James P. Allison, PhD
The FDA approval of ipilimumab (Yervoy) for melanoma in 2011 ushered in a new era of antibodies that target immune checkpoints. Since this milestone, several combinations and monotherapies have gained rapid approval, with continued expansion on the horizon, according to James P. Allison, PhD, at the 2015 Society for Melanoma Research Congress.
“A few years ago, the best you could hope for in advanced melanoma was to improve survival a little bit, but now we have immunotherapies that provide durable responses that last decades,” said Allison, professor and chair of immunology at MD Anderson Cancer Center.
“Immunotherapies are successful because they have specificity, memory, and adaptability,” he said. “These agents don’t just recognize certain peptides on cancer, but can recognize many different mutations—as well as changes in cancer cells—that contribute to the development and persistence of tumors.”
The advent of immune checkpoint inhibition has not only altered treatment paradigms for patients with cancer, but it has also changed the way that researchers think about new therapies. Traditionally, targeted therapies and vaccines have been directed against a single mutation or peptide on the cancer cell; however, with the checkpoint inhibitors there are more factors at play.
“Immunotherapies, such as checkpoint inhibitors, don’t target tumor cells, and our research work does not involve using vaccines or cytokines to turn on the immune system,” Alison said. “Checkpoint inhibitor therapies work by blocking inhibitory pathways, in order to create an anti-tumor response.”
In effect, the checkpoint inhibitors that Allison has researched work to unleash or “take the brake off” the immune system. “This approach was a radical departure, so it was at first difficult for us to be taken seriously,” he said.
Allison’s research was the first to show that CTLA-4-targeted agents, when combined with a GM-CSF tumor cell vaccine, could eradicate melanoma. “It leads to cure in experiments we’ve now done in thousands of mice. And the cure rate in these experiments is never less than 85%,” Allison said.
The fully human antibody ipilimumab has now been used to treat over 50,000 patients with melanoma and other cancers, including those that affect the prostate, kidney, bladder, ovarian and lungs. The longest surviving patient treated with ipilimumab remains alive 10 years after undergoing initial therapy for melanoma metastasized to the lungs, Allison noted.
Ipilimumab results in objective responses in several tumor types, and the adverse events that accompany treatment—colitis hepatitis, and hypophysitis—can generally be managed with steroids, said Allison.
After follow-up of over 10,000 patients treated with ipilimumab, researchers now know that the use of this agent can lead to long-term survival in about 22% of cases. “I think we can think about starting to apply the word cure to these patients,” Allison said.
Allison’s work, which led to the approval of ipilimumab, has also illuminated the mechanisms and efficacy of PD-1 inhibitors. Now, just 4 years after the first checkpoint inhibitor was approved, there are two PD-1 inhibitors indicated for metastatic melanoma.
The next step in advancing cancer treatment with checkpoint inhibitors is to expand research into the use of these agents in combination, according to Allison. When checkpoint inhibitors are combined, their efficacy increases and patient survival improves. “The effect of combining these treatments is not synergistic, but additive,” Allison said.
In the phase III CheckMate-067 trial, the combination of nivolumab and ipilimumab demonstrated an objective response rate of 57.6% in patients with advanced melanoma. On top of these responses, 13.1% of patients treated with the combination had stable disease.
“With this treatment, two thirds of patient had some response. And among those who had an objective response, half had 80% or more tumor shrinkage,” Allison said.
Researchers now hope to improve available therapies so that 50% of those treated with combination checkpoint inhibitors experience long-term survival, Allison said. Next, these combination strategies are likely to move into other types of cancer, such as lung cancer and renal cell carcinoma.
“Eventually, we expect that these immunotherapies will be combined with more standard therapies in combating tumors such as renal cell cancers—so that we can increase treatment efficacy and improve outcomes,” Allison said. “There are many new opportunities for using checkpoint inhibitor therapies outside of melanoma.”