Before Nobel Prize winner James P. Allison tested his radical cancer-fighting theory in people, he was saving the lives of Berkeley mice.
On Monday, Allison was awarded the Nobel Prize in Physiology or Medicine with Tasuku Honjo of Japan for their work on cancer immunotherapy, which has led to new types of drugs and prolonged the lives of many patients, including former President Jimmy Carter.
Now at the University of Texas M.D. Anderson Cancer Center, Allison conducted human testing while at Memorial Sloan Kettering Cancer Center in New York.
But the conceptual foundation was built at UC Berkeley in the mid-1990s, while Allison was serving as director of the campus’s Cancer Research Laboratory. Animal trials also were conducted at Berkeley.
“Jim made the key discovery at Berkeley,” said David Raulet, director of Berkeley’s Immunotherapeutics and Vaccine Research Initiative (IVRI), who was recruited by Allison to come to UC-B from the Massachusetts Institute of Technology. “The mouse experiments – proof of principle, in animals – were at Berkeley.”
Allison, now 70, came to Berkeley in 1995 after earning his PhD in immunology from the University of Texas at Austin.
While in graduate school in Texas, he asked professors about the immune system’s T-cells, which protect the body from invaders.
Their answer was unsatisfying, he told a meeting of the International Cancer Immunotherapy Conference on Monday. “I was told: ‘They go around the body, in the blood and the lymphs, and do stuff,’ “ he said.
He wondered: How do they know what to do? “I decided to figure out how T-cells work,” he said, in a soft Texas twang.
At that time, most scientists believed that the immune system would not be useful against cancer, because healthy and cancerous cells look so much alike. They also feared that targeting cancer cells would kill healthy cells.
At Berkeley, Allison dove headlong into research that focused on T-cells’ role in fighting off, not just bacteria and viruses, but also cancer.
“The dogma at the time was, ‘Don’t even bother,’ ” said Matthew “Max” Krummel, in a prepared statement. He was a graduate student and postdoctoral fellow with Allison in the 1990s and is now a professor of pathology and a member of the joint immunology group at UCSF.
“What was heady about the moment was that we didn’t really listen to the dogma, we just did it,” Krummel said.
To be sure, the biological mechanism isn’t straightforward — so neither was the research. Eventually, Allison and Honjo, working separately, discovered that T-cells are prevented from attacking cancer by certain proteins, which act as “brakes.”
Allison identified a specific protein receptor, called CTLA-4, that seemed to be holding T-cells back. UC Berkeley postdoctoral fellow Dana Leach discovered that blocking the receptor would unleash the immune system to attack a cancerous tumor. This discovery made it possible to develop drugs that disable CTLA-4 – essentially, taking the brakes off the immune system.
Their findings — curing cancer in Berkeley mice — led to a landmark paper published in Science in 1996. Allison, Leach and Krummel showed that antibodies against CTLA-4 released the brake and allowed the immune system to attack the tumors. The technique was so effective it caused tumors to disappear, they wrote.
“I don’t know if I could have accomplished this work anywhere else than Berkeley,” Allison said in a 2015 interview with UC-B’s Robert Sanders.
“There were a lot of smart people to work with, and it felt like we could do almost anything,” he said. “I always tell people that it was one of the happiest times of my life, with the academic environment, the enthusiasm, the students, the faculty.”
Allison spent the next few years amassing more data in mice to show how anti-CTLA-4 antibodies work. Then, working with a biotech firm called Medarex, he developed a therapy that was later acquired by Bristol-Myers Squibb and approved by the FDA to treat metastatic skin cancers, called melanoma.
“Jim is a force of nature,” said Raulet. “He’s someone who is a very charismatic and hugely motivated scientist, who also enjoys having a good time. Part of his strength as a scientist is his collaborative effect, and his ability to work with a lot of people. This helped make his science a success.”
He left UC Berkeley in 2004 for New York City’s Memorial Sloan Kettering research center to be closer to the clinical trials.
“My research got to the point where all the animal work showed that checkpoint blockade had a lot of potential in people, and working with patients at Berkeley wasn’t possible. There’s no hospital, no patients,” he said in the 2015 interview.
Immunotherapy now has taken its place along with surgery, chemotherapy and radiation as a reliable and objective way to treat cancer. The strategy is used for not just melanoma, but also cancers of the lung, kidney, bladder, head and neck, as well as Hodgkin lymphoma.
The drugs — a class called checkpoint inhibitors, which include ipilimumab (Yervoy), nivolumab (Opdivo) and pembrolizumab (Keytruda) — are expensive and have severe side effects. They don’t work for all patients. But they offer remission in many people, lifting a death sentence.
Allison’s influence endures in Berkeley, where he helped build the research environment of the university’s Department of Molecular and Cell Biology, as well as the department’s division of immunology, said Raulet.
“His actions helped create the superb research environment here,” said Raulet, “which is so conducive to making the fundamental discoveries that will be the basis of the next generation of medical breakthroughs.”
UC Berkeley research led to Nobel Prize for James Allison