ctla4-inhibition-and-inhibitors

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). The contexts in which they have been tested are subtly different, and only ipilimumab has been FDA-approved for the treatment of metastatic melanoma (as of March 2011; FDA 2011).

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
			melanoma	adjuvant	FDA Approved	Eggermont et al. 2014
			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.mycancergenome.org/content/molecular-medicine/ctla4-inhibition-and-inhibitors/ (Updated February 10).

Last Updated: October 29, 2015

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