Skip to main content

Advertisement

Log in

Immune-Related Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitors

  • Hot Topics (B Cronstein, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

With the advent of cancer immunotherapy and immune checkpoint inhibitors, patients with malignancies can now achieve durable remissions for conditions previously described as terminal. However, immune-related adverse events (irAEs) associated with cancer immunotherapy have become an anticipated consequence of enhanced T cell activation. Through an extensive literature review, we assess the most recent clinical and basic research data concerning immune checkpoint blockade and describe the spectrum of associated irAEs as well as their management.

Recent Findings

Anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies are widely used in the management of an array of tumors with incredible clinical remissions. However, irAEs cause significant morbidity and mortality and in some cases, result in withdrawal of cancer therapy and initiation of immunosuppression.

Summary

While this is an exciting time in oncology, irAEs are a barrier to adequate care and therefore deserve close attention and improved capacity to predict and prevent toxicity. Rheumatologists should be familiar with these topics in the eventuality of patient evaluation and management.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Weiden J, Tel J, Figdor CG. Synthetic immune niches for cancer immunotherapy. Nat Rev Immunol. 2018;18(3):212–9. https://doi.org/10.1038/nri.2017.89.

    Article  CAS  PubMed  Google Scholar 

  2. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73. https://doi.org/10.1186/s12916-016-0623-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8. https://doi.org/10.1038/ni1102-991.

    Article  CAS  PubMed  Google Scholar 

  5. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68. https://doi.org/10.1056/NEJMra1703481.

    Article  PubMed  Google Scholar 

  6. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14. https://doi.org/10.1016/j.cell.2015.03.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. CD28 costimulation: from mechanism to therapy. Immunity. 2016;44(5):973–88. https://doi.org/10.1016/j.immuni.2016.04.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28. https://doi.org/10.1056/NEJMoa063842.

    Article  CAS  PubMed  Google Scholar 

  9. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328(6127):267–70. https://doi.org/10.1038/328267a0.

    Article  CAS  PubMed  Google Scholar 

  10. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65. https://doi.org/10.1084/jem.182.2.459.

    Article  CAS  PubMed  Google Scholar 

  11. Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993;366(6450):76–9. https://doi.org/10.1038/366076a0.

    Article  CAS  PubMed  Google Scholar 

  12. Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA Jr, Lombard LA, et al. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993;262(5135):909–11. https://doi.org/10.1126/science.7694363.

    Article  CAS  PubMed  Google Scholar 

  13. Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, et al. The interaction properties of costimulatory molecules revisited. Immunity. 2002;17(2):201–10. https://doi.org/10.1016/S1074-7613(02)00362-X.

    Article  CAS  PubMed  Google Scholar 

  14. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51. https://doi.org/10.1016/S1074-7613(00)80089-8.

    Article  CAS  PubMed  Google Scholar 

  16. Tang W, Chen Y, Chen S, Sun B, Gu H, Kang M. Programmed death-1 (PD-1) polymorphism is associated with gastric cardia adenocarcinoma. Int J Clin Exp Med. 2015;8(5):8086–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Mojtahedi Z, Mohmedi M, Rahimifar S, Erfani N, Hosseini SV, Ghaderi A. Programmed death-1 gene polymorphism (PD-1.5 C/T) is associated with colon cancer. Gene. 2012;508(2):229–32. https://doi.org/10.1016/j.gene.2012.07.059.

    Article  CAS  PubMed  Google Scholar 

  18. • Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol. 2016;34:539–73. https://doi.org/10.1146/annurev-immunol-032414-112049. Excellent review of coinhibitory pathways targeted for treatment.

    Article  CAS  PubMed  Google Scholar 

  19. Davis DM, Dustin ML. What is the importance of the immunological synapse? Trends Immunol. 2004;25(6):323–7. https://doi.org/10.1016/j.it.2004.03.007.

    Article  CAS  PubMed  Google Scholar 

  20. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21(4):687–92. https://doi.org/10.1158/1078-0432.CCR-14-1860.

    Article  CAS  PubMed  Google Scholar 

  21. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8. https://doi.org/10.1016/j.jhep.2013.02.022.

    Article  CAS  PubMed  Google Scholar 

  23. Chung KY, Gore I, Fong L, Venook A, Beck SB, Dorazio P, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28(21):3485–90. https://doi.org/10.1200/JCO.2010.28.3994.

    Article  CAS  PubMed  Google Scholar 

  24. Calabro L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14(11):1104–11. https://doi.org/10.1016/S1470-2045(13)70381-4.

    Article  CAS  PubMed  Google Scholar 

  25. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, 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. 2010;28(19):3167–75. https://doi.org/10.1200/JCO.2009.26.7609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. https://doi.org/10.1056/NEJMoa1200690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976–83. https://doi.org/10.1016/S1470-2045(16)30053-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. • Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. https://doi.org/10.1056/NEJMoa1503093. Seminal trial comparing CTLA-4 and PD-1 antagonists in the treatment of advanced melanoma.

    Article  CAS  PubMed  Google Scholar 

  29. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20. https://doi.org/10.1016/S0140-6736(16)00561-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. https://doi.org/10.1056/NEJMoa1302369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785–92. https://doi.org/10.1200/JCO.2015.66.1389.

    Article  CAS  PubMed  Google Scholar 

  32. Farolfi A, Ridolfi L, Guidoboni M, Nicoletti SV, Piciucchi S, Valmorri L, et al. Ipilimumab in advanced melanoma: reports of long-lasting responses. Melanoma Res. 2012;22(3):263–70. https://doi.org/10.1097/CMR.0b013e328353e65c.

    Article  CAS  PubMed  Google Scholar 

  33. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7. https://doi.org/10.1200/JCO.2012.41.6750.

    Article  CAS  PubMed  Google Scholar 

  34. Gupta A, De Felice KM, Loftus EV Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015;42(4):406–17. https://doi.org/10.1111/apt.13281.

    Article  CAS  PubMed  Google Scholar 

  35. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18. https://doi.org/10.1016/S1470-2045(15)00083-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. •• Brahmer JR, Lacchetti C, Thompson JA. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2018;14(4):247–9. https://doi.org/10.1200/JOP.18.00005. American Society of Clinical Oncology treatment guidelines for irAEs.

    Article  PubMed  Google Scholar 

  37. • Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018. https://doi.org/10.1002/cncr.31629.

  38. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7. https://doi.org/10.1016/1074-7613(95)90125-6.

    Article  CAS  PubMed  Google Scholar 

  39. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–8. https://doi.org/10.1126/science.270.5238.985.

    Article  CAS  PubMed  Google Scholar 

  40. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of Vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45–51. https://doi.org/10.1001/jamadermatol.2015.2707.

    Article  PubMed  Google Scholar 

  41. Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359(6375):582–7. https://doi.org/10.1126/science.aao4572.

    Article  CAS  PubMed  Google Scholar 

  42. Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368–79. https://doi.org/10.1093/annonc/mdx108.

    Article  CAS  PubMed  Google Scholar 

  43. Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391. https://doi.org/10.1038/ncomms10391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020–30. https://doi.org/10.1200/JCO.2013.53.0105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368–76. https://doi.org/10.1093/annonc/mdw443.

    Article  CAS  PubMed  Google Scholar 

  46. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2(2):234–40. https://doi.org/10.1001/jamaoncol.2015.4368.

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by a grant from the NIH (R01 AI25640).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adam Mor.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Hot Topics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sandigursky, S., Mor, A. Immune-Related Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitors. Curr Rheumatol Rep 20, 65 (2018). https://doi.org/10.1007/s11926-018-0770-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-018-0770-0

Keywords

Navigation