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.
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).
Last Updated: May 25, 2018