In the world of cancer, no recent breakthrough has inspired as much excitement and hope as immune checkpoint inhibitors. These drugs — which include ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), and others — work by taking the brakes off immune cells, allowing them to better fight cancer.
Unlike most other cancer drugs, checkpoint inhibitors target the immune system rather than the cancer itself. They are credited with opening an entirely new approach to cancer therapy and saving many lives.
Immunologist James P. Allison, who now directs the immunotherapy program at MD Anderson Cancer Center in Houston, was the main pioneer of this approach. While a professor at the University of California, Berkeley, in 1996, he discovered that an antibody made to block a molecule on T cells called CTLA-4 could cure cancer in mice. He was so impressed by this result that he tried to convince pharmaceutical companies to develop this antibody as a drug, initially with little success.
In 2004, Dr. Allison joined MSK as Chair of the Immunology Program in the Sloan Kettering Institute. He was inspired to come to MSK in part by the opportunity to work with clinicians and translational researchers to bring his drug to patients. He succeeded, and the results have proved more impressive than anyone could have imagined.
“Jim Allison’s work transformed the way we think about the immune system as an ally in the fight against cancer,” says Craig B. Thompson, MSK’s President and CEO. “He deserves a lot of credit for pursuing this idea even when it was unpopular. MSK is proud to have been the home base for Dr. Allison as he was working to bring this new form of therapy to patients.”
Ipilimumab, the CTLA-4-blocking drug, was approved by the US Food and Drug Administration in 2011 for the treatment of metastatic melanoma. It was the first drug ever shown to improve survival in this deadly disease.
At a press conference, Dr. Allison said that he didn’t go into immunology thinking he would try to cure cancer. He was mainly interested in understanding how T cells — the “soldiers” of the immune system — recognize and defend against foes. The breakthrough result, he said, is testimony to the value of funding basic scientific research. He also noted that, as is often true in science, many people contributed to the breakthrough. ”Science advances on the efforts of many,” he said in a statement provided by MD Anderson. “A succession of graduate students, postdoctoral fellows and colleagues at MD Anderson, the University of California, Berkeley, and Memorial Sloan Kettering Cancer Center played important roles in this research.”
A Second Checkpoint
Tasuku Honjo, of Kyoto University in Japan, was one of the discoverers of another immune checkpoint called PD-1. Like CTLA-4, PD-1 acts like a brake on T cells. Releasing this brake with an antibody unleashes the T cells to fight cancer. Drugs targeting PD-1 are also now approved by the FDA for the treatment of several types of cancer, including lung, bladder, kidney, and lymphoma.
For some people with cancer, the combination of anti-CTLA-4 and anti-PD-1 drugs works better than either drug alone. MSK’s Jedd Wolchok led the pivotal clinical trials showing that the combination of these drugs was safe and effective for people with metastatic melanoma.
“When I joined the MSK faculty in 2000, the median survival for patients with advanced melanoma was seven months with the best treatment available at that time,” Dr. Wolchok recalled in 2015 when the combination was approved. ”Now we are routinely hearing about two- and three-year survival.”
Some patients even appear to be cured.
During the announcement of the award, the Nobel committee showed a survival curve of patients who had received this combination, documenting that nearly 70% of patients with BRAF-mutated metastatic melanoma were still alive at 3 years. The data were from a clinical trial led by Dr. Wolchok and published in the New England Journal of Medicine in 2017.
Because these drugs work by unleashing the immune system, they can sometimes cause severe immune-related side effects, although these can usually be managed safely. Another limitation is that they work for only a fraction of the patients who receive them, which points to the need for more research.
Dr. Wolchok, who now directs the Melanoma Service at MSK, worked closely with Dr. Allison when they were colleagues at MSK, and continues to collaborate with him as part of the Parker Institute for Cancer Immunotherapy. He is elated by the choice of Dr. Allison and Dr. Honjo as this year’s Nobel awardees. “The world of cancer treatment changed because of their lifetime work and dedication,” he said.
Immunotherapy has actually been a focus at MSK since the late 1890s. And MSK scientists have been a part of all the major immunotherapy advances throughout the history of cancer treatment.
We congratulate Drs. Allison and Honjo on this superlative honor.