Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: the underlying mechanisms and clinical management

Abstract

Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities.

Figure 1

T-cell targets for immunoregulatory antibody therapy [10]; reproduced with permission from Mellman et al. 2011 [10].

Figure 2

Kinetics of appearance of irAEs according to organ system involved [11]; adapted with permission from Weber et al. 2012 [11].

Figure 3

Skin biopsy showing severe dermatitis with epidermal spongiosis, papillary dermal edema, and a prominent inflammatory infiltrate in both the superficial and deep dermis [12]; reproduced with permission from Phan et al. 2003 [12].

Figure 4

Immune-related maculopapular rash in a patient receiving ipilimumab.

Figure 5

Ulcerated colonic mucosa, as viewed by colonoscopy, in a patient experiencing ipilimumab-related colitis.

Figure 6

Histopathologic analyses showing focal active colitis (a) with crypt destruction, loss of goblet cells, and neutrophilic infiltrates in the crypt epithelium (b) [13]; reproduced with permission from Maker et al. 2005 [13].

Figure 7

Magnetic resonance images of the brain demonstrating ipilimumab-associated hypophysitis. (a) Prior to therapy, with no metastatic disease indicated. (b) Diffuse enlargement of the pituitary gland following reports of cognitive impairment during therapy. (c) Resolution of hypophysitis after discontinuation of ipilimumab and initiation of hormone-replacement therapy [14]; reproduced with permission from Carpenter et al. 2009 [14].

Figure 8

Ophthalmologic images of ipilimumab-associated uveitis in both eyes. (a, b) At the time of presentation, with irregular pupils caused by iris adhesions to the lens; (c, d) the same patient after 4 days of topical corticosteroid therapy [15]; reproduced with permission from Attia et al. 2005 [15].