Elsevier

Seminars in Oncology

Volume 37, Issue 5, October 2010, Pages 499-507
Seminars in Oncology

Immunologic checkpoints for cancer treatment: From scientific rationale to clinical application
The Emerging Toxicity Profiles of Anti–CTLA-4 Antibodies Across Clinical Indications

https://doi.org/10.1053/j.seminoncol.2010.09.007Get rights and content

The promising new class of immunomodulating antibodies directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) has been extensively tested in clinical trials and found to be active against cutaneous melanoma and other tumor histotypes. Inhibition of CTLA-4 characteristically induces well-identified side effects for which the definition “immune-related adverse events” (irAEs) has been proposed. IrAEs mainly include colitis/diarrhea, dermatitis, hepatitis, and endocrinopathies; uveitis, nephritis, and inflammatory myopathy also have been reported occasionally. These unique side effects are likely a direct result of breaking immune tolerance upon CTLA-4 blockade and are generally mild, reversible, and manageable, following specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. However, patient–physician communication and early treatment are also emerging as critical issues to successfully manage irAEs, thus avoiding major complications. The major experience in identifying and managing CTLA-4 treatment-related side effects has derived from studies in melanoma patients; nevertheless, accumulating clinical experiences are clearly demonstrating that irAEs are class-specific events, and that they are fully overlapping in patients with tumors of different histotypes. This review provides an overview of current safety data on CTLA-4 antagonists and of available strategies to optimize their clinical use in cancer patients.

Section snippets

Presentation and Management of Immune-Related Adverse Events Across Clinical Indications

Although safety data on anti–CTLA-4 mAbs derive essentially from clinical trials in cutaneous melanoma patients (Table 1), this novel therapeutic strategy also is being extensively tested in nonmelanoma indications such as lung, prostate, and renal cancer. These studies are clearly showing that completely overlapping irAEs can be observed, regardless of tumor histotype, identifying them as class-specific toxicities. In the following sections the major irAEs observed with ipilimumab and

Conclusions

The novel immunotherapeutic approach based on CTLA-4 targeting by therapeutic mAbs is a promising strategy that will likely impact the current management of human tumors of different histotypes. Well-defined irAEs are commonly associated with CTLA-4 blockade and represent the toxicity profile to be expected with this therapeutic approach. Noteworthy, the clinical experience built with anti–CTLA-4 mAbs in recent studies has demonstrated a better safety profile as compared to earlier trials,

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