Background/Purpose

CTLA-4 is a costimulatory molecule that downregulates T-cell activation and promotes an immunotolerance, well known by rheumatologist since the use of Abatacept. 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-lymphocytes proliferation. This induction of a tolerance break against the tumor may be responsible for immune related adverse events (irAEs) in most responder patients, some of which concerning rheumatologists.

Objective

To assess the incidence and nature of irAEs in oncologic treatment with 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. Reading and data extraction were performed independently by two readers. Pooled incidence was calculated using R software with the package meta. Heterogeneity was quantified using I².

Results

The literature search identified 491 articles and a manual search retrieved 4 other articles. Finally, 121 articles were full-text reviewed and 80 finally included in the study. 1265 patients from clinical trials were included for meta-analysis.

Anti-CTLA-4 antibodies were mainly given for melanoma, and in few studies for renal cell carcinoma, mesothelioma and pancreatic, gastric, oesophagal, colorectal, prostatic and bladder cancer.

Described irAEs consisted of skin lesions such as rash, pruritus and vitiligo, colitis, and less frequently inflammatory hepatitis, hypophysitis, thyroiditis and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated thrombocytopenia, auto immune inflammatory myopathy and polyarthritis.

The overall incidence of all-grade irAEs was 72% (CI95%: 61%-83%). The overall incidence of high-grade irAEs was 24% (CI95%: 18%-30%).

The risk of developing irAEs was dependent of dosage with incidence of all-grade irAEs being evaluated to 61% (CI95%: 56%-66%) for Ipilimumab 3mg/kg and 78,5% (CI95%: 65%-72%) for Ipilimumab 10 mg/kg.

Death due to irAEs occurred in less than 1% of patients (colic bowel perforation).

The median time of onset of irAEs was about nine weeks (IQR: 6-12) after the onset of treatment, corresponding with the first three cycles but varies according to the organ system involved.

Such immune activation could also be indicative for tumor-specific T-cell activation, and irAEs occurrence was associated with clinical response to CTLA-4 blocking: 61% of the patients presenting with irAEs experience a clinical remission (partial or complete), or at least a stabilisation of the cancer.

Conclusion

The price of potential long-term survival to metastatic tumors (such as melanoma) is atypical immune toxicity, reflecting the immune mechanism of action of anti-CTLA-4 antibodies. Rheumatologists will be involved in care of some irAEs such as arthralgia or polymyalgia rheumatica/giant cell arteritis, as recently published. 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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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-related-adverse-events-associated-with-anti-ctla-4-antibodies-systematic-review-and-meta-analysis/