Recent advances in the clinical application of agents that block immunoregulatory molecules have led to unprecedented optimism about the potential of these novel therapies for bringing about durable antitumor responses in patients with various advanced malignancies. However, enhancing immune responses to cancer via modulation of these immune checkpoints is associated with drug-related toxicities that are distinct from those associated with traditional chemotherapeutic agents and molecularly targeted therapies. Because the use of checkpoint blockade agents will likely be widely expanded in the near term, it is critical that healthcare practitioners caring for oncology patients have a basic familiarity with these immune-related adverse events (irAEs), their variable presentations, and recommendations regarding their evaluation and management.
To understand the mechanism of checkpoint blocker–related autoimmune toxicities, it is helpful to consider their mechanism of action. At a basic level, the role of the human immune system, and of T lymphocytes in particular, is to activate against non-self–antigens (eg, viral proteins or cancer neoantigens resulting from tumoral genetic and epigenetic alterations) and to tolerate self-antigens. Antigen recognition by a T-cell receptor is followed by interactions between a tightly regulated cadre of immunoregulatory molecules that either activate or inhibit T-cell activation. Some of the best studied of these checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the pathway composed of programmed death 1 (PD-1) and one of its major ligands, programmed death ligand 1 (PD-L1).
When they are engaged with their respective binding partners, CTLA-4 and PD-1 promote immune tolerance via downregulation of T-cell activation.[4,5] The application of antibody antagonists of these immune checkpoints promotes T-cell activation, which can lead to tumor destruction as well as clinically relevant decreases in self-tolerance. This immune dysregulation is among the mechanisms underlying the autoimmune toxicities related to immune checkpoint blockers.
Incidence of Immune Checkpoint–Blockade Toxicities
The adverse event (AE) profiles of checkpoint-blocking drugs (ie, incidence of toxicities and organ systems most frequently affected) vary depending on agent and target. In clinical studies, toxicity severity is described using the Common Terminology Criteria for Adverse Events (CTCAE), which grades toxicities on a scale of 1 (mildest) to 5 (death related to that toxicity).
The CTLA-4 antibody ipilimumab is the most widely studied checkpoint-blocking agent. In 2011, after extensive clinical testing, it was approved by the US Food and Drug Administration (FDA) for use in patients with advanced melanoma. One seminal study that led to its approval was a phase III trial involving patients with advanced melanoma. Ipilimumab was administered at 3 mg/kg with or without a peptide vaccine to 511 patients. Grade 3 or 4 immune-related toxicities were observed in approximately 15% of patients, and 7 patient deaths were associated with irAEs. A retrospective review of safety data from 1,498 patients treated with ipilimumab on any of 14 phase I–III clinical trials found that drug-related AEs of any grade occurred in 85% of patients. About 25% of patients experienced a grade 3 or 4 drug-related toxicity, and drug-related death was observed in < 1% of patients.
Clinical trials using ipilimumab in tumor types other than melanoma have demonstrated similar AE rates. For example, in a phase III study of ipilimumab administered after patients were treated with radiotherapy for metastatic prostate cancer, 63% of patients had immune-related toxicity of any grade. Similarly, in a phase II study of ipilimumab plus chemotherapy for metastatic non–small-cell lung cancer, the rate of grade 3/4 irAEs was 15% to 20%, depending on the sequence of drug administration.
In a phase II trial of 245 patients with advanced melanoma, study participants were randomly assigned to ipilimumab plus granulocyte macrophage colony-stimulating factor (GM-CSF) or ipilimumab alone. Of note, ipilimumab was administered at 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg. Patients who received combination therapy experienced a significantly lower rate of high-grade AEs (45% vs 58%; two-tailed P = .038). The lower rate of high-grade AEs was accompanied by significantly improved overall survival (OS) in the GM-CSF arm (median, 17.5 vs 12.7 months; hazard ratio, 0.64; P = .014), although further study is required to determine whether the increased OS is linked to improvements in AE rates.
Another CTLA-4 antibody, tremelimumab (CP-675,206; formerly ticilimumab) has been similarly studied in patients with metastatic melanoma and other advanced cancers. In a phase II clinical trial testing tremelimumab in patients with advanced melanoma, 19% of participants had a ≥ grade 3 adverse event. When tested in patients with metastatic colorectal adenocarcinoma, a similar rate of high-grade toxicities was seen, with diarrhea/colitis representing the majority of cases.
PD-1 and PD-L1 antibodies
Although clinical data are still emerging, anti–PD-1 and anti–PD-L1 agents appear to have toxicity profiles that are different from those of CTLA-4 antibodies (Table 1).
Pembrolizumab is a humanized monoclonal antibody (mAb) blocking PD-1 that was approved by the FDA in September 2014 for use in treatment-refractory unresectable or metastatic melanoma. In a phase I clinical trial involving 135 patients with advanced melanoma, grade 3/4 AEs were reported in 13% of subjects. An expansion cohort comprising patients whose disease was refractory to ipilimumab (and, if BRAF-mutant, refractory to BRAF inhibition) was reported separately. In 173 patients, at a median follow-up of 8 months, toxicity rates were similar to those in previous reports.
Nivolumab is a genetically engineered, fully human immunoglobulin (Ig) G-4 mAb specific for human PD-1. In a phase I dose-escalation study conducted in 296 patients with multiple tumor types, grade 3/4 treatment-related toxicities occurred in 41 patients (14%). Treatment-related pneumonitis was observed in 9 patients (3%), 3 cases of which were fatal. Longer-term follow-up of the entire study cohort (306 patients) demonstrated that exposure-adjusted toxicity rates were not cumulative.
BMS-936559 (MDX-1105), a PD-L1–blocking antibody, was tested in a 207-patient phase I trial. A 9% rate of grade 3/4 drug-related irAEs was reported. Similar findings were reported in 140 patients who received MPDL3280A, a human monoclonal IgG1 antibody engineered to block PD-L1 binding. Drug-related grade 3/4 AEs were observed in 14% of patients.
Preclinical evidence suggests that blockade of multiple immune checkpoints can achieve synergistic antitumor activity. Several clinical trials of combinatorial regimens are underway. In a trial of ipilimumab plus nivolumab in patients with metastatic melanoma, a 53% rate of treatment-related AEs of grade 3 or 4 was reported when the drugs were administered concurrently. When ipilimumab was followed sequentially by nivolumab, the rate dropped to 18%, which is closer to observed rates for the single agents.
1. Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol. 2014;11:24-37.
2. Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol. 2014;11:91-9.
3. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-64.
4. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev. 2008;224:141-65.
5. Bour-Jordan H, Esensten JH, Martinez-Llordella M, et al. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev. 2011;241:180-205.
6. National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, DHHS. May 29, 2009. NIH publication # 09-7473.
7. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.
8. Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29:abstr 8583.
9. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-12.
10. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-54.
11. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (ipi) versus ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl):abstr CRA9007.
12. Kirkwood JM, Lorigan P, Hersey P, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16:1042-8.
13. Chung KY, Gore I, Fong L, 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;28:3485-90.
14. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.
15. Robert C, Ribas A, Wolchok JD, 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 2014;384:1109-17.
16. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.
17. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020-30.
18. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.
19. Hamid O, Sosman JA, Lawrence DP, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(suppl):abstr 9010.
20. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917-27.
21. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
22. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-7.
23. Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol. 2014;32:e69-71.
24. Tarhini AA, LaFramboise WA, Petrosko P, et al. Clustered genomic variants specific to patients who develop immune-related colitis after ipilimumab for prediction of toxicity. J Clin Oncol. 2014;32(suppl 5S):abstr 9024.
25. Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. J Transl Med. 2013;11:75.
26. Weber J, Thompson JA, Hamid O, 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. 2009;15:5591-8.
27. Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823-30.
28. Lacouture ME, Wolchok JD, Yosipovitch G, et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71:161-9.
29. Minkis K, Garden BC, Wu S, et al. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013;69:e121-8.
30. Kaehler KC, Piel S, Livingstone E, et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol. 2010;37:485-98.
31. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283-9.
32. Carpenter KJ, Murtagh RD, Lilienfeld H, et al. Ipilimumab-induced hypophysitis: MR imaging findings. AJNR Am J Neuroradiol. 2009;30:1751-3.
33. Torino F, Barnabei A, De Vecchis L, et al. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist. 2012;17:525-35.
34. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013;31:1071-7.
35. Bompaire F, Mateus C, Taillia H, et al. Severe meningo-radiculo-nevritis associated with ipilimumab. Invest New Drugs. 2012;30:2407-10.
36. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol. 2014;16:589-93.
37. Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13:278-80.
38. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-7.
39. Pembrolizumab prescribing information. Available from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed September 22, 2014.
40. Ipilimumab package insert. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Accessed September 22, 2014.
41. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab-associated colitis: CT findings. Am J Roentgenol. 2013;200:W468-74.
42. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681-8.
43. Pages C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res. 2013;23:227-30.
44. Reuben A. Hepatotoxicity of immunosuppressive drugs. In: Kaplowitz N, DeLeve LD, editors. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier; 2013. p. 569-91.
45. Chmiel KD, Suan D, Liddle C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29:e237-40.
46. Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013;2013:857519. Epub 2013 Apr 17.
47. Kaehler KC, Egberts F, Lorigan P, Hauschild A. Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient. Melanoma Res. 2009;19:333-4.
48. Lammert A, Schneider H, Bergmann T, et al. Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or immunosuppressive therapy. Exp Clin Endocrinol Diabetes. 2013;121:581-7.
49. Rubin KM. Managing immune-related adverse events to ipilimumab: a nurse’s guide. Clin J Oncol Nurs. 2012;16:E69-75.
50. Ledezma B, Heng A. Real-world impact of education: treating patients with ipilimumab in a community practice setting. Cancer Manage Res. 2013;6:5-14.