Cardiotoxicity of Immunotherapy: Incidence, Diagnosis, and Management

Cardio-oncology (EH Yang, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cardio-oncology

Abstract

Purpose of review

This review describes cardiotoxicity associated with adoptive T cell therapy and immune checkpoint blockade.

Recent findings

Cardiotoxicity is a rare but potentially fatal complication associated with novel immunotherapies. Both affinity-enhanced and chimeric antigen receptor T cells have been reported to cause hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Immune checkpoint inhibitors are generally well-tolerated but have the potential to cause myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, arrhythmia, and cardiogenic shock. Electrocardiography, cardiac biomarker measurement, and cardiac imaging are key components of the diagnostic evaluation. For suspected myocarditis, endomyocardial biopsy is recommended if the diagnosis remains unclear after initial testing.

Summary

The incidence of immunotherapy-associated cardiotoxicity is likely underestimated and may increase as adoptive T cell therapy and immune checkpoint inhibitors are used in larger populations and for longer durations of therapy. Baseline and serial cardiac evaluation is recommended to facilitate early identification and treatment of cardiotoxicity.

Keywords

Immunotherapy Cardiotoxicity Adoptive T cell therapy Cytokine release syndrome Immune checkpoint inhibitor Myocarditis 

Notes

Compliance with Ethical Standards

Conflict of Interest

Aarti Asnani declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Lee RE, Lotze MT, Skibber JM, Tucker E, Bonow RO, Ognibene FP, et al. Cardiorespiratory effects of immunotherapy with interleukin-2. J Clin Oncol Off J Am Soc Clin Oncol. 1989;7(1):7–20.CrossRefGoogle Scholar
  2. 2.
    White RL Jr, Schwartzentruber DJ, Guleria A, MacFarlane MP, White DE, Tucker E, et al. Cardiopulmonary toxicity of treatment with high dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal cell carcinoma. Cancer. 1994;74(12):3212–22.CrossRefPubMedGoogle Scholar
  3. 3.
    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. 2015;385(9967):517–28.CrossRefPubMedGoogle Scholar
  4. 4.
    Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(7):917–24.CrossRefGoogle Scholar
  5. 5.
    Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5(197):197ra03.CrossRefGoogle Scholar
  6. 6.
    Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993;90(2):720–4.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914–21.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, 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 Off J Am Soc Clin Oncol. 2015;33(6):540–9.CrossRefGoogle Scholar
  9. 9.
    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;5(177):177ra38.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Porter DL, Hwang WT, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    •• Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71. This detailed case report described two patients treated with T cells expressing an affinity-enhanced receptor against MAGE-A3 who developed cardiotoxicity attributed to cross-reactivity with the skeletal muscle protein titin. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.CrossRefPubMedGoogle Scholar
  17. 17.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.CrossRefPubMedGoogle Scholar
  18. 18.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(33):4199–206.CrossRefGoogle Scholar
  22. 22.
    Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.CrossRefPubMedGoogle Scholar
  25. 25.
    Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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;6(224):224ra25.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4(132):132ra53.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Love VA, Grabie N, Duramad P, Stavrakis G, Sharpe A, Lichtman A. CTLA-4 ablation and interleukin-12 driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes. Circ Res. 2007;101(3):248–57.CrossRefPubMedGoogle Scholar
  31. 31.
    Lucas JA, Menke J, Rabacal WA, Schoen FJ, Sharpe AH, Kelley VR. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol. 2008;181(4):2513–21.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319–22.CrossRefPubMedGoogle Scholar
  33. 33.
    Tarrio ML, Grabie N, Bu DX, Sharpe AH, Lichtman AH. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol. 2012;188(10):4876–84.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9(12):1477–83.CrossRefPubMedGoogle Scholar
  35. 35.
    Wang J, Okazaki IM, Yoshida T, Chikuma S, Kato Y, Nakaki F, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol. 2010;22(6):443–52.CrossRefPubMedGoogle Scholar
  36. 36.
    •• Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55. This detailed case report described two patients treated with a combination nivolumab and ipilimumab therapy who developed fulminant autoimmune myocarditis. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tajiri K, Aonuma K, Sekine I. Immune checkpoint inhibitor-related myocarditis. Jpn J Clin Oncol. 2017:1–6.Google Scholar
  38. 38.
    Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:210–25.CrossRefPubMedGoogle Scholar
  39. 39.
    •• Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation. 2017;136(21):2085–7. This observational study described clinical characteristics, treatments, and outcomes in a series of 30 patients with ICI cardiotoxicity. CrossRefPubMedGoogle Scholar
  40. 40.
    Norwood TG, Westbrook BC, Johnson DB, Litovsky SH, Terry NL, McKee SB, et al. Smoldering myocarditis following immune checkpoint blockade. J Immunother Cancer. 2017;5(1):91.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kimura T, Fukushima S, Miyashita A, Aoi J, Jinnin M, Kosaka T, et al. Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci. 2016;107(7):1055–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Geisler BP, Raad RA, Esaian D, Sharon E, Schwartz DR. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer. 2015;3:4.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yun S, Vincelette ND, Mansour I, Hariri D, Motamed S. Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. Case Rep Oncol Med. 2015;2015:794842.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Fitzmaurice TF, Brown C, Rifai N, Wu AH, Yeo KT. False increase of cardiac troponin I with heterophilic antibodies. Clin Chem. 1998;44(10):2212–4.PubMedGoogle Scholar
  46. 46.
    Ribas A, Comin-Anduix B, Economou JS, Donahue TR, de la Rocha P, Morris LF, et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res. 2009;15(1):390–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559–74.CrossRefPubMedGoogle Scholar
  48. 48.
    Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–4.CrossRefPubMedGoogle Scholar
  49. 49.
    Lukens JR, Cruise MW, Lassen MG, Hahn YS. Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model. J Immunol. 2008;180(7):4875–84.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang DY, Okoye GD, Neilan TG, Johnson DB, Moslehi JJ. Cardiovascular toxicities associated with cancer immunotherapies. Curr Cardiol Rep. 2017;19(3):21.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cardio-Oncology Program and CardioVascular InstituteBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA

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