Skip to main content

Advertisement

SpringerLink
Log in

Cardiovascular Toxicities Associated with Cancer Immunotherapies

  • Cardio-Oncology (SA Francis, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of review

We review the cardiovascular toxicities associated with cancer immune therapies and discuss the cardiac manifestations, potential mechanisms, and management strategies.

Recent findings

The recent advances in cancer immune therapy with immune checkpoint inhibitors and adoptive cell transfer have improved clinical outcomes in numerous cancers. The rising use of cancer immune therapy will lead to a higher incidence in immune-related adverse events. Recent studies have highlighted several reports of severe cases of acute cardiotoxic events with immune therapy including fulminant myocarditis. We believe that immune-mediated myocarditis is a driving mechanism behind these cardiovascular toxicities and requires vigilant screening and prompt management with corticosteroids and immune-modulating drugs, especially with combination immune therapies.

Summary

While the incidence of serious cardiovascular toxicities with immune therapy appears low, these can be life-threatening especially when manifesting as acute immune-mediated myocarditis. Further collaborative studies are needed to effectively identify, characterize, and manage these events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

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

  1. Kragel AH, Travis WD, Steis RG, Rosenberg SA, Roberts WC. Myocarditis or acute myocardial infarction associated with interleukin-2 therapy for cancer. Cancer. 1990;66(7):1513–6.

    Article  CAS  PubMed  Google Scholar 

  2. Sonnenblick M, Rosin A. Cardiotoxicity of interferon. A review of 44 cases. Chest. 1991;99(3):557–61.

    Article  CAS  PubMed  Google Scholar 

  3. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Roth ME, Muluneh B, Jensen BC, Madamanchi C, Lee CB. Left ventricular dysfunction after treatment with ipilimumab for metastatic melanoma. Am J Ther. 2016;23(6):e1925-e1928.

    Article  PubMed  Google Scholar 

  5. 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.

    PubMed  PubMed Central  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tadokoro T, Keshino E, Makiyama A, Sasaguri T, Ohshima K, Katano H, et al. Acute lymphocytic myocarditis with anti-PD-1 antibody nivolumab. Circ Heart Fail. 2016;9(10).

  8. Laubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer. 2015;3:11.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. •• 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. Case report documenting fulminant myocarditis with combination ICI with histopathologic evidence of selective clonal T-cell populations within the myocardium, tumor and skeletal muscle.

    Article  PubMed  Google Scholar 

  11. Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991(262):3-11.

  14. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161(5):1169–88.

    Article  CAS  PubMed  Google Scholar 

  15. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.

    Article  CAS  PubMed  Google Scholar 

  16. White Jr RL, 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.

    Article  PubMed  Google Scholar 

  17. Lee RE, Lotze MT, Skibber JM, Tucker E, Bonow RO, Ognibene FP, et al. Cardiorespiratory effects of immunotherapy with interleukin-2. J Clin Oncol. 1989;7(1):7–20.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang J, Yu ZX, Hilbert SL, Yamaguchi M, Chadwick DP, Herman EH, et al. Cardiotoxicity of human recombinant interleukin-2 in rats. A morphological study. Circulation. 1993;87(4):1340–53.

    Article  CAS  PubMed  Google Scholar 

  19. Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A. 1999;96(1):185–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1(5):405–13.

    Article  CAS  PubMed  Google Scholar 

  21. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65.

    Article  CAS  PubMed  Google Scholar 

  22. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7.

    Article  CAS  PubMed  Google Scholar 

  23. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.

    Article  CAS  PubMed  Google Scholar 

  25. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.

    Article  PubMed  Google Scholar 

  26. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. • 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. Phase 3 clinical trial with higher dose of ipilimumab with one reported case of myocarditis.

    Article  CAS  PubMed  Google Scholar 

  28. • 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. Phase 3 clinical trial that led to the approval of the first combination immune therapy in cancer. One patient developed myocarditis in the single ipilimumab arm.

    Article  PubMed  Google Scholar 

  29. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65(3):1089–96.

    CAS  PubMed  Google Scholar 

  31. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.

    Article  CAS  PubMed  Google Scholar 

  32. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600–9.

    Article  CAS  PubMed  Google Scholar 

  38. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374(26):2542–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.

    Article  CAS  PubMed  Google Scholar 

  40. Gibson R, Delaune J, Szady A, Markham M. Suspected autoimmune myocarditis and cardiac conduction abnormalities with nivolumab therapy for non-small cell lung cancer. BMJ Case Rep. 2016;2016.

  41. Koelzer VH, Rothschild SI, Zihler D, Wicki A, Willi B, Willi N, et al. Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study. J Immunother Cancer. 2016;4:13.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, Danforth DN, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol. 2016;34(20):2389–97.

    Article  PubMed  Google Scholar 

  51. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5.

    Article  CAS  PubMed  Google Scholar 

  52. 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. 2011;29(7):917–24.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Jungbluth AA, Antonescu CR, Busam KJ, Iversen K, Kolb D, Coplan K, et al. Monophasic and biphasic synovial sarcomas abundantly express cancer/testis antigen NY-ESO-1 but not MAGE-A1 or CT7. Int J Cancer. 2001;94(2):252–6.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  Google Scholar 

  55. van den Berg JH, Gomez-Eerland R, van de Wiel B, Hulshoff L, van den Broek D, Bins A, et al. Case report of a fatal serious adverse event upon administration of T cells transduced with a MART-1-specific T-cell receptor. Mol Ther. 2015;23(9):1541–50.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370–83.

    Article  CAS  PubMed  Google Scholar 

  57. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50.

    Article  CAS  PubMed  Google Scholar 

  58. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Smith SC, Ladenson JH, Mason JW, Jaffe AS. Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates. Circulation. 1997;95(1):163–8.

    Article  CAS  PubMed  Google Scholar 

  62. Lauer B, Niederau C, Kuhl U, Schannwell M, Pauschinger M, Strauer BE, et al. Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol. 1997;30(5):1354–9.

    Article  CAS  PubMed  Google Scholar 

  63. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio Jr JJ, et al. Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol. 1987;1(1):3–14.

    CAS  PubMed  Google Scholar 

  64. Mahrholdt H, Goedecke C, Wagner A, Meinhardt G, Athanasiadis A, Vogelsberg H, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation. 2004;109(10):1250–8.

    Article  PubMed  Google Scholar 

  65. Mahrholdt H, Wagner A, Judd RM, Sechtem U. Assessment of myocardial viability by cardiovascular magnetic resonance imaging. Eur Heart J. 2002;23(8):602–19.

    Article  CAS  PubMed  Google Scholar 

  66. Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138(10):807–11.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Divisions of Oncology, Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, 777 Preston Research Bldg., Nashville, TN, 37232, USA

    Daniel Y. Wang, Douglas B. Johnson & Javid J. Moslehi

  2. Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Gosife Donald Okoye & Javid J. Moslehi

  3. Department of Medicine, Cardio-Oncology Program, Vanderbilt University Medical Center, Nashville, TN, USA

    Gosife Donald Okoye & Javid J. Moslehi

  4. Division of Cardiovascular Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Thomas G. Neilan

  5. Department of Medicine, Cardio-Oncology Program, Massachusetts General Hospital, Boston, MA, USA

    Thomas G. Neilan

Authors
  1. Daniel Y. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gosife Donald Okoye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas G. Neilan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Douglas B. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Javid J. Moslehi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas B. Johnson.

Ethics declarations

Conflict of Interest

Daniel Y. Wang, Gosife Donald Okoye, and Thomas G. Neilan declare that they have no conflict of interest.

Douglas B. Johnson reports being on the advisory board for BMS and Genoptix, and grants from Incyte.

Javid J. Moslehi reports personal fees from Pfizer, Novartis, Bristol-Myers Squibb, Takeda, Ariad, Vertex, Acceleron, Incyte, Verastem, RGenix, StemCentRx, Heat Biologics, and Pharmacyclics

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.

Additional information

This article is part of the Topical Collection on Cardio-Oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, D.Y., Okoye, G.D., Neilan, T.G. et al. Cardiovascular Toxicities Associated with Cancer Immunotherapies. Curr Cardiol Rep 19, 21 (2017). https://doi.org/10.1007/s11886-017-0835-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-017-0835-0

Keywords

Search

Navigation