Adverse reactions of immune checkpoint inhibitors

Our objective was to consider the adverse reactions associated with usage of immune checkpoint inhibitors (ICI). The literature review includes a search for scientific papers from the databases PubMed, Embase, eLibrary, CyberLeninka and Web of Science, CNKI and MEDLINE by the following keywords: “immune checkpoint inhibitors”, “immune-mediated adverse events”, “immune checkpoints”, “antitumor therapy”, “immune system”, “side effects”. Over the past decade, the discovery of immune checkpoints followed by development of appropriate inhibitors have provided breakthrough advances in cancer treatment. The ICI-based therapy has opened a new era of antitumor treatment and has really improved clinical prognosis in the cancer patients. The antitumor effect of ICI is based on the blockade of CTLA-4 and PD-1/PD-L1 signaling pathways, thus promoting antitumor activity of lymphocytes. However, inhibition of immune checkpoints may also provoke dysregulation of immune responses and appearance of a new type of adverse reactions associated with changed activity of immunocompetent cells in the host organism, i.e., immunerelated side effects (irAEs). The most common side effects concern skin, hepatobiliary, and endocrine systems. Of note, the frequency of adverse events affecting cardiovascular and nervous systems is relatively low among total number of cases, but the consequences lead to disability of patients and are often fatal. Currently, hormonal drugs, immunosuppressants, and cytokine antagonists are mainly used to treat adverse events of ICI. However, these treatments may cause suppression of the immune system in patients, thereby weakening their antitumor immune response. There are still many unresolved issues related to irAEs, such as unclear mechanisms and biomarkers, tools for early detection of these adverse events, and development of more advanced individual treatments for such complications. The researchers believe that the above problems can be solved with wider use of immunotherapy, deeper studies on ICI and related adverse immune reactions, thus enabling full-scale implementation of ICI potential in anticancer therapy and improving clinical outcomes. Accordingly, the topic is quite relevant and requires close attention from practitioners and scientists.

1. Akturk H.K., Kahramangil D., Sarwal A., Hoffecker L., Murad M.H., Michels A.W. Immune checkpoint inhibitor-induced type 1 diabetes: a systematic review and meta-analysis. Diabetes Med., 2019, Vol. 36, pp. 1075-1081.

2. Andrade Vila J.H., da Silva J.P., Guilhen C.J. Even low dose of mycophenolate mofetil in a mother recipient of heart transplant can seriously damage the fetus. Transplantation, 2008, Vol. 86, pp. 369-370.

3. Arnaud-Coffin P., Maillet D., Gan H.K. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int. J. Cancer, 2019, Vol. 145, pp. 639-648.

4. Ascierto P.A., Del V.M., Robert C., Mackiewicz A., Chiarion-Sileni V., Arance A. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol., 2017, Vol. 18, pp. 611-622.

5. Barclay J., Creswell J., Leon J. Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway. Arch. Esp. Urol., 2018, Vol. 71, pp. 393-399.

6. Bergqvist V., Hertervig E., Gedeon P., Kopljar M., Griph H., Kinhult S. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol. Immunother., 2017, Vol. 66, pp. 581-592.

7. Blair H.A., Deeks E.D. Abatacept: a review in rheumatoid arthritis. Drugs, 2017, Vol. 77, pp. 1221-1233.

8. Bucheit A.D., Hardy J.T., Szender J.B. Conception and viable twin pregnancy in a patient with metastatic melanoma while treated with CTLA-4 and PD-1 checkpoint inhibition. Melanoma Res., 2020, Vol. 30, pp. 423-425.

9. Burotto M., Gormaz J.G., Samtani S. Viable pregnancy in a patient with metastatic melanoma treated with double checkpoint immunotherapy. Semin. Oncol., 2018, Vol. 45, pp. 164-169.

10. Butterfield L.H., Kaufman H.L., Johnson D.H. SITC’s Guide to Managing Immunotherapy Toxicity, 1 edn. New York: Springer Publishing Company, 2019.

11. Campochiaro C., Farina N., Tomelleri A., Ferrara R., Lazzari C., De Luca G. Tocilizumab for the treatment of immune-related adverse events: a systematic literature review and a multicentre case series. Eur. J. Intern. Med., 2021, Vol. 93, pp. 87-94.

12. Cardinale D., Sandri M.T., Colombo A., Colombo N., Boeri M., Lamantia G., Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation, 2004, Vol. 109, pp. 2749-2754.

13. Chauvet E., Blanchard R.G., Manel V., Delmont E., Boucraut J., Garcia-Tarodo S. Autoantibodies to a nodal isoform of neurofascin in pediatric chronic inflammatory demyelinating polyneuropathy. Child Neurol. Open, 2023, Vol. 10, 2329048X221149618X. doi: 10.1177/2329048X221149618.

14. Chera A., Stancu A.L., Bucur O. Thyroid-related adverse events induced by immune checkpoint inhibitors. Front. Endocrinol. (Lausanne), 2022, Vol. 13, 1010279. doi: 10.3389/fendo.2022.1010279.

15. Chocarro L., Blanco E., Zuazo M., Arasanz H., Bocanegra A., Fernandez-Rubio L. Understanding LAG-3 signaling. Int. J. Mol. Sci., 2021, Vol. 22, no. 10, 5282. doi: 10.3390/ijms22105282.

16. Collins L.K., Chapman M.S., Carter J.B., Samie F.H. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr. Probl. Cancer, 2017, Vol. 41, pp. 125-128.

17. Common terminology criteria for adverse events (CTCAE) V5. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

18. Couey M.A., Bell R.B., Patel A.A. Delayed immune-related events (dire) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance. J. Immunother. Cancer, 2019, Vol. 7, 165. doi: 10.1186/s40425-019-0645-6.

19. Cuyas E., Verdura S., Martin-Castillo B., Alarcon T., Lupu R., Bosch-Barrera J. Tumor cell-intrinsic immunometabolism and precision nutrition in cancer immunotherapy. Cancers (Basel), 2020, Vol. 12, no. 7, 1757. doi: 10.3390/cancers12071757.

20. Cuzzubbo S., Javeri F., Tissier M., Roumi A., Barlog C., Doridam J. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur. J. Cancer, 2017, Vol. 73, pp. 1-8.

21. Davies M., Duffield E.A. Duffield EA: safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events. Immunotargets Ther., 2017, Vol. 6, pp. 51-71.

22. de Filette J., Andreescu C.E., Cools F., Bravenboer B., Velkeniers B. A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Horm. Metab. Res., 2019, Vol. 51, pp. 145-156.

23. Drobni Z.D., Alvi R.M., Taron J., Zafar A., Murphy S.P., Rambarat P.K. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation, 2020, Vol. 142, pp. 2299-2311.

24. Duma N., Lambertini M. It is time to talk about fertility and immunotherapy. Oncologist, 2020, Vol. 25, pp. 277-278.

25. Ellis S.R., Vierra A.T., Millsop J.W., Lacouture M.E., Kiuru M. Dermatologic toxicities to immune checkpoint inhibitor therapy: a review of histopathologic features. J. Am. Acad. Dermatol., 2020, Vol. 83, pp. 1130-1143.

26. Esfahani K., Miller W.J. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N. Engl. J. Med., 2017, Vol. 376, pp. 1989-1991.

27. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary, 2016, Vol. 19, pp. 82-92.

28. Farshidpour M., Hutson W. Immune checkpoint inhibitors induced hepatotoxicity; gastroenterologists’ perspectives. Middle East J. Dig. Dis., 2022, Vol. 14, pp. 244-253.

29. Geisler A.N., Phillips G.S., Barrios D.M., Wu J., Leung D., Moy A.P. Immune checkpoint inhibitor-related dermatologic adverse events. J. Am. Acad. Dermatol., 2020, Vol. 83, pp. 1255-1268.

30. Gupta A., de Felice K.M., Loftus E.J., Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment. Pharmacol. Ther., 2015, Vol. 42, pp. 406-417.

31. Haanen J., Obeid M., Spain L., Carbonnel F., Wang Y., Robert C. Management of toxicities from immunotherapy: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann. Oncol., 2022, Vol. 33, pp. 1217-1238.

32. Hargadon K.M., Johnson C.E., Williams C.J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol., 2018, Vol. 62, pp. 29-39.

33. Haugh A.M., Probasco J.C., Johnson D.B. Neurologic complications of immune checkpoint inhibitors. Expert Opin. Drug Saf., 2020, Vol. 19, pp. 479-488.

34. Haslam A., Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw. Open, 2019, Vol. 2, e192535. doi: 10.1001/jamanetworkopen.2019.2535.

35. Hemon P., Jean-Louis F., Ramgolam K., Brignone C., Viguier M., Bachelez H. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol., 2011, Vol. 186, pp. 5173-5183.

36. Herbst R.S., Baas P., Kim D.W., Felip E., Perez-Gracia J.L., Han J.Y. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016, Vol. 387, pp. 1540-1550.

37. Horisberger A., La Rosa S., Zurcher J.P., Zimmermann S., Spertini F., Coukos G. A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy. J. Immunother. Cancer, 2018, Vol. 6, 156. doi: 10.1186/s40425-018-0481-0.

38. Hosseini A., Gharibi T., Marofi F., Babaloo Z., Baradaran B. CTLA-4: from mechanism to autoimmune therapy. Int. Immunopharmacol., 2020, Vol. 80, 106221. doi: 10.1016/j.intimp.2020.106221.

39. Hurwitz A.A., Sullivan T.J., Sobel R.A., Allison J.P. Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice. Proc. Natl. Acad. Sci. U.S.A., 2002, Vol. 99, pp. 3013-3017.

40. Jaworska K., Ratajczak J., Huang L., Whalen K., Yang M., Stevens B.K. Both PD-1 ligands protect the kidney from ischemia reperfusion injury. J. Immunol., 2015, Vol. 194, pp. 325-333.

41. Jiang X., Wang J., Deng X., Xiong F., Ge J., Xiang B. Role of the tumor microenvironment in PD-L1/PD-1- mediated tumor immune escape. Mol. Cancer, 2019, Vol. 18, 10. doi: 10.1186/s12943-018-0928-4.

42. Kang C.W., Dutta A., Chang L.Y., Mahalingam J., Lin Y.C., Chiang J.M. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Sci. Rep., 2015, Vol. 5, 15659. doi: 10.1038/srep15659.

43. Kostine M., Finckh A., Bingham C.O., Visser K., Leipe J., Schulze-Koops H. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann. Rheum. Dis., 2021, Vol. 80, pp. 36-48.

44. Kouo T., Huang L., Pucsek A.B., Cao M., Solt S., Armstrong T. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol. Res., 2015, Vol. 3, pp. 412-423.

45. Laino A.S., Woods D., Vassallo M., Qian X., Tang H., Wind-Rotolo M. Serum interleukin-6 and c-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition. J. Immunother. Cancer, 2020, Vol. 8, no. 1, e000842. doi: 10.1136/jitc-2020-000842.

46. Larkin J., Chmielowski B., Lao C.D., Hodi F.S., Sharfman W., Weber J. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist, 2017, Vol. 22, pp. 709-718.

47. Le R.Q., Li L., Yuan W., Shord S.S., Nie L., Habtemariam B.A. FDA Approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist, 2018, Vol. 23, pp. 943-947.

48. Li B., Chan H.L., Chen P. Immune checkpoint inhibitors: basics and challenges. Curr. Med. Chem., 2019, Vol. 26, pp. 3009-3025.

49. Liao D., Wang M., Liao Y., Li J., Niu T. A review of efficacy and safety of checkpoint inhibitor for the treatment of acute myeloid leukemia. Front. Pharmacol., 2019, Vol. 10, 609. doi: 10.3389/fphar.2019.00609.

50. Liao W., Zheng H., Wu S., Zhang Y., Wang W., Zhang Z. The systemic activation of programmed death 1-PD-L1 axis protects systemic lupus erythematosus model from nephritis. Am. J. Nephrol., 2017, Vol. 46, pp. 371-379.

51. Lim S., Phillips J.B., Madeira D.S., Zhou M., Fodstad O., Owen L.B. Interplay between immune checkpoint proteins and cellular metabolism. Cancer Res., 2017, Vol. 77, pp. 1245-1249.

52. Lin J.S., Wang D.Y., Mamlouk O. Glass WF, Abdelrahim M, Yee C, Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab. J. Immunother. Cancer, 2020, Vol. 8, no. 2, e001287. doi: 10.1136/jitc-2020-001287.

53. Linsley P.S., Nadler S.G. The clinical utility of inhibiting CD28-mediated costimulation. Immunol. Rev., 2009, Vol. 229, pp. 307-321.

54. Liu X., Wu W., Fang L., Liu Y., Chen W. TNF-alpha inhibitors and other biologic agents for the treatment of immune checkpoint inhibitor-induced myocarditis. Front. Immunol., 2022, Vol. 13, 922782. doi: 10.3389/fimmu.2022.922782.

55. Lythgoe M.P., Liu D., Annels N.E., Krell J., Frampton A.E. Gene of the month: lymphocyte-activation gene 3 (LAG-3). J. Clin. Pathol., 2021, Vol. 74, pp. 543-547.

56. Ma B., Anandasabapathy N. Immune checkpoint blockade and skin toxicity pathogenesis. J. Invest. Dermatol., 2022, Vol. 142, pp. 951-959.

57. Manos K., Chong G., Keane C., Lee S.T., Smith C., Churilov L. Immune priming with avelumab and rituximab prior to r-CHOP in diffuse large b-cell lymphoma: the phase II AvR-CHOP study. Leukemia, 2023, Vol. 37, no. 5, pp. 1092-1102.

58. Mao X., Ou M.T., Karuppagounder S.S., Kam T.I., Yin X., Xiong Y. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science, 2016, Vol. 353, no. 6307, aah3374. doi: 10.1126/science. aah3374.

59. Marin-Acevedo J.A., Kimbrough E.O., Lou Y. Next generation of immune checkpoint inhibitors and beyond. J. Hematol. Oncol., 2021, Vol. 14, 45. doi: 10.1186/s13045-021-01056-8.

60. Marini A., Bernardini A., Gigli G.L., Valente M., Muniz-Castrillo S., Honnorat J. Neurologic adverse events of immune checkpoint inhibitors: a systematic review. Neurology, 2021, Vol. 96, pp. 754-766.

61. Merlob P., Stahl B., Klinger G. Tetrada of the possible mycophenolate mofetil embryopathy: a review. Reprod. Toxicol., 2009, Vol. 28, pp. 105-108.

62. Merola J.F., Landewe R., McInnes I.B., Mease P.J., Ritchlin C.T., Tanaka Y. Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-alpha inhibitors: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2023, Vol. 401, pp. 38-48.

63. Michel L., Helfrich I., Hendgen-Cotta U.B., Mincu R.I., Korste S., Mrotzek S.M. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur. Heart J., 2022, Vol. 43, pp. 316-329.

64. Moi L., Bouchaab H., Mederos N., Nguyen-Ngoc T., Perreau M., Fenwick C. Personalized cytokine-directed therapy with tocilizumab for refractory immune checkpoint inhibitor-related cholangiohepatitis. J. Thorac. Oncol., 2021, Vol. 16, pp. 318-326.

65. Muley S.A., Jacobsen B., Parry G., Usman U., Ortega E., Walk D. Rituximab in refractory chronic inflammatory demyelinating polyneuropathy. Muscle Nerve, 2020, Vol. 61, pp. 575-579.

66. Nadelmann E.R., Yeh J.E., Chen S.T. Management of cutaneous immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors: a systematic review. JAMA Oncol., 2022, Vol. 8, pp. 130-138.

67. Nastoupil L.J., Chin C.K., Westin J.R., Fowler N.H., Samaniego F., Cheng X. Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma. Blood Adv., 2022, Vol. 6, pp. 1143-1151.

68. Olsen T.A., Zhuang T.Z., Caulfield S., Martini D.J., Brown J.T., Carthon B.C. Advances in knowledge and management of immune-related adverse events in cancer immunotherapy. Front. Endocrinol. (Lausanne), 2022, Vol. 13, 779915. doi: 10.3389/fendo.2022.779915.

69. Patil P.A., Zhang X. Pathologic manifestations of gastrointestinal and hepatobiliary injury in immune checkpoint inhibitor therapy. Arch. Pathol. Lab. Med., 2021, Vol. 145, pp. 571-582.

70. Qi Y., Chen L., Liu Q., Kong X., Fang Y., Wang J. Research progress concerning dual blockade of lymphocyteactivation gene 3 and programmed death-1/Programmed death-1 ligand-1 blockade in cancer immunotherapy: preclinical and clinical evidence of this potentially more effective immunotherapy strategy. Front. Immunol., 2020, Vol. 11, 563258. doi: 10.3389/fimmu.2020.

71. Qian W., Zhao M., Wang R., Li H. Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target. J. Hematol. Oncol., 2021, Vol. 14, 147. doi: 10.1186/s13045-021-01161-8.

72. Quach H.T., Johnson D.B., LeBoeuf N.R., Zwerner J.P., Dewan A.K. Cutaneous adverse events caused by immune checkpoint inhibitors. J. Am. Acad. Dermatol., 2021, Vol. 85, pp. 956-966.

73. Rajha E., Chaftari P., Kamal M., Maamari J., Chaftari C., Yeung S.J. Gastrointestinal adverse events associated with immune checkpoint inhibitor therapy. Gastroenterol. Rep. (Oxf.), 2020, Vol. 8, pp. 25-30.

74. Reddy H.G., Schneider B.J., Tai A.W. Immune checkpoint inhibitor-associated colitis and hepatitis. Clin. Transl. Gastroenterol., 2018, Vol. 9, 180. doi: 10.1038/s41424-018-0049-9.

75. Reich K., Warren R.B., Lebwohl M., Gooderham M., Strober B., Langley R.G. Bimekizumab versus secukinumab in plaque psoriasis. N. Engl. J. Med., 2021, Vol. 385, pp. 142-152.

76. Remash D., Prince D.S., McKenzie C., Strasser S.I., Kao S., Liu K. Immune checkpoint inhibitor-related hepatotoxicity: a review. World J. Gastroenterol., 2021, Vol. 27, pp. 5376-5391.

77. Ribas A., Wolchok J.D. Cancer immunotherapy using checkpoint blockade. Science, 2018, Vol. 359, pp. 1350-1355.

78. Roberto I., Chiara C., Emanuela F., Davide B., Mario R., Antonio B.P. Renal toxicity in patients treated with anti-Pd-1 targeted agents for solid tumors. J. Onco-Nephrol., 2017, Vol. 1, no. 2, pp. 132-142.

79. Rocha M., Correia S.J., Salgado M., Araujo A., Pedroto I. Management of gastrointestinal toxicity from immune checkpoint inhibitor. GE Port. J. Gastroenterol., 2019, Vol. 26, pp. 268-274.

80. Rossi J.F., Lu Z.Y., Jourdan M., Klein B. Interleukin-6 as a therapeutic target. Clin. Cancer Res., 2015, Vol. 21, pp. 1248-1257.

81. Ruggiero A., Potestio L., Camela E., Fabbrocini G., Megna M. Bimekizumab for the treatment of psoriasis: a review of the current knowledge. Psoriasis (Auckl.), 2022, Vol. 12, pp. 127-137.

82. Sarnes E., Crofford L., Watson M. Incidence and US costs of Corticosteroid-Associated adverse events: a systematic literature review. Clin. Ther., 2011, Vol. 33, pp. 1413-1432.

83. Scarsi M., Paolini L., Ricotta D., Pedrini A., Piantoni S., Caimi L. Abatacept reduces levels of switched memory b cells, autoantibodies, and immunoglobulins in patients with rheumatoid arthritis. J. Rheumatol., 2014, Vol. 41, pp. 666-672.

84. Schneider B.J., Lacchetti C., Bollin K. Management of the top 10 most common immune-related adverse events in patients treated with immune checkpoint inhibitor therapy. JCO Oncol. Pract., 2022, Vol. 18, pp. 431-444.

85. Schneider B.J., Naidoo J., Santomasso B.D., Lacchetti C., Adkins S., Anadkat M. Management of immunerelated adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J. Clin. Oncol., 2021, Vol. 39, pp. 4073-4126.

86. Selby M.J., Engelhardt J.J., Quigley M., Henning K.A., Chen T., Srinivasan M. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res., 2013, Vol. 1, pp. 32-42.

87. Shojaie L., Ali M., Iorga A., Dara L. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm. Sin. B, 2021, Vol. 11, pp. 3727-3739.

88. Sibaud V. Dermatologic reactions to immune checkpoint inhibitors : skin toxicities and immunotherapy. Am. J. Clin. Dermatol., 2018, Vol. 19, pp. 345-361.

89. Smolen J.S., Landewe R., Bergstra S.A., Kerschbaumer A., Sepriano A., Aletaha D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann. Rheum. Dis., 2023, Vol. 82, pp. 3-18.

90. Soularue E., Lepage P., Colombel J.F., Coutzac C., Faleck D., Marthey L. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut, 2018, Vol. 67, pp. 2056-2067.

91. Stone J.H., Tuckwell K., Dimonaco S., Klearman M., Aringer M., Blockmans D., Trial of tocilizumab in giant-cell arteritis. N. Engl. J. Med., 2017, Vol. 377, pp. 317-328.

92. Stroud C.R., Hegde A., Cherry C., Naqash A.R., Sharma N., Addepalli .S Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J. Oncol. Pharm. Pract., 2019, Vol. 25, pp. 551-557.

93. Tachibana M., Imagawa A. Type 1 diabetes related to immune checkpoint inhibitors. Best Pract. Res. Clin. Endocrinol. Metab., 2022, Vol. 36, 101657. doi: 10.1016/j.beem.2022.101657.

94. Tanaka T., Narazaki M., Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol., 2014, Vol. 6, a16295. doi: 10.1101/cshperspect.a016295.

95. Tarrio M.L., Grabie N., Bu D.X., Sharpe A.H., Lichtman A.H. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J. Immunol., 2012, Vol. 188, pp. 4876-4884.

96. Topalian S.L., Taube J.M., Anders R.A., Pardoll D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer, 2016, Vol. 16, pp. 275-287.

97. Twomey J.D., Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J., 2021, Vol. 23, 39. doi: 10.1208/s12248-021-00574-0.

98. Vandiver J.W., Singer Z., Harshberger C. Severe hyponatremia and immune nephritis following an initial infusion of nivolumab. Target. Oncol., 2016, Vol. 11, pp. 553-556.

99. Varricchi G., Galdiero M.R., Marone G., Criscuolo G., Triassi M., Bonaduce D. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open, 2017, Vol. 2, e247. doi: 10.1136/esmoopen-2017-000247.

100. Verma N., Jaffer M., Pina Y., Peguero E., Mokhtari S. Rituximab for immune checkpoint inhibitor myasthenia gravis. Cureus, 2021, Vol. 13, e16337. doi: 10.7759/cureus.16337.

101. Viglietta V., Bourcier K., Buckle G.J., Healy B., Weiner H.L., Hafler D.A. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology, 2008, Vol. 71, pp. 917-924.

102. Waight J.D., Chand D., Dietrich S., Gombos R., Horn T., Gonzalez A.M. Selective FcgammaR Co-engagement on APCs modulates the activity of therapeutic antibodies targeting T cell antigens. Cancer Cell, 2018, Vol. 33, pp. 1033-1047.

103. Wanchoo R., Karam S., Uppal N.N., Barta V.S., Deray G., Devoe C. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am. J. Nephrol., 2017, Vol. 45, pp. 160-169.

104. Wang D.Y., Salem J.E., Cohen J.V., Chandra S., Menzer C., Ye F. Fatal Toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol., 2018, Vol. 4, pp. 1721-1728.

105. Wang J., Okazaki I.M., Yoshida T., Chikuma S., Kato Y., Nakaki F. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int. Immunol., 2010, Vol. 22, pp. 443-452.

106. Wang J., Yang T., Xu J. Therapeutic development of immune checkpoint inhibitors. Adv. Exp. Med. Biol., 2020, Vol. 1248, pp. 619-649.

107. Wang Y., Tong Z., Zhang W., Zhang W., Buzdin A., Mu X. FDA-Approved and emerging next generation predictive biomarkers for immune checkpoint-inhibitors in cancer patients. Front. Oncol., 2021, Vol. 11, 683419. doi: 10.3389/fonc.2021.683419.

108. Wang Z.H., Shen L. Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors. Chronic Dis. Transl. Med., 2018, Vol. 4, pp. 1-7.

109. Westin J.R., Chu F., Zhang M., Fayad L.E., Kwak L.W., Fowler N. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, openlabel, phase 2 trial. Lancet Oncol., 2014, Vol. 15, pp. 69-77.

110. Willsmore Z.N., Coumbe B., Crescioli S., Reci S., Gupta A., Harris R.J. Combined anti-PD-1 and antiCTLA-4 checkpoint blockade: treatment of melanoma and immune mechanisms of action. Eur J. Immunol., 2021, Vol. 51, pp. 544-556.

111. Xu F., Liu J., Liu D., Liu B., Wang M., Hu Z. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res., 2014, Vol. 74, pp. 3418-3428.

112. Xu W., Moor R.J., Walpole E.T. Pregnancy with successful foetal and maternal outcome in a melanoma patient treated with nivolumab in the first trimester: case report and review of the literature. Melanoma Res., 2019, Vol. 29, pp. 333-337.

113. Yamada K., Sawada T., Nakamura M., Yamamura T., Maeda K., Ishikawa E. Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival. World J. Gastroenterol., 2021, Vol. 27, pp. 7190-7206.

114. Zheng Z., Liu Y., Yang J., Tan C., Zhou L., Wang X. Diabetes mellitus induced by immune checkpoint inhibitors. Diabetes Metab. Res. Rev., 2021, Vol. 37, e3366. doi: 10.1002/dmrr.3366.