Cancer immunologists create medicine Nobel Prize

Left: James Allison, right: Tasuku Honjo

James Allison and Tasuku Honjo share the Nobel Prize in Physiology or Medicine 2018.Left: Richard Drew / AP / Shutterstock. Right: MEXT / CC BY 4.0

Two scientists who pioneered a whole new way to treat cancer have won the Nobel Prize in Physiology or Medicine 2018.

James Allison at the University of Texas MD Anderson Cancer Center in Houston and Tasuku Honjo at Kyoto University in Japan will share the 9 million Swedish krona (US $ 1 million) prize.

The pair showed how proteins on immune cells can be used to manipulate the immune system so that it attacks cancer cells. The approach has since led to the development of therapies that have been praised for years for prolonging survival in some people with cancer and have even wiped out all signs of disease in some people with advanced cancers. Researchers are en masse involved in the approach and immunotherapy is now one of the most popular areas in cancer research.

Early excitement

Allison is in New York for an immunology conference and was awakened at 17.30 by a phone call from his son to bring the good news. Towards half past six, colleagues at the door of his hotel room were beating champagne for a makeshift party. The Nobel Committee did not reach him until some time after that.

"It still has not completely penetrated me," Allison said during a press conference. "I was a fundamental scientist, and to truly influence my work, people are one of the best things I can think of, it is everybody's dream."

Tweets by the Nobel Prize that celebrates the winners with colleagues, friends and families in their respective countries

In the nineties, Allison, then at the University of California, Berkeley, was one of several scientists who studied a "checkpoint" protein, CTLA-4, which acts as a brake on immune cells carrying T cells. are called. In 1997, Allison and his colleagues developed an antibody that could bind to CTLA-4, relieved the inhibition of T cell activity and unleashed them to attack cancer cells in mice. A clinical study in 2010 showed that the antibody had a striking effect on people with advanced melanoma, a form of skin cancer1.

Irrespective of Allison, in 1992, Honjo discovered another T-cell protein, PD-1, which also acts as a brake on the immune system, but by a different mechanism. PD-1 became a target in the treatment of cancer. In 2012, research in humans showed that the protein was effective against various types of cancer, including lung cancer, a major killer2. The results were dramatic – some patients with metastatic cancer had prolonged remission, resulting in the possibility of healing.

Release brakes

"The discoveries of Allison and Honjo have added a new pillar in cancer therapy and represent a completely new principle because, unlike previous strategies, it is not based on targeting the cancer cells, but rather on the brakes – the control points. – from the immune system of the host ", said Klas Kärre, member of the Nobel Committee and an immunologist at the Karolinska Institute in Stockholm, who described the work of the prize winners during the Nobel announcement. "The pioneering discoveries of the two laureates are a paradigmatic shift and a milestone in the fight against cancer."

In recent years, clinical work on drugs that inhibit CTLA-4 and PD-1 mechanisms – known as immune checkpoint therapy & # 39; – developed quickly. Treatments that block PD-1 have been shown to be effective in lung and kidney cancer, lymphomas and melanoma. Recent clinical trials in which combined therapies targeting CTLA-4 and PD-1 in patients with melanoma have shown that this approach can be even more effective than CTLA-4 alone3. Studies are now underway to evaluate the effectiveness of control point therapy against most cancers, and scientists are testing countless other checkpoint proteins to see if they can serve as targets.

But Allison and Honjo were not alone: ​​others also made important early discoveries about control point inhibitors, notes Gordon Freeman, an immunologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was disappointed that he was not recognized for his contributions. Freeman, studied with immunologists Arlene Sharpe at Harvard Medical School in Boston and Lieping Chen at Yale University in New Haven, Connecticut, PD-1 and a molecule that binds to it, called PD-L1.

The drug ipilimumab, an antibody that inhibits CTLA-4, received approval from the US Food and Drug Administration (FDA) in 2011 and was the first control point inhibitor to reach patients. But Freeman points out that until now it has been shown that CTLA-4 inhibitors only work with melanoma. And the FDA has approved drugs that target PD-1 and PD-L1 to treat 13 different cancers. "PD-1 and PD-L1 are what works in a very wide variety of people," he says. "And our discoveries were fundamental there."

Freeman says, however, that CTLA-4 paved the way and that Allison played a key role in the fieldwork. "Jim Allison was a real advocate and champion of the idea of ​​immunotherapy," he says. "And CTLA-4 was a first success."

Obvious choices

Immunologist Jerome Galon of the French national biomedical research agency INSERM in Paris was not surprised by the decision of the committee to award the prize to Honjo and Allison. "I think they really deserve it," he says. "You can always multiply and have many other people, but these are the obvious two first choices."

He adds that the price reflects how far the approach of the immune system against cancer has come. When PD-1 inhibitors appeared to be working against lung cancer in 2012, the field broke, with researchers in the academic world and industry racing to find ways to increase the number of patients who benefited from the drugs. "Ten years ago nobody was interested – no one except a few immunologists," says Galon. "It is so & # 39; s big change."

In an interview with 2013 Nature, Allison described the resistance he encountered when he first tried to get pharmaceutical companies interested. "It was very frustrating," he said. "They said:" It can work in mice, but it will never work in people. "The concept was new and it was so unusual."

Allison marched from company to company looking for one to take over the project. In the end Bristol-Myers Squibb from New York was the one who brought ipilimumab over the finish line. Since then, other pharmaceutical companies have developed checkpoint inhibitors that have been approved for use in humans.

Combination therapy

A great attraction, says Galon, is the potential of these drugs to extend patients' lives by years instead of just weeks or months. But only a fraction of the patients experience such dramatic reactions and researchers race to stimulate those numbers by combining checkpoint inhibitors with each other and with other treatments. "The big advantage over other treatments is that patients survive in the long term," he says. "Unfortunately, only a subgroup of patients responds."

Throughout everything it was exciting to see the field develop, Freeman says. "It was really an incredible amount of human creativity and energy," he says. "It's great because so many cancer patients do better."

In 2015 Allison won a prestigious Lasker prize for his work on immunotherapy in cancer. In 2016, Honjo won the Kyoto prize in basic sciences, a global prize awarded by the Inamori Foundation.

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