CTLA-4 Inhibition and CTLA-4 Inhibitors

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a trans-membrane protein found on the surface of T cells, which, when bound to B7 on antigen-presenting cells, prevents T cell activation. This is thought to occur during the immune system’s “priming” phase in lymph nodes. The overall effect is immune down-regulation; thus CTLA-4 is described as an immune checkpoint “off switch” (Hodi et al. 2010; Pardoll 2012; Ribas et al. 2012; Topalian et al. 2012).

Two fully human anti-CTLA-4 monoclonal antibodies have been developed and tested in phase III clinical trials for the treatment of patients with metastatic melanoma: ipilimumab and tremelimumab (Azijli et al. 2014). Ipilimumab has been FDA-approved for the treatment of metastatic melanoma, adjuvant melanoma, and renal cell carcinoma (FDA 2018).


Drug class Target Agent Diseases Line of Therapy Status Source
CTLA-4 inhibitors CTLA-4 ipilimumab (Yervoy) melanoma metastatic FDA Approved Hodi et al. 2010
adjuvant FDA Approved Eggermont et al. 2014
renal cell carcinoma metastatic FDA Approved Motzer et al. 2018
non-small cell lung cancer metastatic Trials complete with results Lynch et al. 2012
small cell lung cancer extensive stage Trials complete with results Reck et al. 2013
tremelimumab melanoma metastatic Trials complete with results Ribas et al. 2013

CTLA-4 inhibitor adverse effects

Treatment with CTLA-4 inhibitors such as ipilimumab is associated with unique adverse events due to the medication’s immune upregulation. The most common adverse effects of CTLA-4 inhibitors in ≥ 5% of patients are colitis and dermatitis (FDA 2011). Less commonly but also observed are various endocrinopathies (hypophysitis, hypothyroidism) or neurologic damage (Guillain-Barre, myasthenia gravis; Johnson et al. 2014; Tarhini 2013). Diarrhea, rash, visual changes, fatigue, and aminotransferase levels should be closely monitored in patients receiving CTLA-4 inhibitors.


Contributors: Wade T. Iams, M.D., Douglas Johnson, M.D., Christine M. Lovly, M.D., Ph.D.

Suggested Citation: Iams, W.T., D. Johnson, C. Lovly. 2015. CTLA-4 Inhibition and CTLA-4 Inhibitors. My Cancer Genome http://www.padiracinnovation.org/content/molecular-medicine/ctla4-inhibition-and-inhibitors/ (Updated February 10).

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Last Updated: May 25, 2018

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