Миокардиты, ассоциированные с иммунной противоопухолевой терапией Checkpoint-ингибиторами

Прогресс в консервативном лечении злокачественных новообразований сопряжен с появлением проблемы отдаленных последствий лекарственной терапии у пациентов с успешно пролеченной онкологией. Checkpoint-ингибиторы — группа противоопухолевых препаратов, относящаяся к иммунотерапии. Среди сердечно-сосудистых наиболее жизнеугрожающим осложнением являются Checkpoint-ассоциированные миокардиты. Данный обзор рассматривает вопросы механизмов развития осложнений иммунной терапии, эпидемиологии и особенностей течения Checkpoint-ассоциированных миокардитов.

1. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol [Internet]. 2018;62(April):29–39. Available from: https://doi.org/10.1016/j.intimp.2018.06.001

2. Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol [Internet]. 2019;20(9):1239–51. Available from: http://dx.doi.org/10.1016/S1470-2045(19)30388-2

3. Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–30.

4. Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, et al. Fiveyear outcomes from the randomized, phase iii trials checkmate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer. J Clin Oncol. 2021;39(7):723–33.

5. Tjulandin S, Demidov L, Moiseyenko V, Protsenko S, Semiglazova T, Odintsova S, et al. Novel PD-1 inhibitor prolgolimab: expanding non-resectable/ metastatic melanoma therapy choice. Eur J Cancer [Internet]. 2021;149:222–32. Available from: https://doi.org/10.1016/j.ejca.2021.02.030

6. Mangan BL, McAlister RK, Balko JM, Johnson DB, Moslehi JJ, Gibson A, et al. Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy. Br J Clin Pharmacol. 2020;86(9):1778–89.

7. Raschi E, Diemberger I, Poluzzi E, De Ponti F. Reporting of immune checkpoint inhibitor-associated myocarditis. Lancet [Internet]. 2018;392(10145):383. Available from: http://dx.doi.org/10.1016/S0140-6736(18)31549-6

8. 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.

9. Cho J, Kim HS, Ku BM, Choi Y La, Cristescu R, Han J, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: An open-label phase II trial. J Clin Oncol. 2019;37(24):2162–70.

10. Jain P, Gutierrez Bugarin J, Guha A, Jain C, Patil N, Shen T, et al. Cardiovascular adverse events are associated with usage of immune checkpoint inhibitors in real-world clinical data across the United States. ESMO Open [Internet]. 2021;6(5):100252. Available from: https://doi.org/10.1016/j.esmoop.2021.100252

11. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science (80- ). 2011;331(6024):1565–70.

12. Radoja S, Rao TD, Hillman D, Frey AB. Mice Bearing Late-Stage Tumors Have Normal Functional Systemic T Cell Responses In Vitro and In Vivo. J Immunol. 2000;164(5):2619–28.

13. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: A moving target in immunotherapy. Blood. 2018;131(1):58–67.

14. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science (80- ). 1996;271(5256):1734–6.

15. Ribas A, Kefford R, Marshall MA, Punt CJA, Haanen JB, Marmol M, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22.

16. Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33(10):1191–6.

17. Sosman JA, Haanen JB, Gonzalez R, Robert C, Ph D, Schadendorf D, et al. New england journal. 2010;711–23.

18. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.

19. Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1-deficient mice: Implication of PD-1 as a negative regulator for B cell responses. Int Immunol. 1998;10(10):1563–72.

20. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motifcarrying immunoreceptor. Immunity. 1999;11(2):141– 51.

21. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (80- ). 2001;291(5502):319–22.

22. Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci [Internet]. 2015;36(9):587–95. Available from: http://dx.doi.org/10.1016/j.tips.2015.06.005

23. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254–67.

24. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):1–11.

25. Quach HT, Dewan AK, Davis EJ, Ancell KK, Fan R, Ye F, et al. Association of Anti-Programmed Cell Death 1 Cutaneous Toxic Effects with Outcomes in Patients with Advanced Melanoma. JAMA Oncol. 2019;5(6):906–8.

26. Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, et al. Association between Immune-Related Adverse Events and RecurrenceFree Survival among Patients with Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2020;6(4):519–27.

27. Flatz L, Berner F, Bomze D, Diem S, Ali OH, Fässler M, et al. Association of Checkpoint InhibitorInduced Toxic Effects with Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer. JAMA Oncol. 2019;5(7):1043–7.

28. Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockadeinduced colitis. Nat Commun [Internet]. 2016;7:1–8. Available from: http://dx.doi.org/10.1038/ncomms10391

29. Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen WS, Derosa L, et al. Gut microbiota signatures are associated with toxicity to combined CTLA4 and PD-1 blockade. Nat Med. 2021;27(8):1432–41.

30. Wei SC, Meijers WC, Axelrod ML, Anang NAS, Screever M, Wescott EC, et al. HHS Public Access. 2021;11(3):614–25.

31. Baban B, Liu JY, Qin X, Weintraub NL, Mozaffari MS. Upregulation of Programmed death-1 and its ligand in cardiac injury models: Interaction with GADD153. PLoS One. 2015;10(4):1–17.

32. Kushnareva E, Kushnarev V, Artemyeva A, Mitrofanova L, Moiseeva O. Myocardial PD-L1 Expression in Patients With Ischemic and Non-ischemic Heart Failure. Front Cardiovasc Med. 2022;8(January):1–8.

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

34. Кушнарева Е.А., Моисеева О.М. Миокардиты, ассоциированные с терапией ингибиторами контрольных точек: систематический анализ клинических случаев. Российский кардиологический журнал. 2020;25(11):3910.

35. Puzanov I, Subramanian P, Yatsynovich YV., Jacobs DM, Chilbert MR, Sharma UC, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer. 2021;9(6):1–11.