Ipilimumab in the treatment of metastatic melanoma: management of adverse events

Abstract

Recently, “ipilimumab,” an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, has been demonstrated to improve overall survival in metastatic melanoma. “CTLA-4” is an immune-checkpoint molecule that downregulates pathways of T-cell activation. Ipilimumab, by targeting CTLA-4, is able to remove the CTLA-4 inhibitory signal, allowing the immune system to react to cancer cells. Due to its immune-based mechanism of action, ipilimumab causes the inhibition of CTLA-4-mediated immunomodulatory effects, the enhancement of antitumor specific immune response mediated by the weakening of self-tolerance mechanisms while exacerbating the development of autoimmune diseases and immune-related adverse events, including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis.

Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab

“…However, in both cases, antithymocyte globulin was also administered (7,12). There are numerous possible causes of this patient's severe hepatitis; nevertheless ipilimumab-induced hepatitis usually responds well to steroids (13).…”

Treating tumors with immune checkpoint inhibitors: Rationale and limitations

“…Guidelines for health care professionals have been set by Bristol-Myers Squibb, the manufacturer of Nivolumab and Ipilimumab, and have been reviewed in detail by Della Vittoria Scarpati and colleagues [45] . In general, high dose oral corticosteroids are recommended for grade 3-4 manifestations and checkpoint inhibitor treatment should be discontinued for grade 4 side effects [45] . Patients with severe diarrhea not responding to high dose corticosteroids may additionally be treated with anti-TNF-α [44,46] .…”

“…Patients with severe diarrhea not responding to high dose corticosteroids may additionally be treated with anti-TNF-α [44,46] . Low-grade skin manifestations may be treated with topical steroids or anti-histamines, and low-grade diarrhea with anti-diarrhea drugs and patient hydration [45] . It should be noted that patients may still respond to immune checkpoint blockade despite the development of adverse events, the administration of corticosteroids or the cessation of treatment [44] .…”

Immunotherapy of Melanoma

“…The mechanism of action of these drugs is closely connected to the side effects: By removing CTLA-4- or PD-1-mediated protection from autoimmunity, autoimmune-inflammatory side effects are seen, classified as immune-related AEs (irAEs) [32]. …”