When James Allison began studying whether the immune system’s T cells could be tweaked to attack tumors, merely entertaining the notion was a good way to sink your scientific career: Cancer immunology was a backwater within oncology, and a vaguely disreputable one at that. Little wonder, then, that after the discovery of a protein “brake” on T cells called CTLA-4, most CTLA-4 research explored whether it could be targeted to treat diabetes and other autoimmune diseases.

Allison, then at the University of California, Berkeley, had other ideas.

He developed an antibody that binds to and thereby blocks the function of CTLA-4. Allison’s mother had died of cancer when he was a boy growing up in Alice, Texas; eventually the disease would kill two of her brothers and Allison’s brother, too. In late 1994, he and his colleagues showed in a mouse experiment that when the antibody blocks, or “inhibits,” CTLA-4, T cells are unleashed like hellhounds, devouring tumors.

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After a lot of additional research and little interest from drug companies, that CTLA-4 antibody became ipilimumab (Bristol-Myers Squibb’s Yervoy). It was the first “checkpoint inhibitor” (a term Allison coined) approved to treat cancer, in 2011.

Ipi was initially used against malignant melanoma, and has now also been approved for kidney cancer and colorectal cancer. It doesn’t work for every patient who receives it. But in about one-quarter of patients with metastatic melanoma, which is otherwise almost always fatal, it seems to be a true cure.

Just as important, ipi demonstrated that the immune system could be enlisted to fight cancer; with the development of five (and counting) other checkpoint inhibitors, immunotherapy has transformed cancer treatment. For this work Allison, who is now chairman of immunology at MD Anderson Cancer Center and has CTLA-4 on his license plate, shared the 2018 Nobel Prize in medicine or physiology.

Read the archived chat below.

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