The Story of Yervoy
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The Story of Yervoy
The drug ipilimumab (Yervoy®) represents another milestone in the development of successful targeted therapies, providing what The New York Times called “the first drug shown to prolong the lives of people with a form of skin cancer called melanoma.” The most fatal of skin cancers, melanoma will take more than 9,000 lives in the United States in 2012. The 5-year survival rate for patients with metastatic disease ranges from less than 10 percent to about 20 percent, depending on where in the body the melanoma has spread.
Ipilimumab may be able to give patients with advanced melanoma more time. Though much remains to be learned about the drug, it could well be the “light at the end of melanoma’s long dark tunnel,” Dr. Vernon Sondak of the Moffitt Cancer Center & Research Institute, said in an interview with the NCI Cancer Bulletin.
A randomized, controlled clinical trial, reported in the New England Journal of Medicine, showed that ipilimumab treatment could significantly extend patient survival. In the trial, patients with advanced melanoma were randomly assigned to receive either ipilimumab or an experimental melanoma vaccine. Those who received ipilimumab lived a median of 10 months after enrolling in the trial compared with a median of about 6.5 months for those who received the experimental vaccine.
Dr. Antoni Ribas, a melanoma researcher at the Jonsson Comprehensive Cancer Center who has also been studying the drug, said in an interview with the NCI Cancer Bulletin that a modest proportion of melanoma patients will have long objective responses, “and are probably cured.”
Engaging the Immune System
Ipilimumab was developed by Dr. James Allison, who is today the head of the immunology program at Memorial Sloan-Kettering Cancer Center. The way the new medication works illustrates a special approach to targeted therapy, Allison told The New York Times: “The treatment is of the immune system, it’s not of the tumor.”
The field of cancer immunology has been evolving for more than a half century. Dr. Lloyd Old, who died in late 2011, was one of its pioneers. He spent much of his career at Memorial Sloan-Kettering, where he created a foundation that Allison and others have been building on for more than two decades. Allison has been focused on T cells, white blood cells known as T lymphocytes that play a key role in the body’s immune response to foreign and abnormal cells.
Similar to some other immunotherapy agents, ipilimumab is a monoclonal antibody designed to recognize and bind to specific cells. But, in this case, the targeted cells aren’t melanoma cells. Instead, ipilimumab binds to a molecule on the surface of T cells. This molecule, called CTLA-4, normally helps T cells put the brakes on their attack on foreign and abnormal cells in order to protect the body’s own tissues. By removing this natural brake on immune responses, ipilimumab is proving to be a breakthrough in melanoma treatment.
Many Collaborate on Ipilimumab
As so often happens in the development of new treatments, many researchers, universities and medical centers, and pharmaceutical companies were involved in the development of ipilimumab. In the 1990s, Allison discovered CTLA-4 while he was a professor at the University of California, Berkeley.
Researchers at several NCI-designated cancer centers were lead investigators in the pivotal phase III clinical trial that ultimately led to FDA approval in March 2011of ipilimumab as a treatment for advanced melanoma. These researchers included Dr. F. Stephen Hodi of the Dana-Farber/Harvard Cancer Center, Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Dr. Jedd D. Wolchok of the Memorial Sloan-Kettering Cancer Center, and Dr. Jeffrey S. Weber of the Moffitt Cancer Center and Research Institute. NCI gave Hodi a career development award for his work on melanoma from 1999 through 2003.
It is important to note that, although the goal of the latest targeted therapies is to provide the greatest benefit with the fewest side effects, significant adverse effects can occur with these drugs. In the ipilimumab clinical trial, 14 people died from problems that were probably related to their treatment. However, research continues to determine who benefits most and whether the side effects can be ameliorated.