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Update on Immunotherapy Cardiotoxicity: Checkpoint Inhibitors, CAR T, and Beyond

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A Correction to this article was published on 02 October 2023

This article has been updated

Opinion statement

Immunotherapy is an innovative approach to cancer treatment that involves using the body’s immune system to fight cancer. The landscape of immunotherapy is constantly evolving, as new therapies are developed and refined. Some of the most promising approaches in immunotherapy include immune checkpoint inhibitors (ICIs): these drugs target proteins on the surface of T-cells that inhibit their ability to attack cancer cells. By blocking these proteins, checkpoint inhibitors allow T-cells to recognize and destroy cancer cells more effectively. CAR T-cell therapy: this therapy involves genetically modifying a patient’s own T-cells to recognize and attack cancer cells. CAR T-cell therapy exhibits favorable response in many patients with refractory hematological cancers with growing clinical trials in solid tumors. Immune system modulators: these drugs enhance the immune system’s ability to fight cancer by stimulating the production of immune cells or inhibiting the activity of immune-suppressing cells. While immunotherapy has shown great promise in the treatment of cancer, it can also pose significant cardiac side effects. Some immunotherapy drugs like ICIs can cause myocarditis, which can lead to chest pain, shortness of breath, and heart failure. Other cardiac side effects of ICIs include arrhythmias, pericarditis, vasculitis, and accelerated atherosclerosis. It is important for patients receiving immunotherapy to be monitored closely for these side effects, as prompt treatment can help prevent serious complications. Patients should also report any symptoms to their healthcare providers right away, so that appropriate action can be taken. CAR T-cell therapy can also illicit an exaggerated immune response creating cytokine release syndrome (CRS) that may precipitate cardiovascular events: arrhythmias, myocardial infarction, and heart failure. Overall, while immune modulating therapy is a promising and expanding approach to cancer treatment, it is important to weigh the potential benefits against the risks and side effects, especially in patients with high risk for cardiovascular complications.

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References and Recommended Reading

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

  1. • Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391(10124):933. Novel paper bringing to attention the cardiovascular effect of checkpoint inhibitors.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Palaskas NL, Segura A, Lelenwa L, Siddiqui BA, Subudhi SK, Lopez-Mattei J, et al. Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy. Eur J Heart Failure. 2021 Oct;23(10):1725–35.

    Article  CAS  Google Scholar 

  3. •• Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. Important case series identifying characteristics in patient diagnosed with checkpoint myocarditis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ballas ZK. The 2018 Nobel Prize in Physiology or Medicine: an exemplar of bench to bedside in immunology. J Allergy Clin Immunol. 2018 Dec;142(6):1752–3.

    Article  PubMed  Google Scholar 

  5. Li Z, Song W, Rubinstein M, Liu D. Recent updates in cancer immunotherapy: a comprehensive review and perspective of the 2018 China Cancer Immunotherapy Workshop in Beijing. J Hematol Oncol. 2018; 11(1):142. Pubmed Central PMCID: PMC6303854 article. CONSENT FOR PUBLICATION: All authors have consented for publication. COMPETING INTERESTS: Wenru Song is an employee of Kira Pharmaceuticals. The authors declare that they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Epub 2018/12/24. eng.

  6. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. Jama. 1994;271(12):907–13.

    Article  CAS  PubMed  Google Scholar 

  7. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217–26.

    Article  CAS  PubMed  Google Scholar 

  9. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.

    Article  CAS  PubMed  Google Scholar 

  10. Balar AV, Kamat AM, de Wit R. Pembrolizumab monotherapy for high-risk, non-muscle invasive bladder cancer - authors’ reply. Lancet Oncol. 2021;22(9):e380.

    Article  PubMed  Google Scholar 

  11. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007 Jul;19(7):813–24.

    Article  CAS  PubMed  Google Scholar 

  12. Berger KN, Pu JJ. PD-1 pathway and its clinical application: a 20year journey after discovery of the complete human PD-1 gene. Gene. 2018;638:20–5.

    Article  CAS  PubMed  Google Scholar 

  13. Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother. 2016;12(11):2777–89.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Society AC. Immune checkpoint inhibitors and their side effects. Accessed at https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html on February 14, 2023.

  15. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4(5):336–47.

    Article  CAS  PubMed  Google Scholar 

  16. Cameron F, Whiteside G, Perry C. Ipilimumab: first global approval. Drugs. 2011;71(8):1093–104.

    Article  PubMed  Google Scholar 

  17. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18(1):155.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022; 19(4): 254-267. Pubmed Central PMCID: 8790946 Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer and Targovax, and receives research funding from BMS and Incyte. D.B.J. and J.J.M. have a patent pending for use of abatacept to reverse ICI toxicities. D.B.J. and J.M.B. have a patent pending for use of MHC II as a biomarker for ICI response. J.M.B. receives research funding from Genentech and Incyte. C.A.N. and J.J.M. declare no competing interests.

  19. •• Tan S, Day D, Nicholls SJ, Segelov E. Immune checkpoint inhibitor therapy in oncology: current uses and future directions: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022;4(5):579–97. Current state of the art review on immune checkpoint inhibitors.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Zhang L, Reynolds KL, Lyon AR, Palaskas N, Neilan TG. The evolving immunotherapy landscape and the epidemiology, diagnosis, and management of cardiotoxicity: JACC: CardioOncology primer. Cardio Oncol. 2021; 3(1): 35-47. Comprehensive review on the evolution of management of ICI-induced cardiotoxicities.

  22. Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZ, Thuny F, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J. 2020;41(18):1733–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229–361.

    Article  PubMed  Google Scholar 

  24. Pudil R, Mueller C, Čelutkienė J, Henriksen PA, Lenihan D, Dent S, et al. Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology. Eur J Heart Failure. 2020;22(11):1966–83.

    Article  CAS  Google Scholar 

  25. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68.

    Article  CAS  PubMed  Google Scholar 

  26. Thuny F, Alexandre J, Salem JE, Mirabel M, Dolladille C, Cohen-Solal A, et al. Management of immune checkpoint inhibitor-induced myocarditis: the French Working Group’s Plea for a pragmatic approach. JACC CardioOncol. 2021 Mar;3(1):157–61.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Patel RP, Parikh R, Gunturu KS, Tariq RZ, Dani SS, Ganatra S, et al. Cardiotoxicity of immune checkpoint inhibitors. Curr Oncol Rep. 2021;23(7):79.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Salem JE, Bretagne M, Abbar B, Leonard-Louis S, Ederhy S, Redheuil A, et al. Abatacept/ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of immune-checkpoint inhibitor myocarditis. Cancer Discov. 2023;23

  29. Zhang L, Reynolds KL, Lyon AR, Palaskas N, Neilan TG. The evolving immunotherapy landscape and the epidemiology, diagnosis, and management of cardiotoxicity: JACC: CardioOncology Primer. JACC Cardio Oncol. 2021 Mar;3(1):35–47.

    Article  Google Scholar 

  30. Suero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis with immune checkpoint inhibitor therapy: evidence, diagnosis, and management: JACC: CardioOncology State-of-the-Art Review. JACC Cardio Oncol. 2022;4(5):598–615. Evidence supporting association between ICI therapy and accelerated atherosclerosis.

    Article  Google Scholar 

  31. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018 Dec;19(12):1579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dolladille C, Akroun J, Morice PM, Dompmartin A, Ezine E, Sassier M, et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Europ Heart J. 2021;42(48):4964–77.

    Article  CAS  Google Scholar 

  33. Bar J, Markel G, Gottfried T, Percik R, Leibowitz-Amit R, Berger R, et al. Acute vascular events as a possibly related adverse event of immunotherapy: a single-institute retrospective study. Eur J Cancer. 2019 Oct;120:122–31.

    Article  CAS  PubMed  Google Scholar 

  34. Chitturi KR, Xu J, Araujo-Gutierrez R, Bhimaraj A, Guha A, Hussain I, et al. Immune checkpoint inhibitor-related adverse cardiovascular events in patients with lung cancer. JACC Cardio Oncol. 2019;1(2):182–92.

    Article  Google Scholar 

  35. Ganatra S, Dani SS, Yang EH, Zaha VG, Nohria A. Cardiotoxicity of T-cell antineoplastic therapies: JACC: CardioOncology Primer. JACC Cardio Oncol. 2022 Dec;4(5):616–23.

    Article  Google Scholar 

  36. Larson RC, Maus MV. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 2021 Mar;21(3):145–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Milone MC, Xu J, Chen SJ, Collins MA, Zhou J, Powell DJ Jr, et al. Engineering enhanced CAR T-cells for improved cancer therapy. Nat Cancer. 2021;2(8):780–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Einsele H, Borghaei H, Orlowski RZ, Subklewe M, Roboz GJ, Zugmaier G, et al. The BiTE (bispecific T-cell engager) platform: development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020;126(14):3192–201.

    Article  CAS  PubMed  Google Scholar 

  39. Wang S, Sun J, Chen K, Ma P, Lei Q, Xing S, et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med. 2021;19(1):140.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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(16):1509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    Article  PubMed  Google Scholar 

  44. Ali A, Boutjdir M, Aromolaran AS. Cardiolipotoxicity, inflammation, and arrhythmias: role for interleukin-6 molecular mechanisms. Front Physiol. 2018;9:1866.

    Article  PubMed  Google Scholar 

  45. 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 Trans Med. 2013;5(197):197ra03.

    Article  Google Scholar 

  46. 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 Trans. 2019;25(4):625–38.

    Article  CAS  Google Scholar 

  47. •• Ganatra S, Carver JR, Hayek SS, Ky B, Leja MJ, Lenihan DJ, et al. Chimeric antigen receptor T-cell therapy for cancer and heart: JACC Council Perspectives. J Am Coll Cardiol. 2019;74(25):3153–63. Expert opinion on cardiovascular evaluation and management of cytokine release syndrome with chimeric antigen receptor T-cell therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Alvi RM, Frigault MJ, Fradley MG, Jain MD, Mahmood SS, Awadalla M, et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). J Am Coll Cardiol. 2019;74(25):3099–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lefebvre B, Kang Y, Smith AM, Frey NV, Carver JR, Scherrer-Crosbie M. Cardiovascular effects of CAR T cell therapy: a retrospective study. JACC Cardio Oncol. 2020;2(2):193–203.

    Article  Google Scholar 

  50. • Salem JE, Ederhy S, Lebrun-Vignes B, Moslehi JJ. Cardiac events associated with chimeric antigen receptor T-cells (CAR-T): a VigiBase perspective. J Am Coll Cardiol. 2020;75(19):2521–3. Supportive data on the cardiovascular events with chimeric antigen receptor T-cell therapy.

    Article  CAS  PubMed  Google Scholar 

  51. Ganatra S, Redd R, Hayek SS, Parikh R, Azam T, Yanik GA, 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.

    Article  CAS  PubMed  Google Scholar 

  52. Apel A, Ofran Y, Wolach O, Shimony S, Ram R, Levi I, et al. Safety and efficacy of blinatumomab: a real world data. Ann Hematol. 2020 Apr;99(4):835–8.

    Article  CAS  PubMed  Google Scholar 

  53. Fradley MG, Damrongwatanasuk R, Chandrasekhar S, Alomar M, Kip KE, Sarnaik AA. Cardiovascular toxicity and mortality associated with adoptive cell therapy and tumor-infiltrating lymphocytes for advanced stage melanoma. J Immunother. 2021;44(2):86–9.

    Article  CAS  PubMed  Google Scholar 

  54. Cobb DA, Lee DW. Cytokine release syndrome biology and management. Cancer J. 2021;27(2):119–25.

    Article  CAS  PubMed  Google Scholar 

  55. Ganatra S, Parikh R, Neilan TG. Cardiotoxicity of immune therapy. Cardiol Clin. 2019;37(4):385–97.

    Article  PubMed  Google Scholar 

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Correspondence to Carrie Lenneman MD, MSCI.

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Patel, M., Hudson, O., Han, J. et al. Update on Immunotherapy Cardiotoxicity: Checkpoint Inhibitors, CAR T, and Beyond. Curr. Treat. Options in Oncol. 24, 1489–1503 (2023). https://doi.org/10.1007/s11864-023-01130-y

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