In a new study entitled “Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial” researchers show that advanced stage melanoma patients submitted to surgery and treated afterwards with ipilimumab improved recurrence-free survival. The study was published in the journal The Lancet.
Ipilimumab is a monoclonal antibody used in the treatment of unresectable or metastatic melanoma, i.e., melanoma that cannot be surgically removed or has spread from the primary tumor to distant locations within the body. It targets a protein – the cytotoxic T lymphocytic antigen-4 (CTLA-4) – expressed by a crucial group of immune cells, the T cells, to counteract how tumors defend themselves from the immune system.
But what is ipilimumab’s mode of action? Tumor cells are capable of hijacking the immune system’s natural mechanisms to prevent hyper or prolonged activation of its immune cells, which would eventually lead to tissue damage. To this end, the immune system relies on mechanisms to “shutdown” the immune response. As such, one strategy employed consists in inducing the expression of CTLA-4, a protein that acts as an “off” switch when expressed on the surface of T cells. By targeting CTLA-4, ipilimumab prevents its expression when administered to advanced melanoma patients, triggering a sustained and more prolonged anti-melanoma T cell response.
In this study, performed as a collaboration of international scientists, researchers hypothesized whether giving ipilimumab to advanced melanoma patients, who were submitted to primary tumor surgery and removal of regional lymph nodes, was an effective way to improve their survival. Specifically, researcher’s administered ipilimumab to 475 advanced melanoma patients and compared their outcomes with a placebo group of 476 patients. They found that patients upon ipilimumab treatment survived longer and remained free of melanoma recurrence for 26.1 months, while in patients who received placebo this period was significantly reduced to 17.1 months. Moreover, 46.5 percent of patients treated with ipilimumab survived 3 years without experiencing recurrence, when compared to only 34.8 percent of patients in the placebo group.
The research team identified, however, that ipilimumab treated patients exhibited a higher degree of toxicity, which included gastrointestinal disorders, kidney malfunction and inflammation of the pituitary gland. However, the drug used in the trial was higher than the normal dosage used in melanoma treatment. Despite promising, additional studies are required to minimize the adverse effects of ipilimumab while enhancing its therapeutic activity in advanced melanoma cases.