Abstract
BackgroundThree checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported.ObjectivesTo conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity.Data SourcesWe searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015.Study SelectionStudies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included.Data ExtractionWe extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes.Data Synthesis191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab.LimitationsOur study is limited by information available in the original reports.ConclusionsEvidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported.
Highlights
Advances in checkpoint blockade therapy have expanded our understanding of the complex interactions between the immune system, cancer cells, and their environment
Evidence from case reports shows that cancer patients develop immunotherapy-related adverse events (irAEs) following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases
While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported
Summary
Advances in checkpoint blockade therapy have expanded our understanding of the complex interactions between the immune system, cancer cells, and their environment. Most human cancers have evidence of adaptive immune dysregulation with genetic and epigenetic alterations in tumor cells, resulting in diverse antigenic expression that can elicit an immune activation. This immune activation is primarily T-cell mediated and regulated by stimulatory, co-stimulatory, and inhibitory (checkpoint) signals [2,3,4]. Ipilimumab, was the first agent approved for advanced melanoma It is a fully human IgG1 mAb that blocks the cytotoxic T lymphocyte antigen 4 (CTLA-4), a checkpoint inhibitor of T cell activation [6]. Pembrolizumab is the second immune checkpoint inhibitor therapy to receive FDA approval in 2014 for patients with advanced melanoma It is an engineered humanized IgG4 mAb that regulates T cell activation by blocking programmed cell death protein 1 (PD-1). While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported
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