Leading Immunotherapy Researcher Lands in Qatar

Courtesy of the Society for Immunotherapy of Cancer

Francesco M. Marincola, MD

When Francesco M. Marincola, MD, decides it’s time for a change, he doesn’t leave any room for doubt.

Marincola made a bold move earlier this year when he left a longterm position as a tenured senior investigator at the National Institutes of Health (NIH), in Bethesda, Maryland, and moved nearly 7000 miles to the Middle East to build a research program at a private hospital in Qatar.

A few months later, the 60-year-old doctor, who remains president of the Society for Immunotherapy of Cancer (SITC) with its roster of leading US researchers, symbolically wrapped up the previous 25 years of his career. He coauthored a paper in the journal Immunity that sets forth evidence that tumors have overlapping immune signatures that offer prognostic and predictive indicators of whether immunotherapy will result in positive outcomes, as well as a way to evaluate the impact of an immunotherapy on a tumor.¹

Marincola, who also made a big change early in his career when he left his native Italy to study at Stanford University in California, took his latest leap because he was frustrated by limits on biomedical research in the United States—including restricted funding and insufficient support for the larger, more collaborative efforts he considers vital. As a result, the doctor said, he was eager to play a bigger role in “policy making and the strategy of research.”

At Sidra Medical and Research Center in Doha, where he stepped into the role of chief research officer eight months ago, Marincola is tasked with building a research program to rival the best in the Western world.

“Sidra’s focus is on women and child care, high-level care, and educating the health community, in addition to a very strong focus on research, particularly translational aspects of research,” said Marincola, who at the NIH also served as chief of the Infectious Disease and Immunogenetics Section. “We are building on the work of the many institutions in Qatar that are doing basic research, like Cornell University and others, and trying to create a research infrastructure that is closer to the patients. We’re looking for investigators interested in applying what they know directly to developmental therapeutics, or investigators who will try to understand the mechanisms of disease by studying patients. We’re supporting the research community in Qatar and the region by linking basic and clinical research and the patients.”

The end result, Marincola hopes, will be a “clinical research center where we can treat patients safely using nonstandard, experimental treatments in addition to tertiary level care. We want Sidra to be like the NIH, a place people go to seek alternative therapies when the standard fails.”

At the same time, he hopes, the program will stand as an example of what can be accomplished when research incorporates the level of collaboration truly needed to exploit today’s genomic investigation techniques.

Getting Started at Sidra

The privately owned Sidra is Qatar’s first academic hospital, and its focus on women and children is a reasonable starting point, since “there seems to be a higher incidence of perinatal problems in the country,” Marincola said. Many children are affected by genetic disorders, he noted, “because the population here in the Middle East and Northern Africa tend to marry within their families more frequently, which exposes them to a higher risk of diseases that are genetically dependent upon people from the same family who carry the same predisposition.”

To handle such problems, Marincola plans to establish a comprehensive program to identify genetic characteristics and biological mechanisms that predispose patients to the conditions, and then treat some of the diseases via genetic engineering.

“Sidra will be the engine to identify new diseases in collaboration with many groups across the world, along with the character of these diseases, validation of their cause, and treatment,” he said.

Marincola anticipates some challenges along the way, particularly since he’ll be setting up “a whole support system for research the way it’s done elsewhere, in a place that is geographically separated from most larger institutions.” On the other hand, the doctor said, starting the program from scratch may be an advantage, since there will be no need to change entrenched ways of doing things.

While building the program, Marincola intends to keep a smaller portion of his attention trained on his personal research efforts, starting with the relocation of his genetics lab, currently at NIH, to Sidra.

early clinical trials for the treatment of cancer with immunotherapy,” he said. “My main work in the past has been in melanoma, developing therapies and understanding their mechanisms, but I have become more interested recently in other cancers, because some seem treatable with immunotherapies that used to work predominantly in melanoma. Here at Sidra, there is not much melanoma, so our idea is to do clinical trials in other cancers, like breast cancer, that are relatively common here.”

While Marincola will continue to lecture around the world as SITC president, he has cut back on his frequent visits to China and Colombia, where he has longstanding relationships with several medical schools. He has served as an adjunct professor at several Chinese universities, including Peking Union Medical College in Beijing, and at Universidad del Rosario, in Bogota, Colombia.

“China has a lot of researchers who share my interest in immunology, and they are becoming very, very good at what they do,” Marincola said. “The world really is becoming flat if your intention is to know what everybody is doing and help develop new programs. It’s important to teach them what we can and, at the same time, learn from them.”

Solid Funding: A Rare Gift

A rarity in today’s healthcare landscape, Sidra is funded with “a large endowment and very strong and firm support from the leaders of the country,” Marincola said. “In fact, the chair of the board of Sidra is Her Highness Sheikha Moza Bint Nasser herself.”

It’s a very different dynamic than the frustrating scenario to which Marincola had become accustomed in the United States.

“The short-sightedness of the US in providing funding for research in the last decade has been remarkable,” he said. “We’re still under the illusion that we are a good emerging country for research, but that’s not the case. I travel the world, and it’s amazing how many countries are putting a lot of effort into biomedical research. In Qatar, the ruling family makes research 2.6% of the country’s gross domestic product. In the US, it’s much more limited, and becoming even more so.”

Moreover, the funding the American government does spend on research is too often allocated to smaller projects run by individual investigators, a tendency that is bound to breed problems, Marincola said.

“It creates fragmentation of research,” he said. “Complex research now requires groups working together to answer just one big question, not a lot of little questions.”

Francesco M. Marincola, MD. . . Briefly Speaking

• Is originally from Italy, but is now an American citizen.
• Explains that Sidra, the name of the institute in Qatar where he is building a research program, is an Arabic word for the country’s national tree. The sidra “symbolizes healing and learning,” he said. “People used to gather under the branches of this tree in the desert during hard times, and it also provides fruit used for traditional medicine. Its trifurcated trunk symbolizes patient care, education, and research.”
• As a child, dreamed of being an astrophysicist; his father convinced him to instead become a doctor, believing he’d have an easier time finding a job. “I would look at the stars and wonder, and I always used to read about everything, particularly the universe,” Marincola said. “Now it’s a hobby of mine to read about discoveries in astrophysics.”
• In 2003, founded the Journal of Translational Medicine, and is currently its editor-in-chief. “It was the first journal on translational medicine in the literature, and I wanted to start it because I became very frustrated with how difficult it is to publish results in medical journals when they’re not done experimentally in the lab, or in large clinical trials, yet still demonstrate important insights. I hope there will be more and more journals like this.”
• Doesn’t approve of awards in the research arena. “Scientists should do science for the sake of science, not to get an award,” he said. “There is a lot of competitiveness in the world of science, which I do not appreciate.”
• Is president of both the International Society for Translational Medicine and the Society for Immunotherapy of Cancer.
• Serves on advisory boards of the National Cancer Institute, the Cancer Immunology Trial Network, and the Pharma Foundation, and is on the steering committee for the worldwide cancer immunotherapy Immunoscore initiative.
• Is the author of more than 500 peer-reviewed research articles, whose work has been cited more than 16,000 times.

As a result of this trend, Marincola said, “you have a lot of American investigators trying to survive by creating projects that are very limited and conservative, because they are the most likely to be funded based on NIH guidelines. Large projects, new initiatives, that are broad and need institutional interactions don’t get funding, so most money goes to support individual investigators, not ideas.”

Compounding that problem, Marincola said, “is that, while we continue to cut the funding for research, spending for healthcare continues to skyrocket. If you look at the proportion of money put to research versus the trillions spent in treatment of disease, which doesn’t do anything most of the time, it’s amazing. A fraction of what we spend is to try to identify effective treatments, rather than to treat with things that don’t help for chronic diseases like cancer.”

Marincola called the issue “a political problem, not a research problem,” and suggested that strong advocates in the biomedical research community, along with education of the public and US government about the critical importance of research, are needed.

Making His Mark in Immunology

In conducting his own research throughout his career, Marincola made his mark by developing and validating the idea that cancer can be fought by enhancing the immune process that causes the body’s rejection of a transplanted organ.

He first studied the strategy at the NIH under the mentorship of renowned cancer immunologist Steven A. Rosenberg, MD, PhD, who was honored in OncLive’s Giants of Cancer Care recognition program in July. Marincola, who had recently earned his MD summa cum laude from the University of Milan and trained in surgery at Stanford, was impressed by immunotherapy’s potential. Although the therapy worked only in 7% to 10% of patients, Marincola recalled, it was spectacular when it happened.

“A classic example 20 years ago was interleukin-2,” he said. “You’d give it to patients with advanced melanoma all over their bodies, or for kidney cancer, and there were dramatic responses. Some people are alive now who were supposed to die two months after they were seen at the NIH.”

Fascinated, Marincola spent the next two decades trying to figure out why some patients responded to such therapy and others did not.

“We realized that the only way was to study patients and their tumors at the genetic level, and see if we could identify features to predict response,” he said. “We applied techniques to investigate the whole function, the genome, of a cell. We were pioneers in applying these techniques for the study of tumors and patients before treatment, and in 2000 we identified some genes that were important to predicting response to treatment.”

Subsequently, he said, other investigators published papers confirming that the inflammatory process that accompanies a cancer is not sufficient to banish the disease, but that stimulation of the inflammation can lead to tumor rejection.

“Papers came out that showed how kidney transplants are rejected, and we realized that the genes we saw in the rejection of cancer were the same as those associated with the rejection of a kidney, or with graft-versus-host disease,” he said. “We came up with a hypothesis that all these mechanisms are the same. There’s a group of genes that come up every time you destroy something. They’re good in rejecting cancer and bad when rejecting an organ, but the mecha - nism is the same.”

Recently, scientist Jérôme Galon, PhD, of the Laboratory of Integrative Cancer Immunology in France, identified what Marincola and colleagues had hypothesized in the first place: that the genes involved in rejection of a cancer or an organ were not only predictors of response to immunotherapy, but also harbingers of good prognosis for patients with cancer.

Marincola joined Galon and others in describing three key concepts in immunotherapy: immune contexture, which includes the type, density, and location of adaptive immune cells within the tumor; the Immunoscore, a standardized immune stratification system; and the immunologic constant of rejection (ICR), which defines tissuespecific signatures detectable as the tumor regresses during immunotherapy.¹

Specifically, the paper identifies 13 ICR genes associated with T helper type 1 cell polarization, related chemokines, and cytotoxic mechanisms that more frequently correlated “with the broader phenomenon of immune-related, tissue-specific destruction.”¹

Marincola said the method of immunotherapy evaluation “worked much better than the classification of cancer using TNM staging; it was much more accurate. Hopefully, now that we understand the mechanism, it will be easier to identify and target treatments.”

Getting There

Marincola landed at Sidra without ever applying for the position.

He was on sabbatical at Cornell in Qatar when the opening at Sidra came up. He was involved in discussions about the endeavor with leaders there, and was eventually offered the job.

Contrary to what Americans might expect, living in the oilrich, nondemocratic country hasn’t been much of a culture shock, Marincola said.

“Qatar is a very modern small country, and not that different from living in any town in the United States,” he said. “There is a flavor of the Arab Muslim world, but things are done in the same way they are in the United States. The official language is Arabic, but everybody is highly educated and speaks English very well, better than in most countries in the world where the first language is not English. In addition, Qatar is in the middle of the world—you can be in India in three hours, in Thailand in four, in Europe in five, and in Kenya in six—so it’s an interesting place to be.”

Marincola is also taking in stride the personal changes the move has brought.

His grown children, Jamie, Paula, and Rachel—the youngest of whom is 20—did not move to Qatar along with him, and neither did his wife, Elizabeth, who had just relocated to San Francisco to take a job as CEO of the Public Library of Science.

“She’s a highly successful professional and wants to follow her career, too,” Marincola said. “We also felt that only one person at a time should explore being away from the United States, to see how things go. Nowadays, we both travel so much that this won’t be a major limitation for our relationship.”

In fact, Marincola’s family has come to expect him to focus closely on his career.

“I’m a workaholic,” he said. “To me, it’s a sacrifice not to work. I always liked it, and I like the intellectual stimulation of being in the academic community.”

True to form, Marincola is already laying out the path his career might take after the research program at Sidra has been established—with a caveat.

“I’d like to eventually move into running a cancer institute somewhere one day, a comprehensive one where you actually treat patients, and to continue to do research in cancer on the side,” he said. “Or, maybe I’ll just retire.”

Reference

1. Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013;39(1):11-26.