russjcardiolРоссийский кардиологический журналRussian Journal of Cardiology1560-40712618-7620«SILICEA-POLIGRAF» LLC10.15829/1560-4071-2020-3910russjcardiol-3910Research ArticleОБЗОРЫ ЛИТЕРАТУРЫREVIEWМиокардиты, ассоциированные с терапией ингибиторами контрольных точек: систематический анализ клинических случаевImmune checkpoint inhibitor myocarditis: a systematic case studyhttps://orcid.org/0000-0002-8723-2765КушнареваЕ. А.KushnarevaE. A.

Врач-кардиолог, аспирант.Санкт-Петербург.

St. Petersburg.

Kushnareva.cardio@gmail.comhttps://orcid.org/0000-0002-7817-3847МоисееваО. М.MoiseevaO. M.

Доктор медицинских наук, главный научный сотрудник НИО некоронарогенных заболеваний сердца, директор Института сердца и сосудов.Санкт-Петербург.

St. Petersburg.

moiseeva.cardio@gmail.comНациональный Медицинский Исследовательский Центр им. В.А. Алмазова Минздрава РоссииРоссияAlmazov National Medical Research CenterRussian Federation202006062020251139103910Copyright © Кушнарева Е.А., Моисеева О.М., 20202020Кушнарева Е.А., Моисеева О.М.Kushnareva E.A., Moiseeva O.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://russjcardiol.elpub.ru/jour/article/view/3910

Миокардиты относятся к жизнеугрожающим осложнениям противоопухолевой терапии моноклональными антителами, ингибирующими контрольные точки иммунитета. За последние 10 лет препараты данной группы стали использоваться в лечении широкого спектра гематологических заболеваний и солидных опухолей. На фоне неуклонно растущей продолжительности жизни онкологических больных на передний план все чаще выходят проблемы, связанные с развитием осложнений терапии злокачественных новообразований. С 2016г в научной литературе появляются публикации, посвященные случаям развития аутоиммунных миокардитов на фоне терапии ингибиторами контрольных точек (ИКТ), среди которых достаточно много одноцентровых ретроспективных и наблюдательных исследований. Вместе с тем, проблема диагностики и лечения аутоиммунных миокардитов, ассоциированных с применением ИКТ, по-прежнему остается нерешенной. В данной работе представлен обзор литературы по проблеме ИКТ-ассоциированных миокардитов, а также результаты систематического анализа публикаций из поисковой базы данных PubMed.

Myocarditis is a life-threatening complication of immune checkpoint inhibitor therapy. Over the past ten years, drugs in this group have been used in the treatment of a wide range of hematological diseases and solid tumors. With steadily growing life expectancy of cancer patients, problems associated with treatment complications are increasingly coming to the fore. Since 2016, publications have appeared on cases of autoimmune myocarditis during checkpoint inhibitor therapy (CIT), among which there are quite a few single-center retrospective and observational studies. At the same time, the problem of diagnosis and treatment of immune checkpoint inhibitor myocarditis remains unresolved.This paper presents a review on the problem of immune checkpoint inhibitor myocarditis, as well as the results of a systematic analysis of PubMed database publications.

ингибиторы контрольных точекмиокардитыкардиотоксичностьcheckpoint inhibitorsmyocarditiscardiotoxicityReferencesHargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: 15. An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39. doi:10.1016/j.intimp.2018.06.001.Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: 15. An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39. doi:10.1016/j.intimp.2018.06.001.Bertrand A, Kostine M, Barnetche T, et al. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med . 2015;13:211. doi:10.1186/s12916-015-0455-8.Bertrand A, Kostine M, Barnetche T, et al. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med . 2015;13:211. doi:10.1186/s12916-015-0455-8.Ganatra S, Neilan TG. Immune Checkpoint Inhibitor-Associated Myocarditis. The Onco- 17. logist. 2018;23:879-86. doi:10.1634/theoncologist.2018-0130.Ganatra S, Neilan TG. Immune Checkpoint Inhibitor-Associated Myocarditis. The Onco- 17. logist. 2018;23:879-86. doi:10.1634/theoncologist.2018-0130.Gallegos C, Rottmann D, Nguyen VQ, et al. Myocarditis with checkpoint inhibitor immunotherapy: case report of late gadolinium enhancement on cardiac magnetic 18. resonance with pathology correlate. Eur Heart J Case Rep. 2019;3(1):yty149. doi:10.1093/ehjcr/yty149.Gallegos C, Rottmann D, Nguyen VQ, et al. Myocarditis with checkpoint inhibitor immunotherapy: case report of late gadolinium enhancement on cardiac magnetic 18. resonance with pathology correlate. Eur Heart J Case Rep. 2019;3(1):yty149. doi:10.1093/ehjcr/yty149.McDowall LM, Fernando SL, Ange N, et al. Immune Checkpoint Inhibitor Mediated 19. myocarditis and ventricular tachycardia storm. HeartRhythm Case Rep. 2019;5(10):497-500. doi:10.1016/j.hrcr.2019.06.006.McDowall LM, Fernando SL, Ange N, et al. Immune Checkpoint Inhibitor Mediated 19. myocarditis and ventricular tachycardia storm. HeartRhythm Case Rep. 2019;5(10):497-500. doi:10.1016/j.hrcr.2019.06.006.Lyon AR, Yousaf N, Battisti NML, et al. Immune checkpoint inhibitors and cardiovascular 20. toxicity. Lancet Oncol. 2018;19:447-58. doi:10.1016/S1470-2045(18)30457-1.Lyon AR, Yousaf N, Battisti NML, et al. Immune checkpoint inhibitors and cardiovascular 20. toxicity. Lancet Oncol. 2018;19:447-58. doi:10.1016/S1470-2045(18)30457-1.Chen D. S., Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity. 2013;39:1-10. doi:10.1016/j.immuni.2013.07.012. 21.Chen D. S., Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity. 2013;39:1-10. doi:10.1016/j.immuni.2013.07.012. 21.Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/blood-2017-06-741033.Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/blood-2017-06-741033.Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing 22. tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616-22. doi:10.1200/JCO.2012.44.6112.Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing 22. tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616-22. doi:10.1200/JCO.2012.44.6112.Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in pa- 23. tients with metastatic melanoma. N Engl J Med. 2010;363:711-23. doi:10.1056/NEJMoa1003466.Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in pa- 23. tients with metastatic melanoma. N Engl J Med. 2010;363:711-23. doi:10.1056/NEJMoa1003466.Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients with 24. advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33:1191-6. doi:10.1200/JCO.2014.56.6018.Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients with 24. advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33:1191-6. doi:10.1200/JCO.2014.56.6018.Chinai JM, Janakiram M, Chen F, et al. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci. 2015;36:587-95. doi:10.1016/j.tips.2015.06.005.Chinai JM, Janakiram M, Chen F, et al. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci. 2015;36:587-95. doi:10.1016/j.tips.2015.06.005.Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2017;377(14):1345-56. doi:10.1056/NEJMoa1709684.Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2017;377(14):1345-56. doi:10.1056/NEJMoa1709684.Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European Journal of Cancer. 2016;54:139-48. doi:10.1016/j.ejca.2015.11.016.Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European Journal of Cancer. 2016;54:139-48. doi:10.1016/j.ejca.2015.11.016.Voskens CJ, Goldinger SM, Loquai 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:e53745. doi:10.1371/journal.pone.0053745.Voskens CJ, Goldinger SM, Loquai 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:e53745. doi:10.1371/journal.pone.0053745.Yun S, Vincelette ND, Mansour I, et al. Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare butlife threatening complication. Case Rep Oncol Med. 2015;2015:1-5. doi:10.1155/2015/794842.Yun S, Vincelette ND, Mansour I, et al. Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare butlife threatening complication. Case Rep Oncol Med. 2015;2015:1-5. doi:10.1155/2015/794842.Frigeri M, Meyer P, Banfi C, et al. Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists. Case Rep Canadian Journal of Cardiology. 2018;34:92. e1-92.e3. doi:10.1016/j.cjca.2017.09.025.Frigeri M, Meyer P, Banfi C, et al. Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists. Case Rep Canadian Journal of Cardiology. 2018;34:92. e1-92.e3. doi:10.1016/j.cjca.2017.09.025.Geisler BP, Raad RA, Esaian D, et al. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer. 2015;3:4. doi:10.1186/s40425-015-0048-2.Geisler BP, Raad RA, Esaian D, et al. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer. 2015;3:4. doi:10.1186/s40425-015-0048-2.Ederhy S, Cautela J, Ancedy Y, et al. Takotsubo-like syndrome in cancer patients treated with immune checkpoint inhibitors. JACC Cardiovasc Imaging 2018;11(8):1187-90. doi:10.1016/j.jcmg.2017.11.036.Ederhy S, Cautela J, Ancedy Y, et al. Takotsubo-like syndrome in cancer patients treated with immune checkpoint inhibitors. JACC Cardiovasc Imaging 2018;11(8):1187-90. doi:10.1016/j.jcmg.2017.11.036.Hu YB, Zhang Q, Li HJ, et al. Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res. 2017;6:8-20. doi:10.21037/tlcr.2017.12.10.Hu YB, Zhang Q, Li HJ, et al. Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res. 2017;6:8-20. doi:10.21037/tlcr.2017.12.10.Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. Journal of Clinical Oncology. 2019;37(24):2162-70. doi:10.1200/JCO.2017.77.3184.Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. Journal of Clinical Oncology. 2019;37(24):2162-70. doi:10.1200/JCO.2017.77.3184.Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749-55. doi:10.1056/NEJMoa1609214.Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749-55. doi:10.1056/NEJMoa1609214.Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933. doi:10.1016/S0140-6736(18)30533-6.Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933. doi:10.1016/S0140-6736(18)30533-6.Liu E, Guha A, Jia K, et al. Cardiogenic shock in a patient being treated with atezolizumab for metastatic non-small cell lung cancer. Lung Cancer. 2017;114:106-107. doi:10.1016/j.lungcan.2017.07.028.Liu E, Guha A, Jia K, et al. Cardiogenic shock in a patient being treated with atezolizumab for metastatic non-small cell lung cancer. Lung Cancer. 2017;114:106-107. doi:10.1016/j.lungcan.2017.07.028.Laubli H, Balmelliet C, Bossard M, et al. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. Journal for ImmunoTherapy of Cancer. 2015;3:11. doi:10.1186/s40425-015-0057-1.Laubli H, Balmelliet C, Bossard M, et al. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. Journal for ImmunoTherapy of Cancer. 2015;3:11. doi:10.1186/s40425-015-0057-1.Fessas P, Possamai LA, Clark J, et al. Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms. Immunology. 2020;159(2):167-77. doi:10.1111/imm.13141.Fessas P, Possamai LA, Clark J, et al. Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms. Immunology. 2020;159(2):167-77. doi:10.1111/imm.13141.Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity. 2020;52(1):17-35. doi:10.1016/j.immuni.2019.Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity. 2020;52(1):17-35. doi:10.1016/j.immuni.2019.

The authors declare that there are no conflicts of interest present.