More than 1.6 million Americans will be diagnosed with a type of cancer this year, but technological advances have opened up never-before-dreamed-of possibilities for cancer diagnoses and treatment. These advances drive the research of two Davidson alumni, whose work with The Cancer Genome Atlas and T-cell immunotherapy has made headlines and, more importantly, moved their respective fields forward in the fight against these devastating diseases.David “Neil” Hayes and Renier Brentjens overlapped two years at Davidson in the late 1980s but unfortunately didn’t know each other. Today they are oncologists at top cancer research centers pursuing cures on the latest frontiers of medicine.
Hayes ’91 is a leader at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, where he and others are mapping the genome of cancers, spurring development of drugs targeted to strains of the disease. The work is part of The Cancer Genome Atlas (TCGA), an international consortium managed by the National Cancer Institute and National Human Genome Research Institute. Hayes calls TCGA “as big a deal as the development of the X-ray and microscope—an entirely new way of looking at tumors.”
At Memorial Sloan Kettering Cancer Center in New York City, Brentjens ’89 specializes in harnessing the immune system to defeat cancer. His therapy, now in phase two clinical trials, takes a patient’s own T cells and alters them to fight leukemia and lymphoma, an approach that has received attention from The New York Times, ABC World News and other national media. In 2013, Science magazine called the work its “Breakthrough of the Year.” Of nearly 100 patients treated so far using the T-cell therapy, more than 80 percent have gone into remission, and about half of those have stayed in remission, Brentjens says.
“There are colleagues of mine who have devoted their entire lives to this work and not been as fortunate as I have,” he says. “Taking something you created in the lab on the bench top and testing this in poor prognosis patients—and it took a while—and seeing there are people still alive because you did what you did—I would be lying if I didn’t say it was a great feeling.”
T Cell Re-engineering
Born in Amsterdam, Renier Brentjens visited the United States for the first time when he was six years old after his dad received a fellowship at the medical school of the State University of New York (SUNY) in Buffalo. His father eventually obtained tenure, and the family moved permanently to the United States when Brentjens was 10.
“If you ask where most of my identity is from, it’s Buffalo—I’m a big Bills and Sabres fan,” he says.
With his father, mother and other family members being doctors, Brentjens “remembers from an early age that I never wanted to do anything but medicine.” Admissions staff at SUNY Buffalo mentioned Davidson in the same breath as Amherst and Williams as good liberal arts schools to prepare for medical school.
“I loved North Carolina from camping there as a kid (at Cape Hatteras),” Brentjens says, “and it was an outstanding school and the tuition was more reasonable than the others.”
Also, his sister, Joanneke ’88, was already a student at Davidson, and his brother, Mathijs ’90, later attended Davidson. Joanneke became a lawyer, and Mathijs, a dermatologist.
Renier took pre-med courses but majored in history. “I knew the rest of my life I would be doing science,” he says.
One of the inaugural Kendrick K. Kelley history scholars, he says the field of study helps him relate to his patients.
“When you’re taking care of a patient, you invade their space. Knowing something about the world, culture and people goes a long way to easing this awkward situation and helps build more comfortable relationship,” he says. “I’m not being cynical about this. I enjoy my patients, and in the business I am in, we have long-standing relationships.”
Lab work at Davidson under neuroscience professor Julio Ramirez helped show Brentjens that medicine was a good fit. “I was working with mice and rats as one of his students when he was just starting out,” Brentjens recalls. “I really enjoyed my time with him; it was my first real taste of science.”
In recent years, Brentjens was thrilled when Ramirez remembered him.
“That’s Davidson—you’re able to email your old professor to say thank you, and he says, ‘Of course, I remember you.’ Something like that is really special. I would be delighted if one of my kids chooses to go to Davidson.”
He and his wife, Tricia Brentjens, an anesthesiologist at Columbia University, have three boys, 17, 15 and 12.
After graduating cum laude from Davidson, Brentjens spent seven years at SUNY Buffalo earning his medical degree and a doctorate in microbiology. He was focusing on infectious diseases when he attended a national meeting at which a key speaker talked about the budding field of gene therapy.
“As he spoke of the future and the potential—that we may use it to treat cancer—I latched onto that,” Brentjens recalls of the early ’90s conference. “The science of gene therapy motivated me.”
Following a two-year residency in internal medicine at Yale-New Haven Hospital, he started a fellowship in medical oncology at Memorial Sloan Kettering Cancer Center in 1998 and became an attending physician there in 2002. Today he runs a lab of 20 that carries his name. He also directs the Cellular Therapeutic Center, made up of 15 physicians who run cell therapy trials with nursing staff, research assistants, secretaries and attending physicians.
Brentjens chose to focus on acute and chronic leukemia for two reasons.
“You never have to deal with surgeons, or if you do, you are telling them what to do,” he says. “And as a group, these are fascinating diseases. Acute leukemia patients are probably the sickest patients who can come back from the dead, so to speak. It’s dramatic and intense. Those who deal with cancers that metastasize are focused on keeping patients alive for as long as possible, but with leukemia, the intent is to cure the disease.”
It was his iteration of a T-cell therapy in Dr. Michel Sadelain’s lab that eventually was translated into several clinical trials, treating acute leukemia and lymphoma patients. The approach takes some of a patient’s T cells, a type of white blood cell that fights infections, and re-engineers them genetically to recognize a protein on cancer cells and destroy them.
A big breakthrough for Brentjens and his colleagues came in 2013. The day The New York Times recounted the success of the first five patients treated with the T-cell immunotherapy, he wanted to buy two copies of the newspaper at the train station, but a vendor would only sell him one.
Thumbing through the sections, he didn’t see anything, but a text from his wife pointed him to the front page above the fold. The visibility was the hammer on the nail of the work.
“It took on a life of its own,” he says.
Apart from more than 400 emails he received that day, and TV coverage that prompted his mother’s comment of “I wish you didn’t have that goatee,” the attention was pivotal.
“That turned the corner of convincing the rest of my scientific colleagues that this was for real,” Brentjens says.
It also resulted in the formation of Seattle-based Juno Therapeutics, which is funding phase two of trials to fine-tune the therapy and help it toward FDA approval, trials which cost “10s of millions of dollars,” Brentjens says. Juno is focusing where Brentjens and his colleagues have had the most success, with B cell acute lymphoblastic leukemia.
Clinical trials have been expanded to lung, breast, ovarian and mesothelioma cancers, but much remains to be tested and learned.
“We have proof of principle,” Brentjens says. “What we don’t know is whether this immune-based therapy will work in solid tumors, and some of our patients do relapse. With respect to this technology, we are at the very early stages of development, we have a Model A Ford, but we need a Ferrari.”
At age five, Neil Hayes moved from his native Atlanta to Winston-Salem, North Carolina. In high school, he looked into attending Davidson because it wasn’t far from home.
“It was close to dumb luck,” he says, noting the profound effect the college had on him. “I learned more than anything a tremendous work ethic, doing a good job learning something,” says the chemistry major. “I struggled at first; I didn’t know how to study.”
The turning point came in a chemistry class taught by John Burnett early in Hayes’ sophomore year.
“I learned to think quantitatively. It’s one thing to speak in anecdotes, but what are the numbers? Just make the left side (of the equation) equal the right side. It helps you see priorities. Things became easy after that.”
Also, during his junior year, he overcame challenges in French through hard work and a study-abroad program in Brittany, France—and his career path emerged.
“I realized I had a people side and a science side, so I thought, ‘OK, I’ll do medicine,’” he recalls.
After finishing medical school at UNC in 1996, Hayes earned a master’s in public health at Harvard in epidemiology. During his three-year residency at Boston University School of Medicine, he began to focus on cancer.
“I realized the genomics revolution was happening,” he says, noting that advances with computers, lasers and other devices were boosting the field. “I was in the right place at the right time,” he says. “The technology came long, and I had the skills.”
He spent four additional years in Boston, earning a master’s in clinical care research and serving as a clinical fellow in hematology and oncology at Tufts. He then worked as a post-doctoral fellow at Dana-Farber Cancer Institute. Afterward, he headed back South to become an assistant professor at the UNC School of Medicine in 2004.
He liked UNC’s cancer research resources and thought he’d gain opportunities much sooner than at highly competitive Dana-Farber.
“I would still be an instructor there,” he says.
He also liked that his wife, Liza Makowski Hayes, a nutritional biochemist, was able to get a job in UNC’s school of public health.
Today Hayes is an associate professor in the medical school and has steadily taken on high-profile responsibilities with UNC Lineberger Comprehensive Cancer Center.
He is director of clinical bioinformatics and co-leader of the overall clinical research program, Lineberger’s work with The Cancer Genome Atlas (TCGA) and its own UNCseq program. He is one of the founders of GeneCentric, a Durham, North Carolina-based firm that offers diagnostic products and seeks to develop drugs based on the cancer genome work.
TCGA, funded by the National Institutes of Health and others, began in the mid-2000s. When Hayes and another Lineberger doctor successfully landed a TCGA grant, it was a coup.
“It was a stretch for us; we weren’t a genomic center and didn’t have a history,” Hayes says. “We had to rally the resources.”
Lineberger’s role in TCGA has been to sequence RNA data for nearly 11,000 patients with more than 30 cancer types, and to analyze the overall cancer genome data being generated and studied by researchers around the globe. RNA is the portion of the genetic code that carries instructions from DNA for making proteins. The sequencing part of TCGA wraps up this summer, Hayes says, but heavy analysis of the work will continue for years.
The essence of TCGA is to provide an instruction, or parts, manual on cancers, Hayes says. Rather than researchers simply comparing the appearance of cancer and normal cells under a microscope, they are drilling down to what tells the cells how to behave, how fast they will grow and, in the case of cancer cells, whether they will respond to a particular drug—all of which is determined by the cell’s DNA, which forms the genome.
“It’s a different way of thinking about cancer and treating it,” Hayes says.
The ultimate goal is to develop drugs that target cancer mutations found in DNA and to cure patients. While that is a ways off because drug development takes years, TCGA is already changing how some cancers (especially brain) are being diagnosed, Hayes says, and the work has been cited more than 10,000 times in papers over the last five years.
As a specialist in cancers of the lung and of the head and neck, he has written papers based on TCGA results about squamous cell versions of these diseases, specifically how they share the NFE2L2 gene and can be treated with potential drugs.
“I’m aware of several pharmaceutical development efforts that are already organized around this,” he says.
TCGA work at Lineberger also has identified a link between some head and neck cancers and the human papillomavirus, the most common sexually transmitted virus in the United States and often linked to cervical cancer. The work was featured on the cover of the January 2015 issue of the journal nature.
As an outgrowth of TCGA, Lineberger began its own sequencing project entitled UNCseq. While TCGA uses tumor samples a decade or more old, UNCseq focuses on tumors of current patients who have advanced cancers and are not responding to usual treatments.
Working in a 10-person lab that bears Hayes’ name, researchers carefully prepare tumor and normal tissues samples using ultrasound and sequencing equipment that costs millions of dollars. The sequencing machines—now in their sixth generation since 2007, Hayes says—send the samples’ genome data to desktop computers for study.
Hayes and his fellow researchers pore over the information in colorful linear graphs on their computer screens. The data and their observations then go to the Molecular Pathology Tumor Board at Lineberger, who studies them and makes treatment recommendations.
But the board’s job is not easy. The datasets are big and complex, and the board typically makes recommendations in only about half of the 20 cases it examines each week.
A partnership announced in 2015 with IBM is expected to accelerate the process dramatically for Lineberger and 14 other participating cancer centers.
The vision is for IBM’s Watson supercomputer to crunch voluminous datasets in minutes—not weeks—providing more, faster and greater detailed treatment recommendations, pulling not just from genome data but from databases on drugs, clinical trials, medical literature and other resources.
“The interpretation of data is nontrivial,” Hayes says. “It’s beyond what humans can deal with, and certainly beyond people who haven’t had the training we have. I live and breathe this genetic stuff. If we’re going to transfer this into the community, and not just to the community oncologist, we’ve either got to train people like me all over the world or find another way to disseminate this information. Watson, and things like Watson, are probably a way to go.”
Cancer is a collection of diseases—100 or more, and growing. To wipe out these diseases, the treatments of the future—targeting the disease type and not the category—will have to be personalized to an extent not yet possible. That’s going to require far more research, and to Hayes’ point, more people trained to interpret and disseminate the data.
Malcolm Campbell, professor of biology and director of the James G. Martin Genomics Program at Davidson, says the time is now for anyone studying medicine to delve into the field of genomics.
“It’s coming fast—the role of genomic medicine in health care is at the tip of the iceberg,” he says. “Undergraduates, especially if they are pre-med, should be taking genomics.”
Both Hayes and Brentjens are excited about President Barack Obama’s $1 billion National Cancer Moonshot initiative to cure cancer but have yet to see details or funding.
“There’s been a lot of rhetoric, but it’s still extremely difficulty to operate and run a lab—the competitiveness is as hard as it’s ever been,” Brentjens says. “I write and review a lot of grants, and you’re more likely not to get funding than to get it. If society wants the scientific establishment to come up with cures, it has to do more than throw around rhetoric, it has to throw money at it.”