, Stephan A. Grupp; Interleukin 6 Is Not Made By Chimeric Antigen Receptor T Cells and Does Not Impact Their Function. Blood. 2016;128(22):654.

29. 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 Dec 28;377(26):2531-2544.

30. Caimi PF, Pacheco Sanchez G, Sharma A, Otegbeye F, Ahmed N, Rojas P, et al. Prophylactic Tocilizumab Prior to Anti‑CD19 CAR‑T Cell Therapy for Non‑Hodgkin Lymphoma. Front Immunol. 2021 Oct 12;12:745320. doi: 10.3389/fimmu.2021.745320. PMID: 34712233; PMCID: PMC8546323.

31. 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 Feb 19;6(224).

32. Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The other side of CAR T‑ cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden. Am Soc Clin Oncol Educ Book. 2019;39: 433-444.

33. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64-73.

34. Karschnia P, Jordan JT, Forst DA, Arrillaga‑Romany IC, Batchelor TT, Baehring JM, et al. Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood. 2019 May 16;133(20):2212-2221. doi: 10.1182/blood- 2018-12-893396. Epub 2019 Feb 26. PMID: 30808634.

35. Topp MS, van Meerten T, Wermke M, Lugtenburg EJ, Minnema M, Song KW, et al. Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi‑ cel) in patients with relapsed/refractory large B‑ cell lymphoma (R/R LBCL). 2019. J Clin Oncol. 2019;37.

36. 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.

37. Shah NN, Highfill SL, Shalabi H, Yates B, Jin J, Wolters PL, et al. CD4/CD8 T‑Cell Selection Affects Chimeric Antigen Receptor (CAR) T‑Cell Potency and Toxicity: Updated Results From a Phase I Anti‑CD22 CAR T‑Cell Trial. J Clin Oncol. 2020 Jun 10;38(17):1938-1950.

38. Kenderian SS, Oluwole OO, McCarthy PL, Reshef R, Shiraz P, et al; ZUMA-19: A Phase 1/2 Multicenter Study of Lenzilumab Use With Axicabtagene Ciloleucel (Axi‑Cel) in Patients (Pts) With Relapsed or Refractory Large B Cell Lymphoma (R/R LBCL). Blood 2020;136(Supplement 1).

39. Huarte E, O’Connor RS, Peel MT, Nunez‑Cruz S, Leferovich J, Juvekar A, et al. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T‑ cell Therapy. Clin Cancer Res. 2020 Dec 1;26(23):6299-6309.

40. Mestermann K, Giavridis T, Weber J, Rydzek J, Frenz S, Nerreter T, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019 Jul 3;11(499).

41. Weber EW, Lynn RC, Sotillo E, Lattin J, Xu P, Mackall CL. Pharmacologic control of CAR‑T cell function using dasatinib. Blood Adv. 2019 Mar 12;3(5):711-717.

42. Al‑Mansour M, Al‑Foheidi M, Ibrahim E. Efficacy and safety of second‑generation CAR T‑ cell therapy in diffuse large B‑ cell lymphoma: A meta‑analysis. Mol Clin Oncol. 2020 Oct;13(4):33. doi: 10.3892/mco.2020.2103. Epub 2020 Jul 29. PMID: 32789017; PMCID: PMC7416618.

43. Shimabukuro‑Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018 Jun 15;6(1):56. doi: 10.1186/ s40425-018-0343-9. PMID: 29907163; PMCID: PMC6003181.