Immune Netw.  2020 Feb;20(1):e9. 10.4110/in.2020.20.e9.

Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors

• Choi J
• Lee SY

• KMID: 2471049
• DOI: http://doi.org/10.4110/in.2020.20.e9

Abstract

Immune checkpoint inhibitors (ICIs) have been changing the paradigm of cancer treatment. However, immune-related adverse effects (irAEs) have also increased with the exponential increase in the use of ICIs. ICIs can break up the immunologic homeostasis and reduce T-cell tolerance. Therefore, inhibition of immune checkpoint can lead to the activation of autoreactive T-cells, resulting in various irAEs similar to autoimmune diseases. Gastrointestinal toxicity, endocrine toxicity, and dermatologic toxicity are common side effects. Neurotoxicity, cardiotoxicity, and pulmonary toxicity are relatively rare but can be fatal. ICI-related gastrointestinal toxicity, dermatologic toxicity, and hypophysitis are more common with anti- CTLA-4 agents. ICI-related pulmonary toxicity, thyroid dysfunction, and myasthenia gravis are more common with PD-1/PD-L1 inhibitors. Treatment with systemic steroids is the principal strategy against irAEs. The use of immune-modulatory agents should be considered in case of no response to the steroid therapy. Treatment under the supervision of multidisciplinary specialists is also essential, because the symptoms and treatments of irAEs could involve many organs. Thus, this review focuses on the mechanism, clinical presentation, incidence, and treatment of various irAEs.

Keyword

Immune checkpoint inhibitor; Adverse events; Programmed cell death 1

MeSH Terms

Autoimmune Diseases
Cardiotoxicity
Homeostasis
Incidence
Myasthenia Gravis
Organization and Administration
Specialization
Steroids
T-Lymphocytes
Thyroid Gland
Steroids

Figure

• 

  Figure 1. Enterocolitis related to immune checkpoint inhibitors. (A) Before steroid treatment, axial contrast computed tomography scan shows wall thickening and abnormal enhancement in intestine. (B) After steroid treatment, intestinal wall thickening and abnormal enhancement are reduced.

• 

  Figure 2. Inflammatory arthritis related to immune checkpoint inhibitors on both knees; axial contrast computed tomography scan show moderate joint effusion of both knees (right > left) with associated synovial thickening.

• 

  Figure 3. Exacerbation of psoriasis under immune checkpoint inhibitors; plaque psoriasis with silvery scales on trunk.

Reference

References

1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366:2443–2454.

2. Tang J, Yu JX, Hubbard-Lucey VM, Neftelinov ST, Hodge JP, Lin Y. Trial watch: The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat Rev Drug Discov. 2018; 17:854–855.

3. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018; 4:1721–1728.

4. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017; 377:1345–1356.

5. Yu Y, Ruddy KJ, Tsuji S, Hong N, Liu H, Shah N, Jiang G. Coverage evaluation of CTCAE for capturing the immune-related adverse events leveraging text mining technologies. AMIA Jt Summits Transl Sci Proc. 2019; 2019:771–778.

6. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, 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; 36:1714–1768.

7. Haanen JB, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K. ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29:iv264–iv266.

8. Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, Luiten RM. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015; 33:773–781.

9. Deltombe C, Garandeau C, Renaudin K, Hourmant M. Severe allograft rejection and autoimmune hemolytic anemia after anti-PD1 therapy in a kidney transplanted patient. Transplantation. 2017; 101:e291.

10. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018; 378:158–168.

11. Byrne EH, Fisher DE. Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer. 2017; 123:2143–2153.

12. Kimbara S, Fujiwara Y, Iwama S, Ohashi K, Kuchiba A, Arima H, Yamazaki N, Kitano S, Yamamoto N, Ohe Y. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab. Cancer Sci. 2018; 109:3583–3590.

13. Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014; 6:230ra45.

14. 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:e0124059.

15. Haanen JB, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K. ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017; 28:iv119–iv142.

16. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372:2521–2532.

17. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017; 390:1853–1862.

18. de Malet A, Antoni G, Collins M, Soularue E, Marthey L, Vaysse T, Coutzac C, Chaput N, Mateus C, Robert C, et al. Evolution and recurrence of gastrointestinal immune-related adverse events induced by immune checkpoint inhibitors. Eur J Cancer. 2019; 106:106–114.

19. Geukes Foppen MH, Rozeman EA, van Wilpe S, Postma C, Snaebjornsson P, van Thienen JV, van Leerdam ME, van den Heuvel M, Blank CU, van Dieren J, et al. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open. 2018; 3:e000278.

20. Gupta A, De Felice KM, Loftus EV Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015; 42:406–417.

21. Samaan MA, Pavlidis P, Papa S, Powell N, Irving PM. Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management. Nat Rev Gastroenterol Hepatol. 2018; 15:222–234.

22. Beniwal-Patel P, Matkowskyj K, Caldera F. Infliximab therapy for corticosteroid-resistant ipilimumab-induced colitis. J Gastrointestin Liver Dis. 2015; 24:274.

23. Hsieh AH, Ferman M, Brown MP, Andrews JM. Vedolizumab: a novel treatment for ipilimumab-induced colitis. BMJ Case Rep. 2016; 2016:bcr2016216641.

24. Gong J, Chehrazi-Raffle A, Placencio-Hickok V, Guan M, Hendifar A, Salgia R. The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies. Clin Transl Med. 2019; 8:9.

25. Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer. 2017; 17:271–285.

26. Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, No D, Gobourne A, Littmann E, Huttenhower C, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016; 7:10391.

27. Pezo RC, Wong M, Martin A. Impact of the gut microbiota on immune checkpoint inhibitor-associated toxicities. Therap Adv Gastroenterol. 2019; 12:1756284819870911.

28. Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, DuPont HL, Jiang ZD, Abu-Sbeih H, Sanchez CA, Chang CC, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018; 24:1804–1808.

29. Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol. 2019; 15:231–244.

30. Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018; 31:965–973.

31. De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, Roche B, Antonini TM, Coilly A, Laghouati S, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018; 68:1181–1190.

32. Wang W, Lie P, Guo M, He J. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis of published data. Int J Cancer. 2017; 141:1018–1028.

33. Kim KW, Ramaiya NH, Krajewski KM, Jagannathan JP, Tirumani SH, Srivastava A, Ibrahim N. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013; 31:1071–1077.

34. Koksal AS, Toka B, Eminler AT, Hacibekiroglu I, Uslan MI, Parlak E. HBV-related acute hepatitis due to immune checkpoint inhibitors in a patient with malignant melanoma. Ann Oncol. 2017; 28:3103–3104.

35. Brahmer JR, Lacchetti C, Thompson JA. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline summary. J Oncol Pract. 2018; 14:247–249.

36. Perazella MA, Shirali AC. Nephrotoxicity of cancer immunotherapies: past, present and future. J Am Soc Nephrol. 2018; 29:2039–2052.

37. Paueksakon P, Fogo AB. Drug-induced nephropathies. Histopathology. 2017; 70:94–108.

38. Marco T, Anna P, Annalisa T, Francesco M, Stefania SL, Stella D, Michele R, Marco T, Loreto G, Franco S. The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma. Ther Adv Med Oncol. 2019; 11:1758835919875549.

39. Mamlouk O, Selamet U, Machado S, Abdelrahim M, Glass WF, Tchakarov A, Gaber L, Lahoti A, Workeneh B, Chen S, et al. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer. 2019; 7:2.

40. Izzedine H, Gueutin V, Gharbi C, Mateus C, Robert C, Routier E, Thomas M, Baumelou A, Rouvier P. Kidney injuries related to ipilimumab. Invest New Drugs. 2014; 32:769–773.

41. Manohar S, Kompotiatis P, Thongprayoon C, Cheungpasitporn W, Herrmann J, Herrmann SM. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis. Nephrol Dial Transplant. 2019; 34:108–117.

42. Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, Le DT, Lipson EJ, Glezerman IG, Wolchok J, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016; 90:638–647.

43. Wanchoo R, Karam S, Uppal NN, Barta VS, Deray G, Devoe C, Launay-Vacher V, Jhaveri KD. Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017; 45:160–169.

44. Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, Herold KC. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015; 38:e55–e57.

45. Shirali AC, Perazella MA, Gettinger S. Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients. Am J Kidney Dis. 2016; 68:287–291.

46. Koda R, Watanabe H, Tsuchida M, Iino N, Suzuki K, Hasegawa G, Imai N, Narita I. Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report. BMC Nephrol. 2018; 19:48.

47. Maggiore U, Pascual J. The bad and the good news on cancer immunotherapy: Implications for organ transplant recipients. Adv Chronic Kidney Dis. 2016; 23:312–316.

48. Chang LS, Barroso-Sousa R, Tolaney SM, Hodi FS, Kaiser UB, Min L. Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev. 2019; 40:17–65.

49. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711–723.

50. González-Rodríguez E, Rodríguez-Abreu D; Spanish Group for Cancer Immuno-Biotherapy (GETICA). Immune checkpoint inhibitors: Review and management of endocrine adverse events. Oncologist. 2016; 21:804–816.

51. Boasberg P, Hamid O, O'Day S. Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. Semin Oncol. 2010; 37:440–449.

52. de Filette J, Andreescu CE, 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; 51:145–156.

53. Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, Veloski C, Robert C. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017; 58:70–76.

54. Caturegli P, Di Dalmazi G, Lombardi M, Grosso F, Larman HB, Larman T, Taverna G, Cosottini M, Lupi I. Hypophysitis secondary to cytotoxic t-lymphocyte-associated protein 4 blockade: Insights into pathogenesis from an autopsy series. Am J Pathol. 2016; 186:3225–3235.

55. Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, Nachtigall L. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab. 2014; 99:4078–4085.

56. Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010; 13:29–38.

57. Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, Royal RE, Topalian SL, Haworth LR, Levy C, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005; 28:593–598.

58. Ntali G, Kassi E, Alevizaki M. Endocrine sequelae of immune checkpoint inhibitors. Hormones (Athens). 2017; 16:341–350.

59. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, Tolaney SM. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 2018; 4:173–182.

60. Barroso-Sousa R, Ott PA, Hodi FS, Kaiser UB, Tolaney SM, Min L. Endocrine dysfunction induced by immune checkpoint inhibitors: Practical recommendations for diagnosis and clinical management. Cancer. 2018; 124:1111–1121.

61. Illouz F, Briet C, Cloix L, Le Corre Y, Baize N, Urban T, Martin L, Rodien P. Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists. Cancer Med. 2017; 6:1923–1929.

62. de Filette J, Jansen Y, Schreuer M, Everaert H, Velkeniers B, Neyns B, Bravenboer B. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab. J Clin Endocrinol Metab. 2016; 101:4431–4439.

63. Sui JD, Wang Y, Wan Y, Wu YZ. Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer patients: a meta-analysis of current studies. Drug Des Devel Ther. 2018; 12:1645–1657.

64. Calvo R. Hematological side effects of immune checkpoint inhibitors: the example of immune-related thrombocytopenia. Front Pharmacol. 2019; 10:454.

65. Davis EJ, Salem JE, Young A, Green JR, Ferrell PB, Ancell KK, Lebrun-Vignes B, Moslehi JJ, Johnson DB. Hematologic complications of immune checkpoint inhibitors. Oncologist. 2019; 24:584–588.

66. Jagpal A, Choudhary G, Chokr J. Severe arthritis and tenosynovitis caused by immune checkpoint blockade therapy with pembrolizumab (anti-PD-1 antibody). Proc Bayl Univ Med Cent. 2019; 32:419–421.

67. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; 16:908–918.

68. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018; 360:k793.

69. Cappelli LC, Naidoo J, Bingham CO 3rd, Shah AA. Inflammatory arthritis due to immune checkpoint inhibitors: challenges in diagnosis and treatment. Immunotherapy. 2017; 9:5–8.

70. Naidoo J, Cappelli LC, Forde PM, Marrone KA, Lipson EJ, Hammers HJ, Sharfman WH, Le DT, Baer AN, Shah AA, et al. Inflammatory arthritis: a newly recognized adverse event of immune checkpoint blockade. Oncologist. 2017; 22:627–630.

71. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017; 5:95.

72. Braaten TJ, Brahmer JR, Forde PM, Le D, Lipson EJ, Naidoo J, Schollenberger M, Zheng L, Bingham Rd CO, Shah AA, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2019. DOI: doi: 10.1136/annrheumdis-2019-216109.

73. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D'Angelo SP, Woo KM, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015; 33:3193–3198.

74. Jaber SH, Cowen EW, Haworth LR, Booher SL, Berman DM, Rosenberg SA, Hwang ST. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol. 2006; 142:166–172.

75. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, Motzer RJ, Wu S, Busam KJ, Wolchok JD, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016; 60:12–25.

76. Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014; 71:161–169.

77. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, Bergmann T, Bockmeyer CL, Eigentler T, Fluck M, 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.

78. Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham J, Page DB, Postow MA, Weinstein A, Lucas AS, Ciccolini KT, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016; 4:383–389.

79. Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR, Duvic M, Hwu WJ, Wargo JA, Torres-Cabala CA, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017; 44:158–176.

80. Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013; 2013:857519.

81. Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013; 69:e121–e128.

82. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016; 22:886–894.

83. Zimmer L, Vaubel J, Livingstone E, Schadendorf D. Side effects of systemic oncological therapies in dermatology. J Dtsch Dermatol Ges. 2012; 10:475–486.

84. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. 2017; 41:125–128.

85. Spain L, Tippu Z, Larkin JM, Carr A, Turajlic S. How we treat neurological toxicity from immune checkpoint inhibitors. ESMO Open. 2019; 4:e000540.

86. Johnson DB, Manouchehri A, Haugh AM, Quach HT, Balko JM, Lebrun-Vignes B, Mammen A, Moslehi JJ, Salem JE. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J Immunother Cancer. 2019; 7:134.

87. Spain L, Walls G, Julve M, O'Meara K, Schmid T, Kalaitzaki E, Turajlic S, Gore M, Rees J, Larkin J. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol. 2017; 28:377–385.

88. Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, Lebbe C, Belin C, Ursu R, Carpentier AF. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017; 73:1–8.

89. Manousakis G, Koch J, Sommerville RB, El-Dokla A, Harms MB, Al-Lozi MT, Schmidt RE, Pestronk A. Multifocal radiculoneuropathy during ipilimumab treatment of melanoma. Muscle Nerve. 2013; 48:440–444.

90. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol. 2017; 30:659–668.

91. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018; 391:933.

92. Anquetil C, Salem JE, Lebrun-Vignes B, Johnson DB, Mammen AL, Stenzel W, Léonard-Louis S, Benveniste O, Moslehi JJ, Allenbach Y. Immune checkpoint inhibitor-associated myositis. Circulation. 2018; 138:743–745.

93. Becquart O, Lacotte J, Malissart P, Nadal J, Lesage C, Guillot B, Du Thanh A. Myasthenia gravis induced by immune checkpoint inhibitors. J Immunother. 2019; 42:309–312.

94. Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res. 2016; 4:124–135.

95. McGinnis GJ, Friedman D, Young KH, Torres ER, Thomas CR Jr, Gough MJ, Raber J. Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model. Oncotarget. 2017; 8:9155–9173.

96. McGinnis GJ, Raber J. CNS side effects of immune checkpoint inhibitors: preclinical models, genetics and multimodality therapy. Immunotherapy. 2017; 9:929–941.

97. Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016; 28:288–294.

98. Sun MM, Levinson RD, Filipowicz A, Anesi S, Kaplan HJ, Wang W, Goldstein DA, Gangaputra S, Swan RT, Sen HN, et al. Uveitis in patients treated with CTLA-4 and PD-1 checkpoint blockade inhibition. Ocul Immunol Inflamm. 2019. DOI: doi: 10.1080/09273948.2019.1577978.

99. Abdel-Rahman O, Oweira H, Petrausch U, Helbling D, Schmidt J, Mannhart M, Mehrabi A, Schöb O, Giryes A. Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review. Expert Rev Anticancer Ther. 2017; 17:387–394.

100. Lavezzo MM, Sakata VM, Morita C, Rodriguez EE, Abdallah SF, da Silva FT, Hirata CE, Yamamoto JH. Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes. Orphanet J Rare Dis. 2016; 11:29.

101. Diem S, Keller F, Rüesch R, Maillard SA, Speiser DE, Dummer R, Siano M, Urner-Bloch U, Goldinger SM, Flatz L. Pembrolizumab-triggered uveitis: An additional surrogate marker for responders in melanoma immunotherapy? J Immunother. 2016; 39:379–382.

102. Conrady CD, Larochelle M, Pecen P, Palestine A, Shakoor A, Singh A. Checkpoint inhibitor-induced uveitis: a case series. Graefes Arch Clin Exp Ophthalmol. 2018; 256:187–191.

103. Michel L, Rassaf T, Totzeck M. Cardiotoxicity from immune checkpoint inhibitors. Int J Cardiol Heart Vasc. 2019; 25:100420.

104. Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist. 2018; 23:879–886.

105. Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, Stewart GC, Choueiri TK, Di Carli M, Allenbach Y, et al. Myocarditis in the setting of cancer therapeutics: Proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation. 2019; 140:80–91.

106. Yang S, Asnani A. Cardiotoxicities associated with immune checkpoint inhibitors. Curr Probl Cancer. 2018; 42:422–432.

107. Neilan TG, Rothenberg ML, Amiri-Kordestani L, Sullivan RJ, Steingart RM, Gregory W, Hariharan S, Hammad TA, Lindenfeld J, Murphy MJ, et al. Myocarditis associated with immune checkpoint inhibitors: an expert consensus on data gaps and a call to action. Oncologist. 2018; 23:874–878.

108. Totzeck M, Schuler M, Stuschke M, Heusch G, Rassaf T. Cardio-oncology – strategies for management of cancer-therapy related cardiovascular disease. Int J Cardiol. 2019; 280:163–175.

109. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016; 375:1749–1755.

110. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018; 71:1755–1764.

111. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, Monestier S, Grob JJ, Scemama U, Jacquier A, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation. 2017; 136:2085–2087.

112. Arangalage D, Delyon J, Lermuzeaux M, Ekpe K, Ederhy S, Pages C, Lebbé C. Survival after fulminant myocarditis induced by immune-checkpoint inhibitors. Ann Intern Med. 2017; 167:683–684.

113. Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ, Kerneis M. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019; 380:2377–2379.

114. Esfahani K, Buhlaiga N, Thébault P, Lapointe R, Johnson NA, Miller WH Jr. Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med. 2019; 380:2375–2376.

115. Lyon AR, Yousaf N, Battisti NM, Moslehi J, Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 2018; 19:e447–e458.

116. Tajmir-Riahi A, Bergmann T, Schmid M, Agaimy A, Schuler G, Heinzerling L. Life-threatening autoimmune cardiomyopathy reproducibly induced in a patient by checkpoint inhibitor therapy. J Immunother. 2018; 41:35–38.

117. Tajiri K, Ieda M. Cardiac complications in immune checkpoint inhibition therapy. Front Cardiovasc Med. 2019; 6:3.

118. Wang J, Okazaki IM, Yoshida T, Chikuma S, Kato Y, Nakaki F, Hiai H, Honjo T, Okazaki T. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol. 2010; 22:443–452.

119. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291:319–322.

120. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995; 270:985–988.

121. Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, Chaft JE, Segal NH, Callahan MK, Lesokhin AM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017; 35:709–717.

122. Kalisz KR, Ramaiya NH, Laukamp KR, Gupta A. Immune checkpoint inhibitor therapy-related pneumonitis: patterns and management. Radiographics. 2019; 39:1923–1937.

123. Suresh K, Naidoo J, Lin CT, Danoff S. Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities. Chest. 2018; 154:1416–1423.

124. Ma K, Lu Y, Jiang S, Tang J, Li X, Zhang Y. The relative risk and incidence of immune checkpoint inhibitors related pneumonitis in patients with advanced cancer: a meta-analysis. Front Pharmacol. 2018; 9:1430.

125. Sternschein R, Moll M, Ng J, D'Ambrosio C. Immune checkpoint inhibitor-related pneumonitis. Incidence, risk factors, and clinical and radiographic features. Am J Respir Crit Care Med. 2018; 198:951–953.

126. Cho JY, Kim J, Lee JS, Kim YJ, Kim SH, Lee YJ, Cho YJ, Yoon HI, Lee JH, Lee CT, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer. 2018; 125:150–156.

127. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017; 18:895–903.

128. Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, Hatabu H, Ott PA, Armand PF, Hodi FS. PD-1 inhibitor-related pneumonitis in advanced cancer patients: Radiographic patterns and clinical course. Clin Cancer Res. 2016; 22:6051–6060.

129. Sears CR, Peikert T, Possick JD, Naidoo J, Nishino M, Patel SP, Camus P, Gaga M, Garon EB, Gould MK, et al. Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. An official American Thoracic Society research statement. Am J Respir Crit Care Med. 2019; 200:e31–e43.

130. Delaunay M, Cadranel J, Lusque A, Meyer N, Gounant V, Moro-Sibilot D, Michot JM, Raimbourg J, Girard N, Guisier F, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J. 2017; 50:1700050.

131. Nishino M, Chambers ES, Chong CR, Ramaiya NH, Gray SW, Marcoux JP, Hatabu H, Jänne PA, Hodi FS, Awad MM. Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer. Cancer Immunol Res. 2016; 4:289–293.