Skip to main content

Advertisement

SpringerLink
Log in

Moving towards personalized treatments of immune-related adverse events

  • Review Article
  • Published:

From Nature Reviews Clinical Oncology

View current issue Sign up to alerts

Abstract

The enhancement of immune responses upon treatment with immune checkpoint inhibitors can have the desired outcome of reinvigorating antitumour immune surveillance, but often at the expense of immune-related adverse events (irAEs). This novel disease entity often prompts comparisons with, and extrapolation of treatment approaches from, primary autoimmune disorders. Accordingly, current treatment guidelines for irAEs make generic recommendations adapted from the literature describing primary autoimmune diseases, without taking into consideration the substantial disparity of the immunohistopathological findings within each organ affected by an irAE. The treatment modalities themselves are complex and have many potential drawbacks, such as serious and rarely fatal infections, drug toxicities overlapping with irAEs and the risk of compromising cancer immune surveillance. Herein, we provide an overview of key cellular and soluble immunological factors mediating irAEs and propose a model integrating this knowledge with the immunohistopathological findings of the affected organs for a personalized decision-making process for each patient.

Key points

  • Immune-related adverse events (irAEs) are occasionally serious, and rarely fatal, complications derived from treatment with immune checkpoint inhibitors (ICIs).

  • irAEs can result from either a breach of self-tolerance resulting in the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction.

  • Corticosteroids remain the cornerstone of the treatment of irAEs; however, biological immunomodulatory agents are often needed in patients with severe reactions or reactions affecting vital organs.

  • We propose a personalized immunohistopathologically guided process for choosing the appropriate treatment regimen beyond first-line corticosteroids.

  • Immunomodulatory treatments can have organ-specific toxicities overlapping with the sites affected by irAEs; they can also be associated with an increased risk of serious infections and possible blunting of effects from ICIs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Proposed immunopathogenic mechanisms for immune-related adverse events.
Fig. 2: Most commonly observed histopathological findings by affected organ systems.
Fig. 3: Proposed personalized treatment algorithm for the management of immune-related adverse events.

Similar content being viewed by others

References

  1. June, C. H., Warshauer, J. T. & Bluestone, J. A. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat. Med. 23, 540–547 (2017).

    CAS  PubMed  Google Scholar 

  2. 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 2, e192535 (2019).

    PubMed  PubMed Central  Google Scholar 

  3. Thapa, B. et al. Incidence and clinical pattern of immune related adverse effects (irAE) due to immune checkpoint inhibitors (ICI) [abstract]. J. Clin. Oncol. 37 (Suppl. 15), e14151 (2019).

    Google Scholar 

  4. 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).

    PubMed  PubMed Central  Google Scholar 

  5. Shoushtari, A. N. et al. Measuring toxic effects and time to treatment failure for nivolumab plus ipilimumab in melanoma. JAMA Oncol. 4, 98–101 (2018).

    PubMed  Google Scholar 

  6. Johnson, D. B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749–1755 (2016).

    PubMed  PubMed Central  Google Scholar 

  7. Berner, F. et al. Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer. JAMA Oncol. 5, 1043–1047 (2019).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  9. Calabrese, L. H., Calabrese, C. & Cappelli, L. C. Rheumatic immune-related adverse events from cancer immunotherapy. Nat. Rev. Rheumatol. 14, 569–579 (2018).

    PubMed  Google Scholar 

  10. Godwin, J. L. et al. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J. Immunother. Cancer 5, 40 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Mammen, A. L. et al. Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann. Rheum. Dis. 78, 150–152 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Calabrese, C. et al. Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature. RMD Open 5, e000906 (2019).

    PubMed  PubMed Central  Google Scholar 

  14. Hoefsmit, E. P., Rozeman, E. A., Haanen, J. & Blank, C. U. Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events. ESMO Open 4, e000472 (2019).

    PubMed  PubMed Central  Google Scholar 

  15. Abdel-Wahab, N., Shah, M., Lopez-Olivo, M. A. & Suarez-Almazor, M. E. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review. Ann. Intern. Med. 168, 121–130 (2018).

    PubMed  Google Scholar 

  16. Brahmer, J. R. 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. 36, 1714–1768 (2018).

    CAS  PubMed  Google Scholar 

  17. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Haanen, J. et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 28 (Suppl. 4), iv119–iv142 (2017).

    CAS  PubMed  Google Scholar 

  19. Mamlouk, O. et al. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J. Immunother. Cancer 7, 2 (2019).

    PubMed  PubMed Central  Google Scholar 

  20. Moreira, A. et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur. J. Cancer 106, 12–23 (2019).

    CAS  PubMed  Google Scholar 

  21. Kastner, D. L., Aksentijevich, I. & Goldbach-Mansky, R. Autoinflammatory disease reloaded: a clinical perspective. Cell 140, 784–790 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. McGonagle, D. & McDermott, M. F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).

    PubMed  PubMed Central  Google Scholar 

  23. Strober, W. & Watanabe, T. NOD2, an intracellular innate immune sensor involved in host defense and Crohn’s disease. Mucosal Immunol. 4, 484–495 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Franzosa, E. A. et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 4, 293–305 (2019).

    CAS  PubMed  Google Scholar 

  25. Khoja, L., Day, D., Wei-Wu Chen, T., Siu, L. L. & Hansen, A. R. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann. Oncol. 28, 2377–2385 (2017).

    CAS  PubMed  Google Scholar 

  26. Ko, J. M., Gottlieb, A. B. & Kerbleski, J. F. Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J. Dermatol. Treat. 20, 100–108 (2009).

    CAS  Google Scholar 

  27. Iwahashi, C. et al. New onset or exacerbation of uveitis with infliximab: paradoxical effects? BMJ Open Ophthalmol. 4, e000250 (2019).

    PubMed  PubMed Central  Google Scholar 

  28. Oh, D. Y. et al. Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res. 77, 1322–1330 (2017).

    CAS  PubMed  Google Scholar 

  29. Libert, C. & Dejager, L. How steroids steer T cells. Cell Rep. 7, 938–939 (2014).

    CAS  PubMed  Google Scholar 

  30. Allison, A. C. Mechanisms of action of mycophenolate mofetil. Lupus 14, s2–s8 (2005).

    CAS  PubMed  Google Scholar 

  31. Fixsen, E., Patel, J., Selim, M. A. & Kheterpal, M. Resolution of pembrolizumab-associated steroid-refractory lichenoid dermatitis with cyclosporine. Oncologist 24, e103–e105 (2019).

    PubMed  PubMed Central  Google Scholar 

  32. 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).

    PubMed  PubMed Central  Google Scholar 

  33. Ornstein, M. C. et al. Myalgia and arthralgia immune-related adverse events (irAEs) in patients with genitourinary malignancies treated with immune checkpoint inhibitors. Clin. Genitourin. Cancer 17, 177–182 (2019).

    PubMed  Google Scholar 

  34. Spathas, N. et al. Inflammatory arthritis induced by pembrolizumab in a patient with head and neck squamous cell carcinoma. Front. Oncol. 8, 409 (2018).

    PubMed  PubMed Central  Google Scholar 

  35. Kuswanto, W. F. et al. Rheumatologic symptoms in oncologic patients on PD-1 inhibitors. Semin. Arthritis Rheum. 47, 907–910 (2018).

    CAS  PubMed  Google Scholar 

  36. Cappelli, L. C., Gutierrez, A. K., Bingham, C. O. III & Shah, A. A. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res. 69, 1751–1763 (2017).

    Google Scholar 

  37. 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).

    PubMed  PubMed Central  Google Scholar 

  38. Hottinger, A. F. et al. Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. Neurol. Neuroimmunol. Neuroinflamm 5, e439 (2018).

    PubMed  PubMed Central  Google Scholar 

  39. Chmiel, K. D. et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J. Clin. Oncol. 29, e237–e240 (2011).

    CAS  PubMed  Google Scholar 

  40. Ahmed, T., Pandey, R., Shah, B. & Black, J. Resolution of ipilimumab induced severe hepatotoxicity with triple immunosuppressants therapy. BMJ Case Reports 2015, bcr2014208102 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. Tay, R. Y. et al. Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br. J. Cancer 117, 921–924 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Esfahani, K. et al. Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N. Engl. J. Med. 380, 2375–2376 (2019).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  44. Arbour, K. C. et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J. Clin. Oncol. 36, 2872–2878 (2018).

    CAS  PubMed  Google Scholar 

  45. Scott, S. C. & Pennell, N. A. Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab. J. Thorac. Oncol. 13, 1771–1775 (2018).

    PubMed  Google Scholar 

  46. Fucà, G. et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 4, e000457 (2019).

    PubMed  PubMed Central  Google Scholar 

  47. Horvat, T. Z. 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. 33, 3193–3198 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    CAS  PubMed  Google Scholar 

  49. Faje, A. T. et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 124, 3706–3714 (2018).

    CAS  PubMed  Google Scholar 

  50. Rady, M. Y., Johnson, D. J., Patel, B., Larson, J. & Helmers, R. Corticosteroids influence the mortality and morbidity of acute critical illness. Crit. Care 10, R101 (2006).

    PubMed  PubMed Central  Google Scholar 

  51. Sage, P. T., Paterson, A. M., Lovitch, S. B. & Sharpe, A. H. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41, 1026–1039 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Thibult, M. L. et al. PD-1 is a novel regulator of human B-cell activation. Int. Immunol. 25, 129–137 (2013).

    CAS  PubMed  Google Scholar 

  53. Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Schwab, C. et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J. Allergy Clin. Immunol. 142, 1932–1946 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Rakhmanov, M. et al. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc. Natl Acad. Sci. USA 106, 13451–13456 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  61. Dutertre, M., de Menthon, M., Noel, N., Albiges, L. & Lambotte, O. Cold agglutinin disease as a new immune-related adverse event associated with anti-PD-L1s and its treatment with rituximab. Eur. J. Cancer 110, 21–23 (2019).

    CAS  PubMed  Google Scholar 

  62. Ghosn, J. et al. A severe case of neuro-Sjogren’s syndrome induced by pembrolizumab. J. Immunother. Cancer 6, 110 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Kazatchkine, M. D. & Kaveri, S. V. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N. Engl. J. Med. 345, 747–755 (2001).

    CAS  PubMed  Google Scholar 

  64. Meti, N., Petrogiannis-Haliotis, T. & Esfahani, K. Refractory neutropenia secondary to dual immune checkpoint inhibitors that required second-line immunosuppression. J. Oncol. Pract. 14, 514–516 (2018).

    PubMed  Google Scholar 

  65. Gilardin, L., Bayry, J. & Kaveri, S. V. Intravenous immunoglobulin as clinical immune-modulating therapy. CMAJ 187, 257–264 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Mariotti, F. R., Quatrini, L., Munari, E., Vacca, P. & Moretta, L. Innate lymphoid cells: expression of PD-1 and other checkpoints in normal and pathological conditions. Front. Immunol. 10, 910 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Schindler, K. et al. Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab [abstract]. J. Clin. Oncol. 32 (Suppl. 15), 9096 (2014).

    Google Scholar 

  69. Esfahani, K. et al. Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation. Nat. Commun. 10, 4712 (2019).

    PubMed  PubMed Central  Google Scholar 

  70. Kizawa, R. et al. Eosinophilia during treatment of immune checkpoint inhibitors (ICIs) to predict succeeding onset of immune-related adverse events (irAEs) [abstract]. J. Clin. Oncol. 37 (Suppl. 15), e14110 (2019).

    Google Scholar 

  71. Hua, W. et al. Rapamycin inhibition of eosinophil differentiation attenuates allergic airway inflammation in mice. Respirology 20, 1055–1065 (2015).

    PubMed  Google Scholar 

  72. Zhu, C. et al. mTOR complexes differentially orchestrates eosinophil development in allergy. Sci. Rep. 8, 6883 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  76. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Elkrief, A., Derosa, L., Kroemer, G., Zitvogel, L. & Routy, B. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann. Oncol. 30, 1572–1579 (2019).

    CAS  PubMed  Google Scholar 

  81. Abu-Sbeih, H. et al. Impact of antibiotic therapy on the development and response to treatment of immune checkpoint inhibitor-mediated diarrhea and colitis. J. Immunother. Cancer 7, 242 (2019).

    PubMed  PubMed Central  Google Scholar 

  82. Carswell, E. A. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Haranaka, K., Satomi, N. & Sakurai, A. Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. Int. J. Cancer 34, 263–267 (1984).

    CAS  PubMed  Google Scholar 

  84. Roberts, N. J., Zhou, S., Diaz, L. A. Jr. & Holdhoff, M. Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2, 739–751 (2011).

    PubMed  PubMed Central  Google Scholar 

  85. Efimov, G. A., Kruglov, A. A., Tillib, S. V., Kuprash, D. V. & Nedospasov, S. A. Tumor necrosis factor and the consequences of its ablation in vivo. Mol. Immunol. 47, 19–27 (2009).

    CAS  PubMed  Google Scholar 

  86. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Soularue, E. et al. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut 67, 2056–2067 (2018).

    CAS  PubMed  Google Scholar 

  88. Braaten, T. J. et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann. Rheum. Dis. 79, 332–338 (2020).

    PubMed  Google Scholar 

  89. Johnson, D. H. et al. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J. Immunother. Cancer 6, 103 (2018).

    PubMed  PubMed Central  Google Scholar 

  90. Badran, Y. R. et al. Concurrent therapy with immune checkpoint inhibitors and TNFalpha blockade in patients with gastrointestinal immune-related adverse events. J. Immunother. Cancer 7, 226 (2019).

    PubMed  PubMed Central  Google Scholar 

  91. 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).

    CAS  PubMed  Google Scholar 

  92. Bertrand, F. et al. TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat. Commun. 8, 2256 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Head, L. et al. Biomarkers to predict immune-related adverse events with checkpoint inhibitors [abstract]. J. Clin. Oncol. 37 (Suppl. 8), 131 (2019).

    Google Scholar 

  94. Naidoo, J. et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J. Clin. Oncol. 35, 709–717 (2017).

    CAS  PubMed  Google Scholar 

  95. Slattery, E. et al. Myocarditis associated with infliximab: a case report and review of the literature. Inflamm. Bowel Dis. 17, 1633–1634 (2011).

    PubMed  Google Scholar 

  96. Zhang, H. C., Luo, W. & Wang, Y. Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab. J. Immunother. Cancer 7, 47 (2019).

    PubMed  PubMed Central  Google Scholar 

  97. Edwards, A. et al. Corticosteroids and infliximab impair the performance of interferon-gamma release assays used for diagnosis of latent tuberculosis. Thorax 72, 946–949 (2017).

    PubMed  Google Scholar 

  98. Calabrese, L. H. & Rose-John, S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat. Rev. Rheumatol. 10, 720–727 (2014).

    CAS  PubMed  Google Scholar 

  99. Rossi, J. F., Lu, Z. Y., Jourdan, M. & Klein, B. Interleukin-6 as a therapeutic target. Clin. Cancer Res. 21, 1248–1257 (2015).

    CAS  PubMed  Google Scholar 

  100. Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

    CAS  PubMed  Google Scholar 

  101. Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Wei, L. H. et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22, 1517–1527 (2003).

    CAS  PubMed  Google Scholar 

  103. Hirano, T., Ishihara, K. & Hibi, M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548–2556 (2000).

    CAS  PubMed  Google Scholar 

  104. Weber, J. S. et al. Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 100 (2019).

    Google Scholar 

  105. Naqash, A. R., Yang, L. V., Sanderlin, E. J., Atwell, D. C. & Walker, P. R. Interleukin-6 as one of the potential mediators of immune-related adverse events in non-small cell lung cancer patients treated with immune checkpoint blockade: evidence from a case report. Acta Oncol. 57, 705–708 (2018).

    PubMed  Google Scholar 

  106. Okiyama, N. & Tanaka, R. Varied immuno-related adverse events induced by immune-check point inhibitors - Nivolumab-associated psoriasiform dermatitis related with increased serum level of interleukin-6 [Japanese]. Nihon Rinsho Meneki Gakkai Kaishi 40, 95–101 (2017).

    CAS  PubMed  Google Scholar 

  107. Saibil, S. D. et al. Fatal myocarditis and rhabdomyositis in a patient with stage IV melanoma treated with combined ipilimumab and nivolumab. Curr. Oncol. 26, e418–e421 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Yoshino, K., Nakayama, T., Ito, A., Sato, E. & Kitano, S. Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports. BMC Cancer 19, 1019 (2019).

    PubMed  PubMed Central  Google Scholar 

  109. Phillips, G. S. et al. Treatment outcomes of immune-related cutaneous adverse events. J. Clin. Oncol. 37, 2746–2758 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Stroud, C. R. et al. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J. Oncol. Pharm. Pract. 25, 551–557 (2019).

    CAS  PubMed  Google Scholar 

  111. Nishikawa, T. et al. Transcriptional complex formation of c-Fos, STAT3, and hepatocyte NF-1 alpha is essential for cytokine-driven C-reactive protein gene expression. J. Immunol. 180, 3492–3501 (2008).

    CAS  PubMed  Google Scholar 

  112. Mace, T. A. et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67, 320–332 (2018).

    CAS  PubMed  Google Scholar 

  113. Tsukamoto, H. et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 78, 5011–5022 (2018).

    CAS  PubMed  Google Scholar 

  114. Liu, H., Shen, J. & Lu, K. IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model. Biochem. Biophys. Res. Commun. 486, 239–244 (2017).

    CAS  PubMed  Google Scholar 

  115. Rose-John, S., Winthrop, K. & Calabrese, L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat. Rev. Rheumatol. 13, 399–409 (2017).

    CAS  PubMed  Google Scholar 

  116. Nishimoto, N., Ito, K. & Takagi, N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod. Rheumatol. 20, 222–232 (2010).

    CAS  PubMed  Google Scholar 

  117. Campbell, L., Chen, C., Bhagat, S. S., Parker, R. A. & Ostor, A. J. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology 50, 552–562 (2011).

    CAS  PubMed  Google Scholar 

  118. Zhao, L. et al. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One 6, e18909 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Ahn, S. S. et al. Safety of tocilizumab in rheumatoid arthritis patients with resolved hepatitis B virus infection: data from real-world experience. Yonsei Med. J. 59, 452–456 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Brembilla, N. C., Senra, L. & Boehncke, W. H. The IL-17 family of cytokines in psoriasis: IL-17A and beyond. Front. Immunol. 9, 1682 (2018).

    PubMed  PubMed Central  Google Scholar 

  121. Miossec, P. Update on interleukin-17: a role in the pathogenesis of inflammatory arthritis and implication for clinical practice. RMD Open 3, e000284 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. Kuwabara, T., Ishikawa, F., Kondo, M. & Kakiuchi, T. The role of IL-17 and related cytokines in inflammatory autoimmune diseases. Mediators Inflamm. 2017, 3908061 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  124. Mangan, P. R. et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231–234 (2006).

    CAS  PubMed  Google Scholar 

  125. Yasuda, K., Takeuchi, Y. & Hirota, K. The pathogenicity of Th17 cells in autoimmune diseases. Semin. Immunopathol. 41, 283–297 (2019).

    PubMed  Google Scholar 

  126. Knochelmann, H. M. et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol. Immunol. 15, 458–469 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Tarhini, A. A. et al. Baseline circulating IL-17 predicts toxicity while TGF-beta1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J. Immunother. Cancer 3, 39 (2015).

    PubMed  PubMed Central  Google Scholar 

  128. Callahan, M. K. et al. Evaluation of serum IL-17 levels during ipilimumab therapy: correlation with colitis [abstract]. J. Clin. Oncol. 29 (Suppl. 15), 2505 (2011).

    Google Scholar 

  129. Esfahani, K. & Miller, W. H. Jr. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N. Engl. J. Med. 376, 1989–1991 (2017).

    PubMed  Google Scholar 

  130. Johnson, D. et al. IL17A blockade successfully treated psoriasiform dermatologic toxicity from immunotherapy. Cancer Immunol. Res. 7, 860–865 (2019).

    PubMed  Google Scholar 

  131. Reddy, S. et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N. Engl. J. Med. 360, 2438–2444 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sims, J. E. & Smith, D. E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10, 89–102 (2010).

    CAS  PubMed  Google Scholar 

  133. Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).

    CAS  PubMed  Google Scholar 

  134. Suresh, K. et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J. Clin. Invest. 130, 4305–4315 (2019).

    Google Scholar 

  135. Lim, S. Y. et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Clin. Cancer Res. 25, 1557–1563 (2019).

    CAS  PubMed  Google Scholar 

  136. Dinarello, C. A., Simon, A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug. Discov. 11, 633–652 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Mantovani, A., Barajon, I. & Garlanda, C. IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol. Rev. 281, 57–61 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Cavalli, G. & Dinarello, C. A. Anakinra therapy for non-cancer inflammatory diseases. Front. Pharmacol. 9, 1157 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ngiow, S. F., Teng, M. W. & Smyth, M. J. A balance of interleukin-12 and -23 in cancer. Trends Immunol. 34, 548–555 (2013).

    CAS  PubMed  Google Scholar 

  140. Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    CAS  PubMed  Google Scholar 

  141. Zou, J. J. et al. Structure-function analysis of the p35 subunit of mouse interleukin 12. J. Biol. Chem. 270, 5864–5871 (1995).

    CAS  PubMed  Google Scholar 

  142. Papp, K. A. et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N. Engl. J. Med. 376, 1551–1560 (2017).

    CAS  PubMed  Google Scholar 

  143. Baccala, R., Kono, D. H. & Theofilopoulos, A. N. Interferons as pathogenic effectors in autoimmunity. Immunol. Rev. 204, 9–26 (2005).

    CAS  PubMed  Google Scholar 

  144. Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    CAS  PubMed  Google Scholar 

  145. Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005).

    CAS  PubMed  Google Scholar 

  146. Sandborn, W. J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 376, 1723–1736 (2017).

    CAS  PubMed  Google Scholar 

  147. Lee, E. B. et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370, 2377–2386 (2014).

    PubMed  Google Scholar 

  148. Karachaliou, N. et al. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther. Adv. Med. Oncol. 10, 1758834017749748 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Shin, D. S. et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017).

    CAS  PubMed  Google Scholar 

  151. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Jacquelot, N. et al. Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade. Cell Res. 29, 846–861 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Pitroda, S. P. et al. JAK2 Inhibitor SAR302503 abrogates PD-L1 expression and targets therapy-resistant non-small cell lung cancers. Mol. Cancer Ther. 17, 732–739 (2018).

    CAS  PubMed  Google Scholar 

  154. Lu, C., Talukder, A., Savage, N. M., Singh, N. & Liu, K. JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer. Oncoimmunology 6, e1291106 (2017).

    PubMed  PubMed Central  Google Scholar 

  155. Bournazou, E. & Bromberg, J. Targeting the tumor microenvironment: JAK-STAT3 signaling. JAKSTAT 2, e23828 (2013).

    PubMed  PubMed Central  Google Scholar 

  156. Ghoreschi, K. et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 186, 4234–4243 (2011).

    CAS  PubMed  Google Scholar 

  157. Fleischmann, R. et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial. Arthritis Rheumatol. 71, 1788–1800 (2019).

    CAS  PubMed  Google Scholar 

  158. Wollenhaupt, J. et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res. Ther. 21, 89 (2019).

    PubMed  PubMed Central  Google Scholar 

  159. Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).

    CAS  PubMed  Google Scholar 

  160. Perl, A. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann. N. Y. Acad. Sci. 1346, 33–44 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Abdel-Wahab, N. et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J. Immunother. Cancer 7, 106 (2019).

    PubMed  PubMed Central  Google Scholar 

  162. Albiges, L. et al. Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann. Oncol. 23, 1943–1953 (2012).

    CAS  PubMed  Google Scholar 

  163. Michot, J.-M. et al. The ImmunoTOX multidisciplinary board: A descriptive study of collaborative management of immune-related adverse events [abstract 1756PD]. Ann. Oncol. 30 (Suppl. 5), v719 (2019).

    Google Scholar 

  164. Naidoo, J. et al. A multidisciplinary toxicity team for cancer immunotherapy-related adverse events. J. Natl Compr. Canc Netw. 17, 712–720 (2019).

    PubMed  Google Scholar 

  165. Wagar, L. E., DiFazio, R. M. & Davis, M. M. Advanced model systems and tools for basic and translational human immunology. Genome Med. 10, 73 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Richards, D. M., Kyewski, B. & Feuerer, M. Re-examining the nature and function of self-reactive T cells. Trends Immunol. 37, 114–125 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Richardson, B. The interaction between environmental triggers and epigenetics in autoimmunity. Clin. Immunol. 192, 1–5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Kepp, O., Marabelle, A., Zitvogel, L. & Kroemer, G. Oncolysis without viruses – inducing systemic anticancer immune responses with local therapies. Nat. Rev. Clin. Oncol. 17, 49–64 (2020).

    CAS  PubMed  Google Scholar 

  170. Rojas, M. et al. Molecular mimicry and autoimmunity. J. Autoimmun. 95, 100–123 (2018).

    CAS  PubMed  Google Scholar 

  171. Esfahani, K., Thebault, P., Lapointe, R., Jamal, R. & Miller, W. H. Correlation of immune-related adverse events with peripheral baseline immune markers and overall survival in patients with metastatic melanoma on ipilimumab and chemotherapy [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 9561 (2019).

    Google Scholar 

  172. Khan, S. et al. Immune dysregulation in cancer patients developing immune-related adverse events. Br. J. Cancer 120, 63–68 (2019).

    CAS  PubMed  Google Scholar 

  173. Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl Med. 6, 230ra245 (2014).

    Google Scholar 

  174. Desforges, P., Esfahani, K. & Bouganim, N. Programmed cell death ligand 1-induced coma from diffuse cerebritis. J. Oncol. Pract. 14, 134–135 (2018).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  177. Ganatra, S. & Neilan, T. G. Immune checkpoint inhibitor-associated myocarditis. Oncologist 23, 879–886 (2018).

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Oncology, McGill University, Montreal, Quebec, Canada

    Khashayar Esfahani, Arielle Elkrief & Wilson H. Miller Jr

  2. Department of Immunology and Rheumatology, Cleveland Clinic, Cleveland, OH, USA

    Cassandra Calabrese & Leonard Calabrese

  3. Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal and Institut du Cancer de Montréal, Montreal, Quebec, Canada

    Réjean Lapointe & Bertrand Routy

  4. Department of Medicine, Division of Rheumatology, McGill University, Montreal, Quebec, Canada

    Marie Hudson

Authors
  1. Khashayar Esfahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arielle Elkrief
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cassandra Calabrese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Réjean Lapointe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie Hudson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bertrand Routy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wilson H. Miller Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leonard Calabrese
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.E. and L.C. discussed the contents of this Review. K.E. performed the literature searches. All the authors contributed equally to the writing of the manuscript.

Corresponding author

Correspondence to Khashayar Esfahani.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks L. Cappelli, S. Champiat and M. Kostine for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ClinicalTrials.gov database: https://clinicaltrials.gov

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Esfahani, K., Elkrief, A., Calabrese, C. et al. Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol 17, 504–515 (2020). https://doi.org/10.1038/s41571-020-0352-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-020-0352-8

  • Springer Nature Limited

This article is cited by

Search

Navigation