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Review
. 2015 Sep 4:13:211.
doi: 10.1186/s12916-015-0455-8.

Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis

Anne Bertrand  1 , Marie Kostine  2 , Thomas Barnetche  3 , Marie-Elise Truchetet  4   5 , Thierry Schaeverbeke  6   7
Affiliations
Review

Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis

Anne Bertrand et al. BMC Med. .

Abstract

Background: Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab).

Methods: A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R(©), package meta.

Results: Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65-79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18-30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56-66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69-89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6-12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.

Conclusion: The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

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Figures

Fig. 1
Fig. 1
Mechanism of action: CTLA-4 and anti-CTLA-4 antibodies. Two signals are required to initiate an immune response. For the first signal (signal 1), tumor associated antigen (Ag), is presented by major histocompatibility complex (MHC) on antigen presenting cell (APC) and recognized by the toll-like receptor (TCR) of T-cell. Signal 2 occurs in response to binding of CD80 or CD86 (B7) on APC cell with CD28 receptor on T-cell (a). CTLA-4 is a homolog of CD28 and limits proliferative response of activated T-cell competing with CD28 for ligand B7. This inhibition occurs in response to binding of CD80 or CD86 on APC with CTLA-4 receptor on T-cell and interrupts signal 2 (b). Anti-CTLA-4 antibodies blocks CTLA-4 and enhances T-cell activation and proliferation (c)
Fig. 2
Fig. 2
Flow diagram for identification and selection of studies included in the systematic review and meta-analysis
Fig. 3
Fig. 3
Incidence of global immune-related adverse events (irAEs) with anti-CTLA-4, all-grade (a) and severe grade (b). For ipilimumab treatment, different dosages were used: 3 mg/kg, 10 mg/kg, and 15 mg/kg. Only one study [31] reported global irAEs with tremelimumab treatment, at 15 mg/kg dosage. IrAEs associated with anti-CTAL-4 antibodies (c)
Fig. 4
Fig. 4
Risk ratio of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg for global irAEs all grade (a) and high grade (b)
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