Immunotherapy toxicity in cancer: an oncology view for the internist
DOI:
https://doi.org/10.18041/2665-427X/ijeph.2.9900Keywords:
Immunotherapy, cancer treatment, Immune Checkpoint Blockade, immune-related adverse events, Adverse events, PD-1 inhibitor, PD-L1 inhibitor, programmed cell death 1 inhibitor, cancer immunotherapy, CTLA-4, anti-CTLA4Abstract
Immunotherapy is considered one of the most recent advances in cancer treatment. Thanks to the technological advances developed in the last three decades in immunology and oncology, we have seen a promising uprising on the treatment of different oncological pathologies through the use of the patient's immune system, especially with the development of antibodies directed against various checkpoints of the immune system (Immune Checkpoint Blockade). A brief review of the pathophysiological mechanism of the most frequent irEAs reported in the literature will be done, as well as their incidence and prevalence according to the different immunotherapy drugs available for treating different solid and hematologic neoplasms.
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Dobosz P, Dzieciatkowski T. The intriguing history of cancer immunotherapy. Front Immunol. 2019; 10: 2965. doi: 10.3389/fimmu.2019.02965
Esfahani K, Meti N, Miller WH Jr, Hudson M. Adverse events associated with immune checkpoint inhibitor treatment for cancer. CMAJ. 2019; 191(2): E40-E46. Doi: 10.1503/cmaj.180870.
Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, et al. Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017; 81: 116-129. doi: 10.1016/j.ejca.2017.01.035.
Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol. 2019;12(1):92. doi: 10.1186/s13045-019-0779-5.
Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 1996; 183: 2533-40. doi: 10.1084/jem.183.6.2533
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8: 793-800. doi: 10.1038/nm730.
Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med 2016; 375: 1767-78. doi: 10.1056/NEJMra1514296.
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3: 541-7. doi: 10.1016/1074-7613(95)90125-6.
Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995; 270: 985-8. doi: 10.1126/science.270.5238.985.
Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019; 16: 563-580. doi: 10.1038/s41571-019-0218-0.
Eggermont, AMM, Chiarion-Sileni V, Grob J-J, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016; 375: 1845-1855. doi: 10.1056/NEJMoa1611299.
Hodi FS, O´Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-723. doi: 10.1056/NEJMoa1003466.
Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017; 73: 1-8. doi: 10.1016/j.ejca.2016.12.001.
Lee JB, Kim HR, Ha S-J. Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy. Immune Netw. 2022; 22(1): e2. doi: 10.4110/in.2022.22.e2.
Esfahani K, Meti N, Miller WH Jr, Hudson M. Adverse events associated with immune checkpoint inhibitor treatment for cancer. CMAJ. 2019; 191(2):E40-E46. doi: 10.1503/cmaj.180870.
Teulings H-E, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, et al. 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(7): 773-81. doi: 10.1200/JCO.2014.57.4756.
Min LCK, Li S, Tran DC, Zhu GA, Kim J, Kwong BY, Chang ALS. Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: A retrospective case-control study. J Am Acad Dermatol. 2018; 79(6): 1047-1052. doi: 10.1016/j.jaad.2018.05.035.
Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016; 60: 12-25. doi: 10.1016/j.ejca.2016.02.010.
Dougan M. Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract. Front Immunol. 2017; 8: 1547. doi: 10.3389/fimmu.2017.01547.
Abu-Sbeih H, Ali FS, Luo W, Qiao W, Raju GS, Wang Y. Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2018; 6(1): 95. doi: 10.1186/s40425-018-0411-1.
Johnson DH, Zobniw CM, Trinh VA, Ma J, Bassett RL, Abdel-Wahab N, et al. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer. 2018; 6(1): 103. doi: 10.1186/s40425-018-0412-0.
Kanai, T. et al. Blockade of B7-H1 suppresses the development of chronic intestinal inflammation. J Immunol. 2003; 171: 4156-4163. doi: 10.4049/jimmunol.171.8.4156.
Reynoso ED, Elpek KG, Francisco L, Bronson R, Bellemare-Pelletier A, Sharpe AH, et al. Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol. 2009; 182: 2102-2112. doi: 10.4049/jimmunol.0802769.
Chuzi S, Tavora F, Cruz M , Costa R, Kwang CY, Carneiro BA, et al. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitorrelated pneumonitis. Cancer Manag Res. 2017; 9: 207-213. doi: 10.2147/CMAR.S136818.
Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor- related pneumonitis in patients with advanced cancer: a systematic review and meta- analysis. JAMA Oncol. 2016; 2: 1607-1616. doi: 10.1001/jamaoncol.2016.2453.
Naidoo J, Wang X, Woo KM, Lyriboz T , Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti- programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017; 35: 709-717. doi: 10.1200/JCO.2016.68.2005.
Koelzer VH, Rothschild SI, Zihler D, Wicki A, Willi B, Willi N, et al. Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors- an autopsy study. J Immunother Cancer. 2016; 4: 13. doi: 10.1186/s40425-016-0117-1.
Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary. 2016; 19: 82-92. doi: 10.1007/s11102-015-0671-4
Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, 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. doi: 10.1097/01.cji.0000178913.41256.06.
Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J. Clin. Endocrinol. Metab. 2013; 98: 1361-1375. doi: 10.1210/jc.2012-4075.
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: 230ra245. doi: 10.1126/scitranslmed.3008002.
Caturegli P, Di Dalmazi G, Lombardi M, Grosso F, Larman HB, Larman T, et al. Hypophysitis secondary to cytotoxic T- lymphocyte-associated protein 4 blockade: insights into athogenesis from an autopsy series. Am J Pathol. 2016; 186: 3225-3235. doi: 10.1016/j.ajpath.2016.08.020.
Gonzalez- Rodriguez E, Rodriguez-Abreu D; Spanish Group for Cancer Immuno-Biotherapy (GETICA). Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist. 2016; 21: 804-816. doi: 10.1634/theoncologist.2015-0509.
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: 1755-1764. doi: 10.1016/j.jacc.2018.02.037.
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: 1749-1755 (2016). doi: 10.1056/NEJMoa1609214.
Moslehi JJ, Salem JE, Sosman JA, Lebrun- Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor- associated myocarditis. Lancet. 2018; 391: 933. doi: 10.1016/S0140-6736(18)30533-6.
Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016; 4: 50. doi: 10.1186/s40425-016-0152-y.
Varricchi G, Galdiero MR, Marone G, Criscuolo G, Triassi M, Bonaduce D, et al. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open. 2017; 2: e000247. doi: 10.1136/esmoopen-2017-000247.
Kao JC, Liao B, Markovic SN, Klein CJ , Naddaf E, Staff NP, et al. Neurological complications associated with anti- programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017; 74: 1216-1222. doi: 10.1001/jamaneurol.2017.1912.
Williams TJ, Benavides DR, Patrice K-A, Dalmau JO, Ribeiro deÁAL, Le DT, et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 2016; 73: 928-933. doi: 10.1001/jamaneurol.2016.1399.
Brown MP, Hissaria P, Hsieh AH, Kneebone C. Vallat W. Autoimmune limbic encephalitis with anticontactin-associated protein- like 2 antibody secondary to pembrolizumab therapy. J Neuroimmunol. 2017; 305: 16-18. doi: 10.1016/j.jneuroim.2016.12.016.
Papadopoulos KP, Romero RS, Gonzalez G, Dix JE, Lowy I, Fury M. Anti- Hu-associated autoimmune limbic encephalitis in a patient with PD-1 inhibitor- responsive myxoid chondrosarcoma. Oncologist. 2018; 23: 118-120. doi: 10.1634/theoncologist.2017-0344.
Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017; 82: 128-136. doi: 10.1016/j.ejca.2017.05.041.
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. doi: 10.1002/ijc.30678.
Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int. 2018; 38: 976-987. doi: 10.1111/liv.13746.
Karamchandani DM, Chetty R. Immune checkpoint inhibitor- induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol. 2018; 71: 665-671. doi: 10.1136/jclinpath-2018-205143
Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, et al. Ipilimumab- associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol. 2015; 39: 1075-1084. doi: 10.1097/PAS.0000000000000453.
Butt S, Bhaumik S. Acute demyelinating polyneuropathy caused by nivolumab in a man with metastatic non- small cell lung cancer. J Gerontol Geriatr Res. 2016; 5: 302. Doi: 10.4172/2167-7182.1000302.
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