What Is CTLA-4 and How Does it Work in Treating Metastatic Melanoma?

Since the early 2000s, when Dana-Farber scientists discovered that many cancer cells carry “checkpoint” proteins that ward off an immune system attack on tumors, a great deal of research has focused on the development and testing of agents capable of blocking those proteins. In many patients, such agents have sent cancers into long-term remissions. A checkpoint protein called CTLA-4, which was discovered more than a decade earlier, however, has revolutionized the treatment of metastatic melanoma, one of the most stubborn of all cancers to treat.

immunotherapy, Hodi, melanoma

F. Stephen Hodi, MD, Patrick Ott, MD, PhD, and George Demetri, MD, from Dana-Farber’s Center for Immuno-Oncology.

In 1987, French researchers reported the discovery of CTLA-4 on the surface of immune system T cells, which specialize in identifying and destroying diseased and cancerous cells in the body. The role of CTLA-4, however, was a mystery until 1996, when scientists led by James Allison at the University of California at Berkeley showed that it acts as a brake on the T cell attack on certain cancer cells. These findings, confirmed by later studies, led to the development of ipilimumab, an antibody-based drug that targets CTLA-4. Dana-Farber’s F. Stephen Hodi, MD, led a phase 3 clinical trial of the drug in patients with melanoma that had spread despite previous treatment. The results, published in The New England Journal of Medicine in 2010, showed that patients who received the drug lived significantly longer than those who hadn’t – the first time any treatment had been shown to extend survival times for patients with metastatic melanoma. Some patients treated with the drug had a long-lasting benefit; one group of patients were apparently cured of their disease. Ipilumamb, marketed as Yervoy®, received approval by the Food and Drug Administration in 2011 for the treatment of patients with metastatic melanoma. More than 2,000 metastatic melanoma patients have been treated with the drug over the past 15 years, and about 20 percent have benefited from it. The vast majority of patients in that group are alive today.

Hodi and his colleagues have worked to better understand which patients with melanoma are likely to be helped by ipilimumab, and to extend the drug’s benefits to a larger percentage of patients. In 2014 he published a study showing that patients with high blood levels of the protein VEGF tend to have a poor response to ipilimumab. The findings suggest that such patients may benefit from regimens that combine checkpoint inhibitors like ipilimumab with VEGF-blocking agents such as bevacizumab (Avastin®). Hodi’s team has launched a clinical trial of this combination in patients with advanced melanoma.

 

Beyond ipilimumab

The success of ipilimumab in melanoma has prompted Hodi to organize an early-phase clinical trial of a drug that blocks another checkpoint protein – PD-1 – on T cells. Last year, he and associates at Johns Hopkins University, Yale University, and other research centers published the results of a phase 1 study showing that the PD-1-blocking drug nivolumab can drive metastatic melanoma into remission or hold it in check for more than two years in some patients. The study, published in the Journal of Clinical Oncology, provides the longest-term look to date at how melanoma patients have fared since receiving the drug. Most recently, Hodi reported results of a trial in which patients with advanced melanoma were treated with a combination of ipilimumab and nivolumab. The combination was much more effective than ipilimumab alone when given as initial therapy for the disease. More than 61 percent of patients receiving the combination therapy had their tumors shrink, compared to 11 percent of those who received ipilimumab alone. The combination eradicated all visible signs of the cancer – a “complete response” – in 16 of 72 patients whose tumor cells had normal versions of the gene BRAF, and in five of 23 patients whose melanoma cells had a mutated form of the gene. Because the tandem therapy produced harsher side effects than the ipilimumab-only treatment did, further study will be needed.

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