Jan 07, 2019
Honor sets Dr. Allison, co-laureate Dr. Tasuku Honjo, and their immuno-oncology discoveries on global stage
By Amanda Narod, ASCO Communications
Years before making the groundbreaking discoveries that paved the way for powerful new cancer immunotherapy treatments, James P. Allison, PhD, thought he would follow in his father’s footsteps and become a family doctor. But as an undergraduate at the University of Texas, Austin, Dr. Allison took biology classes and found himself drawn to the lab, which encouraged him to question, make mistakes, and then try all over again.
There was also the pragmatic realization as an undergraduate that taking premed organic chemistry to become a doctor would require too much memorization. “Maybe I’m just lazy or something,” he joked.
It’s an amusing reflection from a man who was recently honored with the 2018 Nobel Prize in Physiology or Medicine for his discoveries in immunotherapy for cancer—an award he shares with Tasuku Honjo, MD, PhD, of Japan. Dr. Allison, an ASCO member, and Dr. Honjo were awarded the 2018 Nobel Prize for their pioneering research in CTLA-4 and PD-1, respectively.
“For more than 100 years scientists attempted to engage the immune system in the fight against cancer. Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed,” said the Nobel Prize Committee in a press statement.
“We congratulate Drs. Allison and Honjo for leading the way towards new therapies that have already transformed the lives of countless patients while providing new hope for millions to come,” said ASCO CEO Clifford A. Hudis, MD, FACP, FASCO.
“There is nothing more exciting to biologists and researchers in our field than when we see a new understanding of human biology finally revealed to help patients,” said 2018-2019 ASCO President Monica M. Bertagnolli, MD, FACS, FASCO. “Dr. Allison’s and Dr. Honjo’s decades of careful work in the laboratory to understand the biology really made immunotherapy something that could help patients. Its just wonderful to see the Nobel Prize awarded in this field.”
Road to T-Cell Titan
Dr. Allison’s is a story of firsts, the hallmark of extraordinary discovery: as a young investigator during his first stay at the University of Texas MD Anderson Cancer Center, he was the first to identify the structure of the T-cell antigen receptor. Subsequently, at the University of California at Berkeley, his lab was the first to establish CD28 as the major co-stimulatory molecule that fully activates naive T cells and prevents anergy in T-cell clones. His laboratory was the first to show that blocking CTLA-4 with antibodies boosts T-cell responses and tumor rejection in mice. He recalled this milestone in a recent interview with Wired:
“Just for the hell of it, I was setting up another experiment, and I decided that since I had these mice that were cured—who were just sitting there, eating—I would inject them with the tumor again, but not treat them with the enzyme this time, and see what happened.”
What happened next was shocking.
“They didn’t get tumors. I went back and injected them with 10 times as much, and they still didn’t get tumors. I injected them with another five times more, and they still didn’t get tumors! Something was happening here.”
Dr. Allison didn’t exactly have colleagues or industry knocking at his door eager to test these findings in humans. The road from the preclinical experiments to U.S. Food and Drug Administration (FDA) approval was long and occasionally frustrating. Treating the immune system instead of killing cancer cells was a new approach often met with skepticism.
“The [pharmaceutical companies] would say, ‘Oh yeah, that’s cool, you can do that in mice, but it won’t come to anything,’” Dr. Allison said. He continued his efforts to develop the strategy into a therapy for humans, but initiation of the first phase I study took 5 years.
Finally, Dr. Allison found a partner, but the first clinical trial—among patients with metastatic melanoma—dashed hopes when it showed no difference between treated and untreated patients at 12 weeks. A second trial, however, also among patients with melanoma, delivered the results that changed cancer care.
Promising results soon emerged from several groups, and in 2010 an important clinical study showed remarkable effects in patients with advanced melanoma. In several patients, signs of remaining cancer disappeared. Such extraordinary results had never been seen before in this patient group.
The culmination of this research was ipilimumab, a human antibody to CTLA-4, the first immune checkpoint blockade therapy approved by the FDA.
“I have been working on T cells since the late ‘60s. What I’ve found is that T cells are amazingly complex when you first look at them. But when you take them apart, it’s not all that complicated,” he said.
Optimism for the Future
Dr. Allison hopes that the excitement around the Nobel Prize brings optimism to patients and encourages them to participate in a clinical trial. He expresses a similar optimism when thinking about what the future holds for progress against cancer—going as far as talking about cures, a controversial word among many clinicians.
“I do understand that using the words ‘cure’ and ‘cancer’ in the same sentence has been verboten for a long time, but having met some patients that are 10, 14, and 18 years out from their cancer diagnosis after a single round of treatment with an anti-CTLA-4 checkpoint inhibitor, telling them that they have a chronic disease, and not a cure, is not very satisfying,” Dr. Allison said.
“I don’t know what the time limit is for being in remission before you can say the patient is cured,” he continued. “But after being disease-free for 5 years, maybe we can consider that a cure. The survival rate is certainly different now for patients with advanced melanoma.”
It’s an outlook he works to instill when teaching the next generation of researchers and physicians.
“As a scientist, I tell my students all the time, no experiment is a bad experiment if you learned something, even if you didn’t get the answer you wanted. Students need to be persistent. I tell my students to pick an area of research and look at the data their studies generate to figure out what they are telling you, and not just whether the information is consistent with their research hypothesis. See what can be learned from the information. [They must] keep going on and not worry about the potential clinical impacts down the road.
“Research success by definition is incremental, you have to build on what you learn and take the information one or two steps further. By really paying attention to the fundamental mechanisms of the research, there is the chance of making a quantum leap. My research in CTLA-4 is a good example of how scientific perseverance pays off,” he said.
Dr. Allison is the chair of the Department of Immunology, the Vivian L. Smith Distinguished Chair in Immunology, director of the Parker Institute for Cancer Research, and the executive director of the Immunotherapy Platform at MD Anderson Cancer Center. In 2015, Dr. Allison was honored with ASCO’s Science of Oncology Award and Lecture for his contributions to the understanding of cancer. He has served on ASCO’s Research Methodologies in Immunotherapy Development Working Group.
A Shared Honor With Dr. Tasuku Honjo
Dr. Allison shares the prize with Dr. Honjo, of Kyoto University, for his separately conducted, equally incredible work in the discovery of PD-1. In animal experiments, PD-1 blockade was also shown to be a promising strategy in the fight against cancer, as demonstrated by Dr. Honjo’s laboratory and other groups. Clinical development ensued, and in 2012 a key study demonstrated clear efficacy in the treatment of patients with different types of cancer. Results were dramatic, leading to long-term remission and a possible cure in several patients with previously untreatable metastatic cancer.
Dr. Honjo is a Distinguished Professor at the Kyoto University Institute for Advanced Study, a professor in the Department of Immunology and Genomic Medicine at Kyoto University, and chair of the Board of Directors of the Foundation for Biomedical Research and Innovation.
ASCO congratulates Dr. Allison and Dr. Honjo on the well-deserved recognition as Nobel laureates. Their brilliant discoveries and their tireless work have transformed the landscape of cancer care, bringing new hope to patients and their families.