The Long Road: Nobel Prize Winner James Allison Highlights the Value of Research

Nobel Prize winner James Allison, PhD, pioneering T-cell researcher, said the award represents the triumph of science and shows the value of research, even if it does not immediately lead to a scientific or commercial success.

The soft-spoken researcher is sharing the award with Tasuku Honjo, MD, PhD. Both men were awarded the Nobel Prize for Physiology or Medicine for their separate, but related, discoveries that uncovered mechanisms that block key proteins and allow the immune system to attack cancer, creating an entirely new way to fight the disease.

Allison's work led to checkpoint therapy—treatments that act as accelerators that activate T cells, the white blood cells that send the immune system into battle, or as brakes, blocking the proteins that stop the T cells in their tracks.

The 70-year-old scientist is chair of the Department of Immunology, the Vivian L. Smith Distinguished Chair in Immunology, director of the Parker Institute for Cancer Research, and executive director of the Immunotherapy Platform at the University of Texas MD Anderson Cancer Center.

The day the Nobel Prize was announced, Allison spoke at a press conference held during the second day of the 4-day International Cancer lmmunotherapy Conference, run by the Cancer Research Institute, the Association for Cancer lmmunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research (AACR). Allison is a Fellow of the AACR Academy and is a former board member.

He said there are “somewhere on the order of 2000 clinical trials going on now with checkpoint inhibitors in combination with something else. And that something else is usually chosen just because a company owns it.” There are very few combinations based on data, he said.

There are also not enough patients in clinical trials, and, given that, whether the result is a clinical signal or not, samples should be collected from every patient, he said.

“You can understand something about a signal by knowing what didn’t happen,” he said.

He also said he thought there was too much emphasis in grantmaking for researchers to state “what the relevance is.”

ASCO and NCCN release guidelines on managing immunotherapy toxicities.

“How do you know what’s going to be relevant or not?” he asked. “I think you should pick your problem, work on it, do the best work you can."He spent his career studying cytotoxic T-lymphocyte antigen 4 (CTLA-4). His lab at the University of California at Berkeley resolved the issue of how the protein blocked the activation of T cells, by opposing the stimulation needed from CD28 proteins. In experiments with mice, Allison showed that blocking CTLA-4 could boost T-cell responses.

His work eventually led to the development of ipilimumab, now sold as Yevoy by Bristol Myers Squibb.

Allison, who was woken with the news at 5:30 in the morning when his son called him, said he first started studying T cells in an immunology undergraduate course in Texas, about 50 years ago, when T cells had just been discovered. He asked the professor more about them after class, intrigued, and the professor replied that they float around the body and “do stuff.”

“I said, ‘well, how do they know what to do?' He said, ‘I don’t know. I don’t know if they even exist,'" Allison recalled.

For deciding to make T cells his life’s work, Allison will split the $1 million prize with Honjo.

Joining Allison at the conference was Jill O’Donnell-Tormey, PhD, the chief executive officer and director of scientific affairs at the Cancer Research Institute, who called Allison a “dyed-in-the-wool” immunologist and noted that in the beginning no one was interested in his work.

Crystal Mackall, MD, conference scientific planning committee member and director of the Stanford Center for Cancer Cell Therapy as well as the Parker Institute for Cancer Immunotherapy, called Allison a “role model for all of us” and said the average citizen needs to know more about why society needs to invest in basic science.

“You make fundamental discoveries and it takes a long time,” said Mackall. But in the end, “you can cure people who are otherwise uncurable.”

Allison, O’Donnell-Tormey, Mackall, and Nina Bhardwaj, MD, PhD, conference cochair and director of cancer immunotherapy, professor of medicine, and Ward-Coleman Chair in Cancer Research at the Tisch Cancer Institute, at the Icahn School of Medicine at Mount Sinai, also spoke at the press conference about the future of immunotherapy.

Mackall and Bhardwaj echoed Allison’s earlier comments about picking combinations to study based on data and science.

Regarding chimeric antigen receptor technology, Crystal said, “we are just scratching the surface of what is possible” and thinks adoptive T-cell technologies will be able to treat solid tumors in the future.

Personalized immunotherapy will require biomarkers, O’Donnell-Tormey said. The expression of programmed death-ligand 1 (PD-L1) on tissues as adjunct biomarkers for the intervention of antibodies is one such example, said Bhardwaj. Understanding the tumor environment and landscape will also be key, she said.

Another exciting future development, Bhardwaj said, is the discovery of neoantigens, arising from a patient’s specific mutations, which could help propel the creation of cancer vaccines and, perhaps, lead to cancer vaccines being combined with other methods.

Researchers are also focusing on understanding more about the concept of resistance, specifically T-cell resistance, and why they stop becoming functional, Mackell said. Bhardwaj said another type of resistance happens at the level of the tumor cells, where they learn to escape recognition by T cells.

“There’s an awful lot of biology that still need to happen,” said O’Donnell-Tormey. She said the reason patients in clinical trials are asked to give so many biopsies is so that researchers have a grasp of what is happening at all phases, including before, during, and after treatment.

As for other predictions, Allison said he thinks within the next 5 years some cancers are headed towards a 100% patient response if they are given the right combinations. “Not many, but at least a few,” he said.

With immunology becoming the fourth pillar of cancer treatment, Allison said it “is the only one that can work nicely with the other ones.” And that has led to a shift in thinking. Instead of killing every last cancer cell, “just kill enough to let the immune system take it out,” he said.

The organizations did not have any warning that Allison would be awarded the Nobel, said O’Donnell-Tormey. “We’ve been anticipating for 3 years that he would get it,” she said.