The 2018 Nobel Prize in Physiology or Medicine has been awarded to two researchers whose discoveries opened up a new field of cancer therapy based on unleashing the immune system to attack tumors.
Tasuku Honjo of Kyoto University and James P. Allison of the University of Texas MD Anderson Cancer Center will split the roughly $1 million prize for work that led to the development of checkpoint inhibitors, a class of cancer drugs that overrides an internal mechanism that keeps immune cells from attacking the body, allowing the cells to go after tumors. According to the American Cancer Society, there are at least six drugs approved by the U.S. Food & Drug Administration to treat various tumors that take advantage of checkpoint inhibition.
One of Allison’s collaborators, melanoma specialist Jedd Wolchok of Memorial Sloan Kettering Cancer Center, says this award is welcome, and not surprising. “The discoveries literally have given rise to a very significant shift in the way we approach cancer treatment,” Wolchok says.
Honjo’s work began in the 1990s, when he and coworkers discovered that the protein PD-1 on T cells could act as a brake in the activation of the immune system by binding to another protein, PD-L1, on other cells. This binding effectively told the T cell to stand down from attack. Many cancer cells try to fool the immune system into not attacking by expressing PD-L1 on their surfaces. Honjo and others found that blocking PD-1 with antibodies reduced the size of tumors. This mechanism eventually led to anti-PD-1 drugs like Merck & Co.’s Keytruda and Bristol-Myers Squibb’s Opdivo.
Allison’s work also began in the 1990s when he and his research team recognized that a protein on the surface of T cells, CTLA-4, was a brake that tamped down the activation of T cell immunity in response to foreign elements in the body. He and colleagues tested whether blocking CTLA-4 could give the immune system free rein in attacking tumors. In tests on mice with cancer, an antibody to CTLA-4 reduced their tumors. That work led to promising clinical trials and the development of Bristol-Myers Squibb’s Yervoy.
In a written statement, Allison says, “I’m honored and humbled to receive this prestigious recognition.” He added that his goal when he started this work was to add to the basic knowledge of the immune system. “I didn’t set out to study cancer, but to understand the biology of T cells, these incredible cells that travel our bodies and work to protect us.”
Current checkpoint inhibitors treat melanoma, lung, kidney and bladder, and head and neck cancers. Several clinical studies are now looking at how checkpoint inhibition can be coupled with other cancer therapies to further treat disease.
Sergio Quezada, a cancer researcher at University College London who was a postdoc in Allison’s lab, says the Nobel, “validates the approach.” Quezada’s work in Allison’s lab looked at the mechanism of how the CTLA-4 inhibitor works. He says that in their animal experiments, they found that CTLA-4, the brake, has the same binding partner as CD28, a protein on the surface of T cells that accelerates immune activity. Blocking CTLA-4 frees up the partner to bind to CD28, spurring activation, he says.
Otis Brawley, chief medical officer of the American Cancer Society, says that the discovery of checkpoint inhibitors and the broader field of immunotherapy is important as part of a five-pronged approach to cancer treatment that includes surgery, chemotherapy, precision medicine, and radiation. “We’ve been trying to harness the immune system to treat cancer for literally 120 years,” Brawley says.
At a press conference today, Allison described being woken up, not by the Nobel committee, but by his son, who bore the news. He says that when he finally did talk to members of the committee, they told him that this is the first time they have given a prize to a cancer treatment, rather than for an understanding of a cancer mechanism.
“I’m lucky enough, as a basic scientist, to see my work, 20 years later, helping patients,” he says, thanking patients for their role in testing checkpoint inhibitors. “We are making progress.”
UPDATE: This story was updated on Oct. 1, 2018, to include new information.