%0 Journal Article
%T Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management
%A Ahmad Tarhini
%J Scientifica
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/857519
%X 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. 1. Introduction Melanoma is considered an ¡°immunogenic¡± tumor¡ªa theory that is supported by several observations and reported in the literature. The host immune system actively responds to melanoma, where advanced malignancy has rarely been reported to undergo spontaneous regression [1¨C4]. This may also be supported by the presence of lymphoid infiltrates at the site of primary melanoma associated with pathologic evidence of tumor regression. T-cell infiltration in primary melanoma was shown to be independently prognostic of improved survival [5]. Moreover, the absence of tumor infiltrating lymphocytes (TILs) at the primary melanoma site was associated with a higher probability of sentinel lymph node (SLN) melanoma metastasis compared with brisk TILs [6]. In patients treated with interferon-¦Á2b (INF¦Á2b), T-cell infiltration within nodal metastasis was associated with benefit from INF¦Á2b therapy [7¨C9]. Clinically, this is also supported by the fact that for three decades, the only two therapeutic agents approved by the US Food and Drug Administration for the treatment of melanoma were immunotherapeutic (adjuvant IFN¦Á and high-dose interleukin-2). Until recent regulatory approvals, patients with advanced melanoma have had few therapeutic options [27], and
%U http://www.hindawi.com/journals/scientifica/2013/857519/