Ribas Builds Foundation for Immunotherapy Success

Antoni Ribas, MD, PhD

Cancer patients around the world are lucky that the graduate engineering programs in Spain require a large amount of high-level math. Had they been just a tad less rigorous, Antoni Ribas, MD, PhD, would never have become an oncologist and uncovered much of what we now know about using immunotherapy to combat cancer.

Ribas has spent the past two decades straddling the worlds of fundamental research and clinical trials, using his discoveries about what will and won’t make the immune system target tumors to get the best responses in important drug tests.

These days, with research dollars pouring into immunotherapy, Ribas is busier than ever, managing about two dozen researchers at his ever-growing laboratory at UCLA’s Jonsson Comprehensive Cancer Center (JCCC). He also is among the scientists who have joined the Parker Institute for Cancer Immunotherapy, a collaborative $250 million research effort launched earlier this year by tech entrepreneur Sean Parker.

In recognition of his many accomplishments in the field, Ribas was honored with a 2015 Giants of Cancer Care award in melanoma.

“Toni didn’t invent any of the individual checkpoint inhibitors that are in use or under investigation, but his research has made checkpoint inhibitors a practical treatment by giving us a better idea about who will benefit from them and, uniquely, studying not only their detailed mechanisms in people but also important aspects of molecular biology that impact therapy of melanoma,” said Kim Margolin, MD, a clinical professor of Medicine at City of Hope.

A Family of Doctors

“That has enabled him and others to design successful trials that get these incredibly promising treatments to real-world patients,” she said. “He’s really everywhere in immunotherapy. Select a big paper at random and there’s a good chance his name will be on it.”Ribas seemed destined for medicine from the day he was born. His father was a doctor. His grandfather was a doctor. His great-grandfather was a doctor. It would have been natural for Ribas to follow in their footsteps; however, he hoped to become an engineer instead. The challenge of finding elegant, mathematical solutions to unique material problems appealed to him more than medicine. Fortunately for patients with cancer, the math eventually overwhelmed him and he shifted his focus to the less quantitative problems of human illness.

“I started engineering school and I realized pretty quickly that it was too complicated. There was just too much math. I needed something easier, and medicine was easier, at least for me, because it only really required the ability to remember a lot of stuff, and I was much better at that than advanced math,” said Ribas, a professor of Medicine, Surgery, and Molecular and Medical Pharmacology at UCLA’s medical school and the director of JCCC’s Tumor Immunology Program.

Ribas chose to follow his father into oncology, mostly because he had spent so much of his childhood hearing about the unique challenges of cancer and watching the field grow from its infancy. He completed his residency at Hospital Vall d’Hebron in 1994 and began what could have been a comfortable lifetime of clinical practice in his native city. But Ribas still had the desire to solve problems, and he decided that he’d indulge it for a short time. “When I finished my training, I had the prospect of doing more of what I had been doing, which was giving chemotherapy. There were no other real options for a medical oncologist in clinical practice in the mid-1990s. My other option was to do a research fellowship and try to discover something entirely new,” he said.

Early Immunotherapy Signals

“I thought it would be more interesting to try to understand the disease better, so I applied for a postdoctoral fellowship at UCLA. I wanted to work in the lab of a surgeon who was doing tumor immunology, which wasn’t a standard clinical treatment back then and was actually pretty far out on the fringes of research,” Ribas said. “Before we left, I told my wife we were coming for 1 or 2 years. It’s now 19 years later, and we’re still here.”The surgeon at UCLA, James Economou, MD, PhD, specialized in studying tumor types, such as liver cancer and melanoma, that responded poorly, if at all, to any treatment oncologists could throw at them. Ribas eventually discovered a technique for using dendritic cell therapy to make mice fight off melanoma, and his initial decision to stay on at UCLA stemmed from his desire to try the same technique in humans.

Dendritic cell therapy never worked in any significant percentage of patients with melanoma, but when it did work, the results were spectacular. “When I did my first melanoma trials, 1 in 10 or 1 in 20 patients who had this disease that had never responded to anything were effectively cured. Most of those responders are still with us today, more than 15 years later. The other patients, unfortunately, had no response at all and they died very quickly.

Dawn of the Checkpoint Era

“Results like these led many to say that immunology would never work for any significant number of patients and that research should focus almost exclusively on the targeted therapies that looked so revolutionary with the responses in trials of Gleevec and Herceptin,” Ribas said. “Perhaps I showed signs of discouragement because a mentor named John Glaspy, MD, MPH, made an argument for the importance of my work that I remember to this day. He said that I was like a person who went to the top of the Empire State Building, dropped 100 balls and found that one of them simply floated in the air rather falling to the ground. Those results wouldn’t be statistically significant either, but they’d be damn interesting, interesting enough to merit serious study.”Immunology researchers like Ribas struggled to increase response rates by finding new ways to stimulate the immune system. Response rates remained depressingly low until James P. Allison, PhD, a professor at The University of Texas MD Anderson Cancer Center and a 2014 Giants of Cancer Care recipient, had a world-changing idea. Immunotherapy might be more effective, he reasoned, if it focused less on speeding up the immune system than on releasing the brakes that tumors put on it.

That insight led to the discovery of many tricks that tumors use to escape the immune system’s wrath. For example, Allison himself discovered that some tumors produce cytotoxic T lymphocyte- associated antigen-4 (CTLA-4), which binds the cytotoxic T lymphocytes the immune system produces and, effectively, turns them off. Researchers developed experimental compounds that bonded with CTLA-4 and unleashed antitumor immune responses.

Not all antitumor immune responses were limited by this particular trick, however, so these experimental compounds could only prove themselves in trials in certain immunogenic cancers. Ribas did early research in this area and participated in the two first-ever phase I trial of a CTLA-4 antagonist.

The design that Ribas created succeeded well enough to push the drug forward to the next trial and to spur development efforts at other drug companies. Trials of ipilimumab (Yervoy) resulted in eventual approval from the FDA in 2011.

Ribas and his colleagues have done even more work to understand how different tumors produce programmed death cell receptor ligand-1 (PDL1), which binds with PD-1 receptor sites on T cells and, again, effectively turns them off so they cannot attack tumors.

Their experiments helped demonstrate that melanomas often express PD-L1 on tumor surfaces as a mechanism of defense when attacked by T cells and that patients whose tumors do this would make good candidates for treatment with immunotherapies that prevented ligands from binding with PD-1. Ribas then translated these discoveries into practical medication strategies by running both the initial and the pivotal trials of pembrolizumab (Keytruda).

“The common aspect of nearly all of the immunotherapies I have worked with from the 1990s until now has been that people who respond to them have generally experienced extremely robust and durable benefits. The thing that has changed has been the response rates, which have gone from the anecdotal level to a substantial minority of all users,” he said.

A Balancing Act

“They should continue to increase as we keep studying tumor biopsies and learning more about what separates responders from nonresponders. It’s clearly not just expressing PD-L1 on the tumor surface because we already test for that before using therapies like pembrolizumab and response rates are still below 50%. As we learn more, we’ll get better at separating responders from nonresponders in advance and, hopefully, getting more people to respond.”Ribas works far longer hours than most people, but, by the standards of world-renowned researchers, he maintains an enviable work—life balance. He typically arrives in the office at 7:30 am on weekday mornings and spends 12 hours at work before leaving the building and the job behind him. Ribas then dedicates his evenings—as well as his weekends—to his wife, his teenage daughter, and his nonmedical interests, which range from hiking to gastronomy.

Ribas rejects the custom among high-achieving Americans to let vacation time go unused—he loves to travel—but he celebrates most other aspects of the nation’s scientific culture.

“This is a place that fosters innovation like no other because it is willing to spend serious money to support young investigators and to allow people to pursue ideas over long periods of time,” he said. “In other countries, grants tend to last a couple of years and they are expected to generate discoveries with immediate applications.” Researchers need to realize that, unlike their colleagues almost anywhere else in the world, “they have the opportunity to pursue such innovative dreams.”

Ribas has repaid the system for the opportunity it provided him by taking significant roles in various learned societies, sharing his discoveries at an endless series of conferences, taking on fellows of his own, and collaborating with countless colleagues across the country and around the globe.

“Toni attends a daunting number of conferences, meets his obligations to endless organizational committees, gets a huge amount of funding for his lab, runs the lab, and writes a huge number of papers—yet he still finds time to respond to e-mail almost immediately. It’s sort of scary,” said Margolin. “There are obviously many keys to his success, starting with the fact that he’s very bright, but the thing I hear discussed most often is his character. He hasn’t risen by forcing others down while he stands on their shoulders.

He has risen by supporting his colleagues and inspiring their support. There are no losers when you collaborate with Toni, which makes a lot of people want to work with him.”

Ribas, in turn, has plenty of projects that he wants to pursue with collaborators inside and outside of his own lab. There’s always the ongoing investigation of the the fundamental interaction between tumors and the immune system, of course, but the full list is almost endless.

In addition to studying the basic science, he is beginning trials that use targeted therapies and immunotherapy in combination with each other. “The most exciting thing, to me, is that we’re just beginning to understand how tumors escape the immune system,” Ribas said. “Hopefully, when we know much more than we do now, we will be able to do far, far more to trigger an immune response than we can now.”