Two researchers—James Allison, PhD, and Tasuku Honjo, MD, PhD—will share this year's Nobel Prize in Physiology or Medicine for their discoveries that CTLA4 and PD-1, respectively, serve as checkpoints that limit the ability of T cells to attack malignant cells.
Two researchers—James Allison, PhD, and Tasuku Honjo, MD, PhD—will share this year's Nobel Prize in Physiology or Medicine for their discoveries that CTLA4 and PD-1, respectively, serve as checkpoints that limit the ability of T cells to attack malignant cells. Their efforts to translate the findings into the clinic drove the development of Bristol-Myers Squibb's CTLA4 inhibitor ipilimumab (Yervoy) and PD-1 inhibitor nivolumab (Opdivo), as well as other therapies, that have led to remarkable responses in patients with cancer.
Allison's interest in T cells began when he took an undergraduate biology course. T cells had just been discovered, and he asked the professor about them. “He said, ‘Well, they go around your body through your tissues, lymphatics, and do stuff,’ ” Allison recalled. “I said, ‘How do they know what to do?’ and he said, ‘I don't know.’… I decided at that time that I was going to figure out how T cells work.”
In the early 1990s, Allison, now at The University of Texas MD Anderson Cancer Center in Houston, launched studies of the T-cell protein CTLA4, which he thought might function as a brake on the immune system. He and his team knocked out CTLA4 in mice and found that without the gene the mice died within a few weeks because they couldn't stop an immune response. Given that result, they theorized that T cells might detect tumors but that the cancer cells themselves were somehow shutting down that response.
To test the idea, his group conducted an experiment in late 1994 in which mice bearing transplanted tumors were treated with an antibody that prevented CTLA4 from binding to its ligands and shutting down the immune response. The experiment proved wildly successful, with tumors in the animals melting away. Notably, researchers didn't need to know which antigens T cells would recognize, and the treatment strategy didn't depend upon the tumor type. Releasing the brake on the CTLA4 checkpoint alone ramped up the immune response.
Just a few years earlier, Honjo, of Kyoto University in Japan, and his lab were searching for the protein signal that tells T cells to die rather than provoke an autoimmune attack. The group discovered PD-1 through subtractive hybridization and assumed that it would be involved in apoptosis. Through its coding DNA sequence, they found that it was expressed solely on immune cells, and they began to work with knockout mice to determine its function. It took months to see any changes in the animals, but they did develop disease, demonstrating that PD-1 was a negative regulator of the immune system—another brake limiting T-cell responses. He went on to show that blocking PD-1 prompted an immune response to tumor cells.
Although it took several years and a tremendous amount of persistence, Allison, Honjo, and others eventually convinced pharmaceutical companies to take a chance on developing CTLA4 and PD-1 inhibitors, which are now approved by the FDA for the treatment of several types of cancer.
“To see my basic science turn into something to benefit people I think is the dream of everybody,” said Allison, who fittingly was attending the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference in New York, NY, when he received word on October 1 that he had won the Nobel Prize.
In Japan, Honjo expressed a similar sentiment: “At the time of PD-1's discovery in 1992, it was purely a matter of basic scientific research, but as this then led to actual treatments and I then eventually began to hear from patients, such as, ‘This treatment has improved my condition and given me strength again, and it is all thanks to you,’ I really began to understand the meaning of what my work had accomplished.”
Researchers and immunologists attending the New York meeting spoke about the significance of immunotherapy for patients. “For the first time, there have been developments in cancer immunotherapy that have really cured people—do I dare say that?—allowed people to live many, many years,” said Nina Bhardwaj, MD, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York. “We will see the impact of these discoveries for decades to come.”
Crystal Mackall, MD, of Stanford University in California, hoped that hearing about the Nobel Laureates would help people understand why strong investment in science is critical. “When you feed people like this who have the talent—and you give them the opportunity—this is the kind of thing that can happen,” she said. “You make fundamental discoveries and it takes a long time, and you've got to keep at it, but at the end of the day you can cure people who are otherwise not curable.” –Suzanne Rose
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