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ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

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Review Article

Cardiovascular Toxicities with Chimeric Antigen Receptor T-cell Therapy

Author(s): Jashan Gill*

Volume 19, Issue 1, 2023

Published on: 02 September, 2022

Article ID: e230622206353 Pages: 11

DOI: 10.2174/1573403X18666220623152350

Price: $65

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating highly refractory and relapsing hematological malignancies in pediatric and adult patients. However, this promising therapy is limited by severe and potentially life-threatening toxicities. Cytokine release syndrome (CRS) is the most commonly observed of these toxicities. The cardiovascular manifestations of CRS include tachycardia, hypotension, left ventricular dysfunction, arrhythmias, troponin elevation, cardiogenic shock, and pulmonary edema. Recent data suggest that cardiotoxicities may be transient and reversible in younger patients with few cardiac comorbidities; however, cardiotoxicities may be fatal in older patients with significant cardiac risk factors. The literature remains sparse regarding long-term cardiotoxicities associated with CAR-T cell therapy. Furthermore, consensus guidelines for monitoring and prevention of cardiotoxicities remain illdefined. Therefore, this review will detail the cardiovascular toxicities of CAR T-cell therapy seen in clinical trials and observational studies, summarize treatment approaches for CRS, outline the currently adopted surveillance protocols for CAR T-cell associated cardiotoxicity, and explore the future directions of research in this rapidly emerging field.

Keywords: CAR T-cell, Cardio-oncology, cytokine release syndrome, cardiomyopathy, cardiotoxicity, chimeric antigen receptor, CD19, BCMA.

Graphical Abstract

[1]
Yang JC, Rosenberg SA. Adoptive t-cell therapy for cancer. Adv Immunol 2016; 130: 279-94.
[http://dx.doi.org/10.1016/bs.ai.2015.12.006] [PMID: 26923004]
[2]
Rosenbaum L. Tragedy, perseverance, and chance - The story of CAR-T Therapy. N Engl J Med 2017; 377(14): 1313-5.
[http://dx.doi.org/10.1056/NEJMp1711886] [PMID: 28902570]
[3]
Tang J, Shalabi A, Hubbard-Lucey VM. Comprehensive analysis of the clinical immuno-oncology landscape. Ann Oncol 2018; 29(1): 84-91.
[http://dx.doi.org/10.1093/annonc/mdx755] [PMID: 29228097]
[4]
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.
[http://dx.doi.org/10.1038/nrclinonc.2017.148] [PMID: 28925994]
[5]
Fitzgerald JC, Weiss SL, Maude SL, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic Leukemia. Crit Care Med 2017; 45(2): e124-31.
[http://dx.doi.org/10.1097/CCM.0000000000002053] [PMID: 27632680]
[6]
Alvi RM, Frigault MJ, Fradley MG, et al. Cardiovascular events among adults treated with chimeric antigen receptor T-Cells (CAR-T). J Am Coll Cardiol 2019; 74(25): 3099-108.
[http://dx.doi.org/10.1016/j.jacc.2019.10.038] [PMID: 31856966]
[7]
Lefebvre B, Kang Y, Smith AM, Frey NV, Carver JR, Scherrer-Crosbie M. Cardiovascular effects of car T cell therapy: A retrospective study. JACC CardioOncology 2020; 2(2): 193-203.
[http://dx.doi.org/10.1016/j.jaccao.2020.04.012] [PMID: 32776016]
[8]
Shalabi H, Sachdev V, Kulshreshtha A, et al. Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies. J Immunother Cancer 2020; 8(2): 8.
[http://dx.doi.org/10.1136/jitc-2020-001159] [PMID: 32883871]
[9]
June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med 2018; 379(1): 64-73.
[http://dx.doi.org/10.1056/NEJMra1706169] [PMID: 29972754]
[10]
Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013; 3(4): 388-98.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0548] [PMID: 23550147]
[11]
Salter AI, Pont MJ, Riddell SR. Chimeric antigen receptor-modified T cells: CD19 and the road beyond. Blood 2018; 131(24): 2621-9.
[http://dx.doi.org/10.1182/blood-2018-01-785840] [PMID: 29728402]
[12]
Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 2018; 15(1): 31-46.
[http://dx.doi.org/10.1038/nrclinonc.2017.128] [PMID: 28857075]
[13]
Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371(16): 1507-17.
[http://dx.doi.org/10.1056/NEJMoa1407222] [PMID: 25317870]
[14]
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): 517-28.
[http://dx.doi.org/10.1016/S0140-6736(14)61403-3] [PMID: 25319501]
[15]
Si Lim SJ, Grupp SA, DiNofia AM. Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Pediatr Blood Cancer 2021; 68(9): e29123.
[http://dx.doi.org/10.1002/pbc.29123] [PMID: 34061452]
[16]
Park JH, Rivière I, Gonen M, et al. Long-Term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018; 378(5): 449-59.
[http://dx.doi.org/10.1056/NEJMoa1709919] [PMID: 29385376]
[17]
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.
[http://dx.doi.org/10.1126/scitranslmed.aac5415] [PMID: 26333935]
[18]
Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 2017; 35(26): 3010-20.
[http://dx.doi.org/10.1200/JCO.2017.72.8519] [PMID: 28715249]
[19]
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): 563-71.
[http://dx.doi.org/10.1038/s41591-018-0010-1] [PMID: 29713085]
[20]
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): 540-9.
[http://dx.doi.org/10.1200/JCO.2014.56.2025] [PMID: 25154820]
[21]
Kochenderfer JN, Somerville RPT, Lu T, 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.
[http://dx.doi.org/10.1200/JCO.2016.71.3024] [PMID: 28291388]
[22]
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): 285-95.
[http://dx.doi.org/10.1016/j.ymthe.2016.10.020] [PMID: 28129122]
[23]
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; 377(26): 2531-44.
[http://dx.doi.org/10.1056/NEJMoa1707447] [PMID: 29226797]
[24]
Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380(1): 45-56.
[http://dx.doi.org/10.1056/NEJMoa1804980] [PMID: 30501490]
[25]
Ali SA, Shi V, Maric I, 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.
[http://dx.doi.org/10.1182/blood-2016-04-711903] [PMID: 27412889]
[26]
Brudno JN, Maric I, Hartman SD, 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): 2267-80.
[http://dx.doi.org/10.1200/JCO.2018.77.8084] [PMID: 29812997]
[27]
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): 1156-66.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1365] [PMID: 27582488]
[28]
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): 3462-71.
[http://dx.doi.org/10.1172/JCI94306] [PMID: 28805662]
[29]
Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 2016; 375(26): 2561-9.
[http://dx.doi.org/10.1056/NEJMoa1610497] [PMID: 28029927]
[30]
Adusumilli PS, Cherkassky L, Villena-Vargas J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med 2014; 6(261): 261ra151.
[http://dx.doi.org/10.1126/scitranslmed.3010162] [PMID: 25378643]
[31]
Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011; 118(23): 6050-6.
[http://dx.doi.org/10.1182/blood-2011-05-354449] [PMID: 21984804]
[32]
Ahmed N, Brawley VS, Hegde M, et al. Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-Positive sarcoma. J Clin Oncol 2015; 33(15): 1688-96.
[http://dx.doi.org/10.1200/JCO.2014.58.0225] [PMID: 25800760]
[33]
Maldini CR, Ellis GI, Riley JL. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol 2018; 18(10): 605-16.
[http://dx.doi.org/10.1038/s41577-018-0042-2] [PMID: 30046149]
[34]
Bouchkouj N, Kasamon YL, de Claro RA, et al. FDA approval summary: Axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. Clin Cancer Res 2019; 25(6): 1702-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2743] [PMID: 30413526]
[35]
FDADISCO. Burst Edition: FDA approval of Tecartus (brexucabtagene autoleucel) for adult patients with relapsed or refractory Bcell precursor acute lymphoblastic leukemia. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-tecartus-brexucabtagene-autoleucel-adult-patients-relapsed-or#:~:text=On%20October%201%2C%202021%2C%20the,cell%20precursor%20acute%20lymphoblastic%20leukemia (Accessed on May 25, 2022).
[36]
FDADISCO. Burst Edition: Breyanzi (lisocabtagene maraleucel). Available from: https://www.fda.gov/drugs/resources-information-approveddrugs/fda-disco-burst-edition-breyanzi-lisocabtagene-maraleucel (Accessed on May 25, 2022).
[37]
O’Leary MC, Lu X, Huang Y, et al. FDA approval summary: Tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Clin Cancer Res 2019; 25(4): 1142-6.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2035] [PMID: 30309857]
[38]
FDADISCO. Burst Edition: FDA approval of ABECMA (idecabtagene vicleucel) the first FDA approved cell-based gene therapy for the treatment of adult patients with relapsed or refractory multiple myeloma. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-abecma-idecabtagene-vicleucel-first-fda-approved-cell-based (Accessed on May 25, 2022).
[39]
Ganatra S, Carver JR, Hayek SS, et al. Chimeric antigen receptor T-Cell therapy for cancer and heart: JACC council perspectives. J Am Coll Cardiol 2019; 74(25): 3153-63.
[http://dx.doi.org/10.1016/j.jacc.2019.10.049] [PMID: 31856973]
[40]
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): 1-2.
[41]
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for Cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25(4): 625-38.
[http://dx.doi.org/10.1016/j.bbmt.2018.12.758] [PMID: 30592986]
[42]
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188-95.
[http://dx.doi.org/10.1182/blood-2014-05-552729] [PMID: 24876563]
[43]
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer 2018; 6(1): 56.
[http://dx.doi.org/10.1186/s40425-018-0343-9] [PMID: 29907163]
[44]
Asnani A. Cardiotoxicity of immunotherapy: Incidence, diagnosis, and management. Curr Oncol Rep 2018; 20(6): 44.
[http://dx.doi.org/10.1007/s11912-018-0690-1] [PMID: 29644505]
[45]
Leick MB, Maus MV. Toxicities associated with immunotherapies for hematologic malignancies. Best Pract Res Clin Haematol 2018; 31(2): 158-65.
[http://dx.doi.org/10.1016/j.beha.2018.03.004] [PMID: 29909916]
[46]
Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol 2016; 64(6): 1403-15.
[http://dx.doi.org/10.1016/j.jhep.2016.02.004] [PMID: 26867490]
[47]
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): 2545-54.
[http://dx.doi.org/10.1056/NEJMoa1708566] [PMID: 29226764]
[48]
Burstein DS, Maude S, Grupp S, Griffis H, Rossano J, Lin K. Cardiac profile of chimeric antigen receptor T cell therapy in children: A single-institution experience. Biol Blood Marrow Transplant 2018; 24(8): 1590-5.
[http://dx.doi.org/10.1016/j.bbmt.2018.05.014] [PMID: 29772353]
[49]
Liu S, Deng B, Yin Z, et al. Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia. Blood Cancer J 2020; 10(2): 15.
[http://dx.doi.org/10.1038/s41408-020-0280-y] [PMID: 32029707]
[50]
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 2019; 15: 323-35.
[http://dx.doi.org/10.2147/TCRM.S150524] [PMID: 30880998]
[51]
Norelli M, Camisa B, Barbiera G, 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.
[http://dx.doi.org/10.1038/s41591-018-0036-4] [PMID: 29808007]
[52]
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.
[http://dx.doi.org/10.1038/s41591-018-0041-7] [PMID: 29808005]
[53]
Jatiani SS, Aleman A, Madduri D, et al. Myeloma CAR-T CRS management With IL-1R antagonist anakinra. Clin Lymphoma Myeloma Leuk 2020; 20(9): 632-636.e1.
[http://dx.doi.org/10.1016/j.clml.2020.04.020] [PMID: 32553791]
[54]
National Library of Medicine. Anakinra for the prevention of cytokine release syndrome and neurotoxicity in patients with B-cell lymphoma receiving CD19-Targeted CAR-T cell therapy Available from: https://www.clinicaltrials.gov/ct2/show/NCT04359784 (Accessed on May 25, 2022).
[55]
Zhang L, Wang S, Xu J, et al. Etanercept as a new therapeutic option for cytokine release syndrome following chimeric antigen receptor T cell therapy. Exp Hematol Oncol 2021; 10(1): 16.
[http://dx.doi.org/10.1186/s40164-021-00209-2] [PMID: 33608054]
[56]
Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: Etiologies, pathophysiology, and management. Kidney Int 2017; 92(1): 37-46.
[http://dx.doi.org/10.1016/j.kint.2016.11.029] [PMID: 28318633]
[57]
Hu Y, Feng J, Shao M, Huang H. Profile of capillary-leak syndrome in patients received chimeric antigen receptor T cell therapy. Blood 2018; 132 (Suppl. 1): 5204-4.
[http://dx.doi.org/10.1182/blood-2018-99-117602]
[58]
Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 2013; 122(6): 863-71.
[http://dx.doi.org/10.1182/blood-2013-03-490565] [PMID: 23770775]
[59]
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): 439-48.
[http://dx.doi.org/10.1056/NEJMoa1709866] [PMID: 29385370]
[60]
Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2020; 382(14): 1331-42.
[http://dx.doi.org/10.1056/NEJMoa1914347] [PMID: 32242358]
[61]
Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet 2020; 396(10254): 839-52.
[http://dx.doi.org/10.1016/S0140-6736(20)31366-0] [PMID: 32888407]
[62]
Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple Myeloma. N Engl J Med 2021; 384(8): 705-16.
[http://dx.doi.org/10.1056/NEJMoa2024850] [PMID: 33626253]
[63]
Ganatra S, Redd R, Hayek SS, et al. Chimeric antigen receptor T-Cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Circulation 2020; 142(17): 1687-90.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048100] [PMID: 33104402]
[64]
Cordeiro A, Bezerra ED, Hirayama AV, et al. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biol Blood Marrow Transplant 2020; 26(1): 26-33.
[http://dx.doi.org/10.1016/j.bbmt.2019.08.003] [PMID: 31419568]
[65]
Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American society of clinical oncology clinical practice guideline. J Clin Oncol 2017; 35(8): 893-911.
[http://dx.doi.org/10.1200/JCO.2016.70.5400] [PMID: 27918725]
[66]
Ghosh AK, Chen DH, Guha A, Mackenzie S, Walker JM, Roddie C. CAR T cell therapy-related cardiovascular outcomes and management: Systemic disease or direct cardiotoxicity? JACC CardioOncology 2020; 2(1): 97-109.
[http://dx.doi.org/10.1016/j.jaccao.2020.02.011] [PMID: 34396213]
[67]
Kanelidis AJ, Raikhelkar J, Kim G, et al. CardioMEMS-Guided CAR T cell therapy for lymphoma in a patient with anthracycline-induced cardiomyopathy. JACC Cardio Oncol 2020; 2(3): 515-8.
[http://dx.doi.org/10.1016/j.jaccao.2020.06.005] [PMID: 34396261]

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