How a Rebellious Scientist Helped Launch the Modern Age of Immunotherapy

Published: Sunday, Jul 05, 2015
James P. Allison, PhD

James P. Allison, PhD

James P. Allison, PhD, 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 Darwin 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, who went on to earn a doctorate in biological science and launch a nearly 40-year career dedicated to stimulating the human immune system to fight cancer. In November 2012, he left several leadership positions at Memorial Sloan Kettering Cancer Center in New York to step into the chairmanship of the Department of Immunology at The University of Texas MD Anderson Cancer Center.

Allison’s readiness to challenge the status quo has never left him. It certainly showed itself as he made discoveries about the workings of T cells, which help protect the body from pathogens. Spurred also by personal and familial experience with cancer, Allison was 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 (Yervoy), which was approved by the FDA on March 25, 2011, as a treatment for unresectable or metastatic melanoma.

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 who in his free time enjoys playing blues harmonica and sailing. “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.” Over the years, Allison’s discoveries have led not only to ipilimumab, but also to a growing interest within the scientific community in creating other immune checkpoint modulators for antitumor therapy.

Another research group has developed nivolumab (Opdivo), which works by blocking an inhibitory molecule known as programmed death-1 (PD-1).

The FDA approved nivolumab as a treatment for patients with unresectable or metastatic melanoma in December 2014 and then expanded its indication into metastatic squamous non–small cell lung cancer less than 3 months later. And researchers reported in June that combining ipilimumab and nivolumab more than tripled median progression-free survival compared with ipilimumab alone (11.5 mo vs 2.9 mo) in a phase III trial among patients with stage III/IV melanoma.

For developing ipilimumab and sparking the burgeoning field of modulating immune checkpoints for antitumor therapy, Allison has been chosen by OncLive to receive one of its Giants of Cancer Care® awards for 2014, in the area of Scientific Advances.

“Winning the Giants of Cancer Care award meant a lot to me,” Allison said. “For a basic scientist to be acknowledged by an award for cancer care is really fulfilling and amazing to me. For a while, I was considered an ivory-tower, pointy-headed intellectual pursuing these arcane ideas about immunology. I think this gives basic scientists credibility in the cancer-care community.”

The Approval of 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-4’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 first used to stimulate T cells to go on the attack, Allison said. Once that has been accomplished, the scientist said, the drug could 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.


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