Skip to main content
SpringerLink
Log in

Immunopathogenesis of Immune-Related Adverse Events from Cancer Immunotherapy

  • Chapter
  • First Online:
Rheumatic Diseases and Syndromes Induced by Cancer Immunotherapy

  • 358 Accesses

Abstract

The introduction of checkpoint inhibitors (ICIs) has revolutionized the treatment of many forms of cancer but has come at a price: the development of a new spectrum of immune-mediated toxicities affecting virtually every organ system. These toxicities, which range from being frequent and mild to rare and severe (even fatal), frequently limit the use of ICIs. The immune-mediated toxicities are referred to as immune-related adverse events (irAEs), pose formidable challenges to both the patient and the provider, and require interprofessional collaboration for optimal management. Many of the agents used to treat irAEs are drawn from the field of autoimmune diseases and are loosely based on similarities in clinical presentations between irAEs and the idiopathic forms of autoimmunity which they resemble. A detailed understanding of the immune mechanisms responsible for these irAEs is vital in order to allow the crafting of immunosuppressive/immunomodulatory therapies which will be effective but not compromise the basic antitumoral properties of ICI-based therapies. This chapter reviews current concepts of immunopathogenesis of irAEs and appraises data from in vitro preclinical models and human diseases to aid our understanding.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med. 2017;23(5):540–7.

    Article  CAS  PubMed  Google Scholar 

  2. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68.

    Article  CAS  PubMed  Google Scholar 

  3. McGonagle D, et al. Mechanistic classification of immune checkpoint inhibitor Toxicity as a pointer to minimal treatment strategies of selected emergent autoimmune diseases to further improve survival. Autoimmun Rev. 2020;19(2):102456

    Google Scholar 

  4. Martinez-Quiles N, Goldbach-Mansky R. Updates on autoinflammatory diseases. Curr Opin Immunol. 2018;55:97–105.

    Article  CAS  PubMed  Google Scholar 

  5. Kahlenberg JM, Kang I. The Clinicopathologic significance of Inflammasome activation in autoimmune diseases. Arthritis Rheumatol. 2019;

    Google Scholar 

  6. McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3(8):e297.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune-related adverse events from cancer immunotherapy. Nat Rev Rheumatol. 2018;14(10):569–79.

    Article  PubMed  Google Scholar 

  8. Johnson DB, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Young A, Quandt Z, Bluestone JA. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol Res. 2018;6(12):1445–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tivol EA, et al. 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(5):541–7.

    Article  CAS  PubMed  Google Scholar 

  11. Kuol N, et al. PD-1/PD-L1 in disease. Immunotherapy. 2018;10(2):149–60.

    Article  CAS  PubMed  Google Scholar 

  12. Lo B, Abdel-Motal UM. Lessons from CTLA-4 deficiency and checkpoint inhibition. Curr Opin Immunol. 2017;49:14–9.

    Article  CAS  PubMed  Google Scholar 

  13. Lo B, et al. CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood. 2016;128(8):1037–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schwab C, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Das R, et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest. 2018;

    Google Scholar 

  16. Olischewsky A, et al. Dose-dependent toxicity of ipilimumab in metastatic melanoma. Eur J Cancer. 2018;95:104–8.

    Article  CAS  PubMed  Google Scholar 

  17. Yoo SH, et al. Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity. ESMO Open. 2018;3(5):e000332.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nakamura Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44(2):117–22.

    Article  CAS  PubMed  Google Scholar 

  19. Deane KD, El-Gabalawy H. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE. Nat Rev Rheumatol. 2014;10(4):212–28.

    Article  CAS  PubMed  Google Scholar 

  20. Huang AC, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545(7652):60–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Calabrese C, et al. Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature. RMD Open. 2019;5(1):e000906.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Callahan MK, et al. Evaluation of serum IL-17 levels during ipilimumab therapy: correlation with colitis. J Clin Oncol. 2011;29(15_suppl):2505.

    Article  Google Scholar 

  23. Squibb B.-M. Yervoy (Ipilimumab), immune-mediated adverse reaction management guide. 2011. http://www.yervoy.com/hcp/rems.aspx.

  24. Khan S, et al. Immune dysregulation in cancer patients developing immune-related adverse events. Br J Cancer. 2019;120(1):63–8.

    Article  CAS  PubMed  Google Scholar 

  25. Curry JL, et al. Gene expression profiling of lichenoid dermatitis immune-related adverse event from immune checkpoint inhibitors reveals increased CD14(+) and CD16(+) monocytes driving an innate immune response. J Cutan Pathol. 2019;46(9):627–36.

    Article  PubMed  Google Scholar 

  26. Iwama S, Arima H. Clinical practice and mechanism of endocrinological adverse events associated with immune checkpoint inhibitors. Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(2):90–4.

    Article  CAS  PubMed  Google Scholar 

  27. Iwama S, et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014;6(230):230ra45.

    Article  PubMed  CAS  Google Scholar 

  28. Cappelli L, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 2016;

    Google Scholar 

  29. Naidoo J, et al. Inflammatory arthritis: a newly recognized adverse event of immune checkpoint blockade. Oncologist. 2017;22(6):627–30.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stamatouli AM, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes. 2018;67(8):1471–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shirai T, et al. Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol. 2016;46(1):86–8.

    Article  PubMed  Google Scholar 

  32. Cooling LL, et al. Development of red blood cell autoantibodies following treatment with checkpoint inhibitors: a new class of anti-neoplastic, immunotherapeutic agents associated with immune dysregulation. Immunohematology. 2017;33(1):15–21.

    Article  PubMed  Google Scholar 

  33. Mammen AL, 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. 2019;78(1):150–2.

    Article  CAS  PubMed  Google Scholar 

  34. Da Gama Duarte J, et al. Autoantibodies may predict immune-related toxicity: results from a phase I study of Intralesional Bacillus Calmette-Guerin followed by Ipilimumab in patients with advanced metastatic melanoma. Front Immunol. 2018;9:411.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Nielen MM, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380–6.

    Article  PubMed  Google Scholar 

  36. Calabrese LH. Sorting out the complexities of autoimmunity and checkpoint inhibitors: not so easy. Ann Intern Med. 2018;168(2):149–50.

    Article  PubMed  Google Scholar 

  37. Abdel-Hamid M, et al. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisiting autoimmune disease: a systematic review. Ann Intern Med. 2017;

    Google Scholar 

  38. Wei SC, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017;170(6):1120–33.e17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pacheco Y, et al. Bystander activation and autoimmunity. J Autoimmun. 2019;103:102301.

    Article  CAS  PubMed  Google Scholar 

  40. Rojas M, et al. Molecular mimicry and autoimmunity. J Autoimmun. 2018;95:100–23.

    Article  CAS  PubMed  Google Scholar 

  41. 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. 2019;5(7):1043–7.

    Article  PubMed  Google Scholar 

  42. Klein L, et al. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol. 2014;14(6):377–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ji C, et al. Myocarditis in cynomolgus monkeys following treatment with immune checkpoint inhibitors. Clin Cancer Res. 2019;

    Google Scholar 

  44. Heaney AP, et al. HLA markers DQ8 and DR53 are associated with lymphocytic Hypophysitis and may aid in differential diagnosis. J Clin Endocrinol Metab. 2015;100(11):4092–7.

    Article  CAS  PubMed  Google Scholar 

  45. Hasan Ali O, et al. Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. Eur J Cancer. 2019;107:8–14.

    Article  CAS  PubMed  Google Scholar 

  46. Cappelli LC, et al. Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis. Rheumatology (Oxford). 2018;

    Google Scholar 

  47. Anderson R, Rapoport BL. Immune dysregulation in Cancer patients undergoing immune checkpoint inhibitor treatment and potential predictive strategies for future clinical practice. Front Oncol. 2018;8:80.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sun JY, et al. Gut microbiome and cancer immunotherapy. J Cell Physiol. 2019;

    Google Scholar 

  49. Gopalakrishnan V, et al. The influence of the gut microbiome on Cancer, immunity, and Cancer immunotherapy. Cancer Cell. 2018;33(4):570–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gopalakrishnan V, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.

    Article  CAS  PubMed  Google Scholar 

  51. Helmink BA, et al. The microbiome, cancer, and cancer therapy. Nat Med. 2019;25(3):377–88.

    Article  CAS  PubMed  Google Scholar 

  52. Routy B, et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat Rev Clin Oncol. 2018;15(6):382–96.

    Article  CAS  PubMed  Google Scholar 

  53. Elkrief A, et al. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann Oncol. 2019;30(10):1572–9.

    Article  CAS  PubMed  Google Scholar 

  54. Goubet AG, et al. The impact of the intestinal microbiota in therapeutic responses against cancer. C R Biol. 2018;341(5):284–9.

    Article  PubMed  Google Scholar 

  55. Routy B, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.

    Article  CAS  PubMed  Google Scholar 

  56. Richardson B. The interaction between environmental triggers and epigenetics in autoimmunity. Clin Immunol. 2018;192:1–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kostine M, et al. Commonly used drugs in rheumatology may alter anti-tumoral reponse to immune checkpoint inhibitors {abstract}. Arthritis Rheumatol. 2019;71(suppl 10). https://acrabstracts.org/abstract/commonly-used-drugs-in-rheumatology-may-alter-anti-tumoral-response-to-immune-checkpoint-inhibitors/. Accessed September 9, 2020.

  58. Braaten TJ, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2019;

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    Leonard H. Calabrese

Authors
  1. Leonard H. Calabrese
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonard H. Calabrese .

Editor information

Editors and Affiliations

  1. Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Maria E. Suarez-Almazor

  2. Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    Leonard H. Calabrese

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Calabrese, L.H. (2021). Immunopathogenesis of Immune-Related Adverse Events from Cancer Immunotherapy. In: Suarez-Almazor, M.E., Calabrese, L.H. (eds) Rheumatic Diseases and Syndromes Induced by Cancer Immunotherapy. Springer, Cham. https://doi.org/10.1007/978-3-030-56824-5_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-56824-5_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-56823-8

  • Online ISBN: 978-3-030-56824-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation