This year’s Nobel prize for physiology or medicine goes to James Allison of the University of Texas, and Tasuku Honjo of the University of Kyoto, in Japan (both pictured), “for their discovery of cancer therapy by inhibition of negative immune regulation”.
The fact that remissions from apparently terminal cancer, though rare, do happen from time to time had long led some to dream that it might be possible to harness the body’s immune system to attack malignancies. The immune system is a network of cells which defends against parasites and pathogens. Yet decades of effort intended to make it assault cancer as well, an idea called immunotherapy, led to nothing. These many failures had, by the 1990s, caused most people and firms to abandon the field.
Dr Allison was one of the few who never lost hope. He was particularly interested in a protein called CTLA-4. This is found on the surfaces of some T-cells, one of the main types of cell in the immune system. By 1994, when he was at the University of California, Berkeley, he and others had discovered that CTLA-4 puts a brake on T-cells’ ability to respond to cancer. In response he developed an antibody that blocks the protein, preventing its braking action on T-cells. Thus unchained, those cells can respond to tumours by attacking them. Tumours in mice vanished when they were given these CTLA-4 blocking antibodies.
So great, however, was the cynicism among oncologists about immunotherapy that Dr Allison’s colleagues were unimpressed by these apparently spectacular results. Cancer, they responded, had been cured in mice many times in ways that did not then go on to work in people.
But more good news was to come from the other side of the Pacific, where Dr Honjo had been working since 1992 on a different immune-system protein. In 1999 he showed that this protein, PD-1, worked like CTLA-4 in that it seemed to tamp down the immune system. When the gene encoding it was switched off, mice would develop autoimmune disease—a sign of an over-active immune system. Again, blocking the protein’s activity seemed a promising strategy in the fight against cancer. Dr Honjo was so convinced that he pushed until he found a biotechnology firm that would try to develop his work into a treatment.
It is now understood that immune “checkpoints”, such as these two proteins, are molecules that regulate the immune system. They prevent it from attacking the body it is part of. But they also restrain it from acting on cancers.
Eventually, a trickle of research started on molecules that work as checkpoint inhibitors, and in 2010 the field finally came of age. That was when Bristol-Myers Squibb, a drug company, released results from a trial of an anti-CTLA-4 antibody on patients with malignant melanoma. The results were astonishing. It was the first medicine able to improve survival from this disease.
Today, research into checkpoint inhibitors is booming. Molecules that affect PD-1 have proved slightly more popular with drug companies, because the side effects connected with CTLA-4 are trickier to handle. More than 1,100 PD-1-related trials are under way. Immunotherapy is now the hottest field in oncology and one that is likely, over the next five to ten years, to transform the way that many cancers are treated.