James P. Allison has never hesitated to buck the system
As a teenager, the pioneering oncology researcher refused to take biology at his small-town Texas high school because the theory of evolution had been omitted from lessons for religious reasons. Instead, Allison took a university correspondence course, working alone in an empty classroom.
“I’d already decided that I wanted to be either a doctor or a scientist, and I knew that evolution is to biology as Newton is to physics, so I refused to take the course. It got me into trouble with some of the teachers,” said Allison, 62, who went on to earn a doctorate in biological science and now serves as chairman of the Immunology Program at the Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York.
That readiness to challenge the status quo has stayed with Allison during a 30-year-plus career dedicated to stimulating the human immune system to fight cancer, particularly through discoveries about the workings of T cells, which help protect the body from pathogens. Spurred also by personal and familial experience with cancer, Allison has been willing to probe his theories even amid skepticism in the scientific community.
A case in point emerged when Allison began to suspect that the molecule CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibited antibody response. He weighed that idea in the face of theories to the contrary: In textbooks, CTLA-4 had been categorized as a molecule that stimulated immune response.
Allison pursued his idea anyway. The result was ipilimumab, the promising melanoma treatment that the FDA is considering for approval, with a decision expected in March.
Allison’s years of work on that project reaffirmed his guiding philosophy.
“Let your mind lead,” advised Allison, a member of the National Academy of Sciences and the Institute of Medicine. “Don’t pay attention to conventional wisdom if you’ve got data that show otherwise. Sometimes it’s hard to go against the system, but you have to do it if something needs to be accepted.”A Move to a New Lab
Living by that credo led Allison not only to success in the lab, but also to MSKCC. He joined the staff there 7 years ago, excited that he would be working at a world-class cancer center with a strong interest in immunological approaches. It is among the 150 sites where clinical trials of ipilimumab were being conducted.
“As I saw my drug developing, I wanted to be a part of it,” Allison said. “I wanted to learn more about what went on in the clinic and to offer advice, because this was a totally new concept. You can’t approach it the same way you would if you were giving a drug that will go into a tumor cell and kill it.”
The move to New York meant the end of a 20-year relationship with the University of California, Berkeley, where Allison had been a professor in the Division of Immunology and director of the Cancer Research Laboratory. In exchange, Allison took on roles as MSKCC’s David H. Koch Chair in Immunologic Studies, director of the Ludwig Center for Cancer Immunotherapy, and attending immunologist in the Department of Medicine.
Now, amid administrative duties, including hiring colleagues, Allison spends his time examining data and overseeing his lab, where researchers carry out his ideas and some of their own.
Specifically, his work at MSKCC has included analyzing patients’ immune responses to help predict which categories of patients will most likely benefit from ipilimumab and under what circumstances.
“Also, I’ve got some ideas for additional targets, and some came from learning what happened in the patients, things we hadn’t noticed in mice,” Allison said. “Now we can go back into mice and observe some of the same things to get new ideas about second-generation drugs.”High Expectations for Ipilimumab
The drug that started it all, ipilimumab, is an antibody that targets CTLA-4, a molecule on the immune system’s T cells that impedes their ability to fight cancer. Once stimulated, T cells can protect the body from disease by attacking alien proteins, or antigens, such as tumor cells.
Normally, after a time, that attack is halted by CTLA-4, even though dangerous cells may remain. Ipilimumab is designed to eliminate CTLA’s “stop” message, so that T cells can continue to fight indefinitely.
Administered intravenously, ipilimumab, also known as CTLA-4 blockade, works best if an anticancer therapy—such as radiation, chemotherapy, freezing, or targeted therapy—is used first to stimulate T cells to go on the attack, Allison said. Once that has been accomplished, the scientist said, the drug can be widely useful.
“You’re treating the immune system, not the cancer, so it can be used, potentially, against every kind of cancer,” he explained, adding that patients do not develop a resistance to the drug.