Developmental History, Clinical Considerations, and Future Perspectives

Michael A. Postow, MD; Jedd D. Wolchok, MD, PhD


The Melanoma Letter. 2012;30(1):1-4. 

In This Article

Unique Spectrum of Side Effects: Immune-related Adverse Events

Ipilimumab is generally well tolerated but can be associated with a host of novel side effects, presumably due to the immune system activation by CTLA-4 blockade. Collectively the spectrum of side effects is described as immune-related adverse events (irAEs). Though rates of irAEs differ in various trials, in the large, phase III trial reported by Hodi, et al (2010), irAEs most commonly affected the skin (rash/vitiligo/pruritis; 43.5% any grade, 1.5% grade 3–4); the liver (hepatitis/rise in liver enzymes; 3.8% any grade, 0% grade 3–4); the bowel (diarrhea/colitis; 29.0% any grade, 7.6% grade 3–4), and the endocrine system (hypophysitis, thyroiditis, adrenal insufficiency; 7.6% any grade, 3.8% grade 3–4).[1]

More rarely, uveitis, conjunctivitis, neuropathy, myopathy, and nephritis have been known to occur. IrAEs are typically responsive to interruption or discontinuation of CTLA-4 blockade in combination with immunosuppressive drugs such as steroids or occasionally tumor necrosis factor-blocking antibodies. At present, there is no clear preventive strategy to avoid irAEs. A randomized, double-blind, placebo-controlled trial assessing the role of prophylactic budesonide in reducing ipilimumab-associated diarrhea showed no benefit.[6] IrAEs are not believed to be true autoimmune diseases, as they typically resolve with cessation of ipilimumab and appropriate immunosuppressive therapy. Given this side effect profile, however, ipilimumab is not recommended for patients with underlying autoimmune diseases, particularly inflammatory bowel diseases and autoimmune hepatitis. Patients with underlying autoimmune conditions were excluded from clinical trials in the development of ipilimumab, and its safety has not been assessed in this patient population.

Retrospective analysis suggests that patients who experience irAEs may be more likely to benefit from anti-CTLA-4 therapy. Serious irAEs, however, are not required for an anti-tumor response, nor does the development of irAEs guarantee clinical benefit. Monitoring for predisposition to irAEs and attempting to separate the therapeutic benefits of anti-CTLA-4 therapy from irAEs are areas of ongoing investigation.


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