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Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies

Nature Reviews Drug Discovery volume 21, pages 495–508 (2022)Cite this article

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Abstract

The immune-related adverse events associated with treatment with immune checkpoint inhibitors result in significant morbidity for patients as well as considerable cost to the health-care system, and can limit the use of these beneficial drugs. Understanding the mechanisms of these side effects and how they can be separated from the antitumour effects of immune checkpoint inhibitors, as well as identifying biomarkers that predict the development of immune-related toxicities, will facilitate the conduct of trials to limit their onset and improve patient outcomes. In this Review, we discuss the different types of immune-related adverse events and how their treatment and identification of possible predictive biomarkers may shed light on their mechanisms, and describe possible strategies and targets for prophylactic and therapeutic intervention to mitigate them.

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Fig. 1: Different mechanisms drive immune-related adverse events.

References

  1. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010). This is the first article to show survival advantage in patients with melanoma treated with CTLA4 blockade.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Du, S. et al. PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes. J. Thorac. Oncol. 13, 510–520 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Vogrig, A. et al. Central nervous system complications associated with immune checkpoint inhibitors. J. Neurol. Neurosurg. Psychiatry 91, 772–778 (2020).

    Article  PubMed  Google Scholar 

  4. Naidoo, J. et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol. Res. 4, 383–389 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cortellini, A. et al. Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients. Clin. Lung Cancer 20, 237–247 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Maher, V. E. et al. Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody. J. Clin. Oncol. 37, 2730–2737 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Weber, J. S. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35, 785–792 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. DuPage, M., Mazumdar, C., Schmidt, L. M., Cheung, A. F. & Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405–409 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018). This is an important review of the mechanisms of ICI therapy.

    Article  PubMed  Google Scholar 

  14. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2366, 2443–2454 (2012). This is the first documentation of the benefit of PD1 blockade in multiple cancers.

    Article  CAS  Google Scholar 

  16. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weber, J. S. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375–384 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Sanderson, K. et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J. Clin. Oncol. 23, 741–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Pauken, K. E., Dougan, M., Rose, N. R., Lichtman, A. H. & Sharpe, A. H. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol. 40, 511–523 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473–486 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Young, A., Quandt, Z. & Bluestone, J. A. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol. Res. 6, 1445–1452 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, Y. et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 5, 1008–1019 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Martins, F. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16, 563–580 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Ramos-Casals, M. et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Prim. 6, 38 (2020).

    Article  PubMed  Google Scholar 

  26. Brunet, J. F. et al. A new member of the immunoglobulin superfamily–CTLA-4. Nature 328, 267–270 (1987).

    Article  CAS  PubMed  Google Scholar 

  27. Linsley, P. S., Brady, W., Urnes, M., Grosmaire, L. S., Damle, N. K. & Ledbetter, J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174, 561–569 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Yshii, L. M. et al. CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model. Brain 139, 2923–2934 (2016).

    Article  PubMed  Google Scholar 

  30. Ascierto, P. A. et al. 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. 18, 611–622 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016). This paper reports that IPI prolongs survival as adjuvant therapy in resected melanoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tarhini, A. A. et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon Alfa-2b for resected high-risk melanoma: North American intergroup E1609. J. Clin. Oncol. 38, 567–575 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. D-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013). This paper provides the first description of the benefit of combination checkpoint inhibition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Konishi, J., Yamazaki, K., Azuma, M., Kinoshita, I., Dosaka-Akita, H. & Nishimura, M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin. Cancer Res. 10, 5094–5100 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Garcia-Diaz, A. et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19, 1189–1201 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014). This article is the first to report the benefit of treatment with an antibody against PD1 in a randomized trial.

    Article  CAS  PubMed  Google Scholar 

  42. Robert, L. et al. CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin. Cancer Res. 20, 2424–2432 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cha, E. et al. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci. Transl. Med. 6, 238ra70 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Harview, C. L. et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl. Med. 9, eaah3560 (2017).

    Article  CAS  Google Scholar 

  45. Johnson, D. B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749–1755 (2016). This paper is the first to report checkpoint inhibition-related myocarditis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Matson, D. R., Accola, M. A., Rehrauer, W. M. & Corliss, R. F. Fatal myocarditis following treatment with the PD-1 inhibitor nivolumab. J. Forensic Sci. 63, 954–957 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  48. Belliere, J. et al. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Br. J. Cancer 115, 1457–1461 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Suresh, K. et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J. Clin. Invest. 129, 4305–4315 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Luoma, A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655–671.e22 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Osorio, J. C. et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann. Oncol. 28, 583–589 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Safa, H. et al. Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. J. Immunother. Cancer 7, 319 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yang, J. C. et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30, 825–830 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Maker, A. V. et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann. Surg. Oncol. 12, 1005–1016 (2005). This article was the first to report immune-related adverse events with checkpoint inhibition.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Weber, J. S. et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26, 5950–5956 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Sibaud, V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am. J. Clin. Dermatol. 19, 345–361 (2018).

    Article  PubMed  Google Scholar 

  58. Freeman-Keller, M. et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin. Cancer Res. 22, 886–894 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Hua, C. et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 152, 45–51 (2016).

    Article  PubMed  Google Scholar 

  60. Wu, J. & Lacouture, M. E. Pruritus associated with targeted anticancer therapies and their management. Dermatol. Clin. 36, 315–324 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang, M. L., Neyaz, A., Patil, D., Chen, J., Dougan, M. & Deshpande, V. Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies. Histopathology 76, 233–243 (2020).

    Article  PubMed  Google Scholar 

  62. Wang, D. Y. et al. Clinical characterization of colitis arising from anti-PD-1 based therapy. Oncoimmunology 8, e1524695 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Badran, Y. R. et al. Immune checkpoint inhibitor-associated celiac disease. J. Immunother. Cancer 8, e000958 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Lang, N. et al. Clinical significance of signs of autoimmune colitis in 18F-fluorodeoxyglucose positron emission tomography-computed tomography of 100 stage-IV melanoma patients. Immunotherapy 1, 667–676 (2019).

    Article  CAS  Google Scholar 

  65. Hughes, M. S. et al. Budesonide treatment for microscopic colitis from immune checkpoint inhibitors. J. Immunother. Cancer 7, 292 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Thompson, J. A. et al. Management of immunotherapy-related toxicities, version 1.2019. J. Natl Compr. Cancer Netw. 17, 255–289 (2019).

    Article  CAS  Google Scholar 

  67. Horisberger, A. et al. A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy. J. Immunother. Cancer 6, 156 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Abu-Sbeih, H. et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study. J. Immunother. Cancer 6, 142 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Weber, J., Thompson, J. A., Hamid, O., Minor, D. & Amin, A. et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin. Cancer Res. 15, 5591–5598 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Barroso-Sousa, R. et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: systematic review and meta-analysis. JAMA Oncol. 4, 173–182 (2018). This systematic review provides a detailed description of endocrinopathies with checkpoint inhibition.

    Article  PubMed  Google Scholar 

  71. Muir, C. A., Menzies, A. M., Clifton-Bligh, R. & Tsang, V. H. M. Thyroid toxicity following immune checkpoint inhibitor treatment in advanced cancer. Thyroid 30, 1458–1469 (2020).

    Article  CAS  PubMed  Google Scholar 

  72. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Faje, A. T. et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J. Clin. Endocrinol. Metab. 99, 4078–4085 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Faje, A. et al. Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis. Eur. J. Endocrinol. 181, 211–219 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Iwama, S., De Remigis, A., Callahan, M. K., Slovin, S. F., Wolchok, J. D. & Caturegli, P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra45 (2014). This article describes the direct on-target effect of an antibody against CTLA4 in inducing hypophysitis.

    Article  PubMed  CAS  Google Scholar 

  76. Karamchandani, D. M. & Chetty, R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective. J. Clin. Pathol. 71, 665–671 (2018).

    Article  CAS  PubMed  Google Scholar 

  77. Johncilla, M. et al. Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am. J. Surg. Pathol. 39, 1075–1084 (2015).

    Article  PubMed  Google Scholar 

  78. Mahmood, S. S. et al. Myocarditis in patients treated with immune checkpoint inhibitors. J. Am. Coll. Cardiol. 71, 1755–1764 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang, L. et al. Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis. Circulation 141, 2031–2034 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Puzanov, I. 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 5, 95 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Haanan, J. B. A. G. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv264–iv266 (2018).

    Article  Google Scholar 

  82. Jain, V., Mohebtash, M., Rodrigo, M. E., Ruiz, G., Atkins, M. B. & Barac, A. Autoimmune myocarditis caused by immune checkpoint inhibitors treated with antithymocyte globulin. J. Immunother. 41, 332–335 (2018).

    Article  PubMed  Google Scholar 

  83. Salem, J. E. et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N. Engl. J. Med. 380, 2377–2379 (2019).

    Article  PubMed  Google Scholar 

  84. Fellner, A. et al. Neurologic complications of immune checkpoint inhibitors. J. Neurooncol. 137, 601–609 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Johnson, D. B. et al. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J. Immunother. Cancer 7, 134 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Michot, J. M. et al. Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage? Eur. J. Cancer 122, 72–90 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Leaf, R. K. et al. Clinical and laboratory features of autoimmune hemolytic anemia associated with immunecheckpoint inhibitors. Am. J. Hematol. 94, 563–574 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Weber, J. S., Postow, M., Lao, C. D. & Schadendorf, D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 21, 1230–1240 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016). This is the first article to report that the microbiome may influence immune-related colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chaput, N. et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28, 1368–1379 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Wang, Y. et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med. 24, 1804–1808 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. FDA. Fecal microbiota for transplantation: safety alert - risk of serious adverse events likely due to transmission of pathogenic organisms. FDA https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission?utm_campaign=FDA%20MedWatch%3A%20Fecal%20Microbiota%20for%20Transplantation&utm_medium=email&utm_source=Eloqua (2020).

  97. Friedlander, P. et al. A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab. J. Immunother. Cancer 6, 90 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Subudhi, S. K. et al. Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc. Natl Acad. Sci. USA 113, 11919–11924 (2016). This paper provides evidence that expanded clonal T cells are associated with immune-related toxicities.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Iyoda, T., Kurita, N., Takada, A., Watanabe, H. & Ando, M. Resolution of infliximab-refractory nivolumab-induced acute severe enterocolitis after cyclosporine treatment in a patient with non-small cell lung cancer. Am. J. Case. Rep. 19, 360–364 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Nayar, N., Briscoe, K. & Fernandez Penas, P. Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma. J. Immunother. 39, 149–152 (2016).

    Article  PubMed  Google Scholar 

  101. Toi, Y. et al. Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer. JAMA Oncol. 5, 376–383 (2019).

    Article  PubMed  Google Scholar 

  102. Giannicola, R. et al. Early blood rise in auto-antibodies to nuclear and smooth muscle antigens is predictive of prolonged survival and autoimmunity in metastatic-non-small cell lung cancer patients treated with PD-1 immune-check point blockade by nivolumab. Mol. Clin. Oncol. 11, 81–90 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. de Moel, E. C. et al. Autoantibody development under treatment with immune-checkpoint inhibitors. Cancer Immunol. Res. 7, 6–11 (2019).

    Article  PubMed  Google Scholar 

  104. Hasan Ali, O. et al. BP180-specific IgG is associated with skin adverse events, therapy response, and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors. J. Am. Acad. Dermatol. 82, 854–861 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Tahir, S. A. et al. Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities. Proc. Natl Acad. Sci. USA 116, 22246–22251 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gowen, M. F. et al. Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors. J. Transl. Med. 16, 82 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kurimoto, C. et al. Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors. Cancer Sci. 111, 1468–1477 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Khan, S. et al. Late-onset immunotherapy toxicity and delayed autoantibody changes: checkpoint inhibitor-induced Raynaud’s-like phenomenon. Oncologist 25, e753–e757 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Raibagkar, P., Ho, D., Gunturu, K. S. & Srinivasan, J. Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: Case report and review of literature. J. Neuroimmunol. 341, 577184 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Osaki, M. et al. Anti-transcriptional intermediary factor 1-γ antibody-positive dermatomyositis induced by nivolumab for lung adenocarcinoma: A case report. Invest. N. Drugs 39, 251–255 (2020).

    Article  CAS  Google Scholar 

  111. Olson, D. J. et al. A case of dual-mechanism immune-related anaemia in a patient with metastatic melanoma treated with nivolumab and ipilimumab. J. Immunother. Cancer 8, e000380 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hassel, J. C. et al. Autoantibodies as predictors for survival and immune-related adverse events in checkpoint inhibition therapy of metastasized melanoma. J. Clin. Oncol. 38 (Suppl.), Abstr. 10011 (2020). This article reports that autoantibodies are associated with immune-related toxicities.

    Article  Google Scholar 

  113. Damin, D. C. et al. Effects of the gastrin-releasing peptide antagonist RC-3095 in a rat model of ulcerative colitis. Dig. Dis. Sci. 55, 2203–2210 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Bins, S. et al. Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients. Br. J. Cancer 118, 1296–1301 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Refae, S. et al. Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors. Invest. N. Drugs 38, 160–171 (2020).

    Article  CAS  Google Scholar 

  117. Simpson, D. et al. Anti-CTLA4 toxicity associates with genetic variation correlating with serum antibody diversity. Ann. Oncol. 29, viii421 (2018).

    Article  Google Scholar 

  118. Yano, S. et al. Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency. Eur. J. Cancer 130, 198–203 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Cortellini, A. et al. Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study. Oncologist 24, e327–e337 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Menzies, A. M. et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann. Oncol. 28, 368–376 (2017). This article describes that anti-PD1 therapy can be tolerated in patients with autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  121. Abu-Sbeih, H. et al. Immune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease. J. Clin. Oncol. 38, 576–583 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Naqash, A. R. et al. Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort. Cancer Immunol. Immunother. 69, 1177–1187 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Weinstock, C. et al. An FDA analysis of the association between adverse events and outcome in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody. J. Clin. Oncol. https://doi.org/10.1200/JCO.2019.37.15_suppl.4549 (2017).

  124. Verzoni, E. et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J. Immunother. Cancer 7, 99–108 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Abu-Sbeih, H. et al. The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients’ outcomes. J. Immunother. Precis. Oncol. 1, 7–18 (2018).

    Article  Google Scholar 

  126. Robert, C., Hwu, W. J., Hamid, O., Ribas, A. & Weber, J. S. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: a landmark analysis in patients with advanced melanoma. Eur. J. Cancer 144, 182–191 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Eggermont, A. M. M. et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol. 6, 519–527 (2020). This article reports immune toxicities associated with positive outcome in resected melanoma.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Mandalà, M. et al. An analysis of nivolumab-mediated adverse events and association with clinical efficacy in resected stage III or IV melanoma (CheckMate 238). J. Clin. Oncol. https://doi.org/10.1200/JCO.2019.37.15_suppl.9584 (2019).

  129. Hosoya, K. & et al. Association between early immune-related adverse events and clinical outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors. Clin. Lung Cancer https://doi.org/10.1016/j.cllc.2020.01.003 (2020).

  130. Perez-Ruiz, E. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569, 428–432 (2019). This article reveals that TNF inhibition may reduce immune toxicity but not clinical efficacy.

    Article  CAS  PubMed  Google Scholar 

  131. Affolter, T. et al. Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice. PLoS ONE 14, e0217276 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liu, J. et al. Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer. Cancer Res. 76, 5288–5301 (2016).

    Article  CAS  PubMed  Google Scholar 

  133. Tsuruoka, K. et al. Exacerbation of autoimmune myocarditis by an immune checkpoint inhibitor is dependent on its time of administration in mice. Int. J. Cardiol. 313, 67–75 (2020).

    Article  PubMed  Google Scholar 

  134. Williams, T. J. et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 73, 928–933 (2016).

    Article  PubMed  Google Scholar 

  135. Marschner, D. et al. MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors. JCI Insight 5, e132334 (2020).

    Article  PubMed Central  Google Scholar 

  136. Song, M. Y. et al. Protective effects of Fc-fused PD-L1 on two different animal models of colitis. Gut 64, 260–271 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Wang, F., Yin, Q., Chen, L. & Davis, M. M. Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade. Proc. Natl Acad. Sci. USA 115, 157–161 (2018).

    Article  CAS  PubMed  Google Scholar 

  138. Lebbé, C. et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV Checkmate 511 trial. J. Clin. Oncol. 37, 867–875 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Diab, A. et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 10, 1158–1173 (2020).

    Article  CAS  PubMed  Google Scholar 

  141. Autio, K. A., Boni, V., Humphrey, R. W. & Naing, A. Probody therapeutics: an emerging class of therapies designed to enhance on-target effects with reduced off-tumor toxicity for use in immuno-oncology. Clin. Cancer Res. 26, 984–989 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Doms, J., Prior, J. O., Peters, S. & Obeid, M. Tocilizumab for refractory severe immune checkpoint inhibitor-associated myocarditis. Ann. Oncol. 31, 1273–1275 (2020).

    Article  CAS  PubMed  Google Scholar 

  143. Haanen, J. et al. Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Ann. Oncol. 21, 724–744 (2020).

    Article  Google Scholar 

  144. Haanen, J. et al. Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy. J. Immunother. Cancer 8, e000604 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Verheijden, R. J. et al. Association of anti-TNF with decreased survival in steroid refractory ipilimumab and anti-PD1-treated patients in the dutch melanoma treatment registry. Clin. Cancer Res. 26, 2268–2274 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Esfahani, K., Hudson, M. & Batist, G. N. Tofacitinib for refractory immune-related colitis from PD-1 therapy. N. Engl. J. Med. 382, 2374–2375 (2020).

    Article  PubMed  Google Scholar 

  147. Risbjerg, R. S., Hansen, M. V., Sørensen, A. S. & Kragstrup, T. W. The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition. Exp. Hematol. Oncol. 9, 9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shiuan, E. et al. Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy. J. Immunother. Cancer 5, 8 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Damsky, W. et al. B cell depletion or absence does not impede anti-tumor activity of PD-1inhibitors. J. Immunother. Cancer 7, 153 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Ghosn, J. et al. A severe case of neuro-Sjögren’s syndrome induced by pembrolizumab. J. Immunother. Cancer 22, 110 (2018).

    Article  Google Scholar 

  151. Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ascierto, P. A. et al. Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy. J. Clin. Oncol. 35, 9520 (2017).

    Article  Google Scholar 

  153. Siu, L. L. et al. Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors [abstract]. Cancer Res. 78 (Suppl.), CT180 (2018).

  154. Goldman, J. W. et al. Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors. J. Clin. Oncol. 38, 3003 (2020).

    Article  Google Scholar 

  155. Angevin, E. et al. Updated analysis of the inducible T-cell co-stimulatory receptor (ICOS) agonist, GSK3359609 (GSK609), combination with pembrolizumab (PE) in patients (pts) with anti-PD-1/L1 treatment-naïve head and neck squamous cell carcinoma (HNSCC). J. Clin. Oncol. 38, 6517 (2020).

    Article  Google Scholar 

  156. Abu-Sbeih, H. et al. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis. J. Immunother. Cancer 7, 93 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ryan J. Sullivan

  2. Laura and Isaac Perlmutter Comprehensive Cancer Center, NYU Grossman School of Medicine, New York, NY, USA

    Jeffrey S. Weber

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The authors contributed equally to all aspects of the article.

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Correspondence to Jeffrey S. Weber.

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Competing interests

J.S.W. is a consultant for Merck, Genentech, AstraZeneca, Pfizer, Regeneron, GSK, Alkermes, Novartis, Celldex, Incyte and EMD Serono. He is a member of the advisory board for BMS, and holds equity in CytoMx, Biond, Neximmune and Immunimax. He is also part of the scientific advisory boards for Celldex, CytoMx, Incyte, Biond, Neximmune and Sellas. J.S.W.’s laboratory has received research support from BMS, Merck, GSK, Novartis, Moderna and AstraZeneca. Moffitt Cancer Center filed a patent on an ipilimumab biomarker and a TIL growth method, in which J.S.W. has been named, as well as in a PD1 biomarker patent by Biodesix. R.J.S. declares no competing interests.

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Glossary

Clonotype

Unique sequence of a T cell receptor chain

Tertiary lymphoid structures

Lymph node-like structures found within the stroma of some tumours.

Bullous pemphigoid

An autoimmune skin disease marked by formation of bullae or blisters, urticarial lesions (hives) and itching due to an immune reaction against desmosomes responsible for anchoring the epidermis and the dermis.

Stevens–Johnson syndrome/toxic epidermal necrolysis

A disorder of the skin and mucous membranes that causes the skin to peel off and die.

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Also known as chronic lymphocytic thyroiditis. An autoimmune condition of the thyroid that presents initially with acute hyperthyroidism and then evolves to a ‘burnt-out’ thyroid with hypothyroidism.

Cholestasis

Slowing of the flow of bile from the liver.

ST segment

Flat segment of the electrocardiogram between the end of the S wave and the beginning of the T wave.

Troponin

A complex of three regulatory proteins found in muscle that indicate heart damage when elevated.

Guillain–Barré syndrome

An autoimmune condition in which there is ascending paralysis starting in the lower extremities.

Autoantibodies

Antibodies that react with normal self-tissue and are often a marker for activity of various autoimmune diseases and themselves can cause pathology.

Time-delay bias

An overestimation of survival or another parameter due to an excess of cases detected later in the course of a disease.

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Sullivan, R.J., Weber, J.S. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies. Nat Rev Drug Discov 21, 495–508 (2022). https://doi.org/10.1038/s41573-021-00259-5

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