Cytotoxic T-lymphocyte-associated protein 4, or CTLA-4, is a protein on the surface of T cells that functions as an immune checkpoint. It affects how T cells recognize cancer cells.
T cells attack foreign invaders such as viruses and cancer cells.
CTLA-4 prevents T cells from attacking healthy parts of the body, but it can also prevent T cells from identifying and killing cancer cells.
Drugs that block CTLA-4 are called immune checkpoint inhibitors. These drugs have the potential to help people live longer with mesothelioma cancer.
Targeting CTLA-4 with immune checkpoint inhibitors is a form of immunotherapy. New immunotherapies are among the most promising mesothelioma treatments in development right now.
What Is CTLA-4?
French researchers discovered CTLA-4 in 1987. Nearly a decade later, scientists at the University of California, Berkley realized the role of CTLA-4.
The protein acts as a break, stopping T cells from attacking cancer cells. Researchers call this breaking mechanism an immune checkpoint.
Immune checkpoints work like on and off switches, activating or deactivating the parts of the immune system.
When activated, CTLA-4 downregulates the immune system by stopping T cells from finding cancer cells.
Scientists have developed drugs to block and deactivate CTLA-4 — a process commonly called a CTLA-4 blockade — which allows T cells to find and attack cancer cells. These drugs are known as immune checkpoint inhibitors.
Other immune checkpoint inhibitors targeted in mesothelioma treatment include PD-1 and PD-L1. Drugs that target these checkpoints include Keytruda (Pembrolizumab), Opdivo (Nivolumab) and Imfinzi (Durvalumab).
What Drugs Target CTLA-4?
Two checkpoint inhibitor drugs work against CTLA-4: Yervoy and tremelimumab.
Yervoy is FDA approved to treat late-stage melanoma. Tremelimumab is not FDA approved, but in 2015 it received orphan drug designation to encourage research into it.
Anti-CTLA-4 Immunotherapy for Mesothelioma
Most of the mesothelioma clinical trials involving Yervoy and tremelimumab combine them with immune checkpoint inhibitors that target other proteins. Studies show that targeting PD-1and CTLA-4 together increases effectiveness.
Mesothelioma researchers are using the combination approach because it has proven more effective in melanoma treatment. For example, when used alone, about 11 percent of melanoma patients respond to Yervoy.
When anti-PD-1 drug Opdivo is added to Yervoy, about 61 percent of melanoma patients respond.
Researchers found that adding Opdivo to Yervoy increases the response rate in mesothelioma patients. In 2017, French researchers announced a significant improvement in response rates at the 2017 ASCO Annual Meeting.
Approximately 44 percent of mesothelioma patients had control of their cancer with Opdivo alone, while 50 percent had control of their cancer using Yervoy combined with Opdivo.
These results justified a phase III trial of Yervoy and Opdivo in mesothelioma patients, which began in 2017.
Less research is available on tremelimumab than Yervoy, but preliminary results show further research is warranted.
Clinical trials are investigating tremelimumab among mesothelioma patients in the U.S.
- One involves combining tremelimumab with surgery.
- Another is combining tremelimumab with durvalumab (Imfinzi).
Clinical trials suggest that Yervoy and tremelimumab are effective for some people with mesothelioma. Further research is necessary to determine which mesothelioma patients may benefit the most from immune checkpoint inhibitors that target CTLA-4.
Additional research is also required to see which drug combinations work best among people with mesothelioma.
10 Cited Article Sources
ams, W.T., Johnson, D. & Lovly, C.M. (2015, October 29). CTLA-4 Inhibition and CTLA-4 Inhibitors.
Retrieved from: https://www.mycancergenome.org/content/drug-class/ctla4-inhibition-and-inhibitors
Dana-Farber Cancer Institute. (2017, May 22). What Is CTLA-4 and How Does it Work in Treating Metastatic Melanoma?
Retrieved from: http://blog.dana-farber.org/insight/2015/12/what-is-ctla-4-and-how-does-it-work-in-treating-metastatic-melanoma/
Guazzelli, A. et al. (2017). Anti-CTLA-4 therapy for malignant mesothelioma.
Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/28231719
Calabro, L. et al. (2015). CTLA4 blockade in mesothelioma: Finally a competing strategy over cytotoxic/target therapy?
Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/25233793
Thomas, A. & Hassan, R. (2017). CTLA-4 blockade in mesothelioma: Ineffective or reason for optimism? 30511-9/abstract
Retrieved from: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)
Burt, B. (2015). CTLA4 blockade in patients with malignant mesothelioma. 00110-1/fulltext
Retrieved from: http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(15)
Roncella, S. et al. (2016). CTLA-4 in mesothelioma patients: Tissue expression, body fluid levels and possible relevance as a prognostic factor.
Retrieved from: https://link.springer.com/article/10.1007/s00262-016-1844-3
McCoy, K.D. & Gros, G.L. (1999). The role of CTLA-4 in the regulation of T cell immune responses.
Retrieved from: https://www.nature.com/articles/icb19991
Scherpereel, A. et al. (2017, June 5). Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial.
Retrieved from: https://meetinglibrary.asco.org/record/145342/abstract
- ClinicalTrials.gov. (2018, January 19). A Phase 2 Study of Durvalumab in Combination With Tremelimumab in Malignant Pleural Mesothelioma. Retrieved from: https://www.clinicaltrials.gov/ct2/show/NCT03075527
How did this article help you?
What about this article isn’t helpful for you?
Did this article help you?
Share this article
Last Modified March 15, 2019