There are distinct advantages to housing the John Wayne Cancer Institute, one of the most respected cancer research facilities in the country, at Providence Saint John’s Health Center. Saint John’s patients have access to better clinical care because of the cutting edge research done at the Institute, and researchers at the Institute have better access to patients. Because of the alliance between the two institutions, Saint John’s patients can get treatment—including those offered in clinical trials—that might not yet be available elsewhere.
Now, with immunotherapy, the Institute is at the forefront of revolutionizing cancer treatment with medications that boost a patient’s own immune system to fight off cancer. And while the progress these new treatment drugs have made in the past few years has been remarkable, and powerful new anti-cancer drugs have been fast-tracked by the Food and Drug Administration, the concept itself could be called a throwback.
Make that a throwback in a good way: Some of the most groundbreaking discoveries in the field actually have been in the works for decades. The late Donald L. Morton, MD, co-founder of the John Wayne Cancer Institute, was an early advocate of immunotherapy research while working at the National Cancer Institute in the 1960s. He had been struggling to design a vaccine for melanoma using modified melanoma cells. Vaccines are a type of immunotherapy that take advantage of the body’s natural ability to recognize and attack harmful substances.
While immunotherapies have, over the years, fallen in and out of favor among medical researchers, Dr. Morton and his colleagues never wavered in their conviction that the body’s own natural mechanisms for fighting germs and other foreign invaders could be employed to battle cancer.
Today the Institute can be proud of its trailblazing legacy in the development of cancer immunotherapies, says Delphine J. Lee, MD, PhD, director of translational immunology and the Dirks/Dougherty Laboratory for Cancer Research. Saint John’s Health Center patients continue to reap the rewards of the Institute’s research. “I’ve been saying all along that the immune system is the key in fighting cancer,” she says. “It has taken a while for the concept to prove itself. But we, at the Institute, were always looking at the immune system.”
One day Dr. Morton saw a patient with melanoma lesions all over her arm. There were no treatments for such an advanced case, so he decided to give the patient an injection of Bacille Calmette-Guérin (BCG), which is made from live but weakened bacteria related to the bacteria that cause tuberculosis. He reasoned that the bacteria might stimulate her immune system to kick into action and fight the cancer.
“Her previous doctors had suggested amputation of her arm, but she was a polio victim whose other arm was paralyzed,” says Mark B. Faries, MD, director of the Donald L. Morton, MD, Melanoma Research Program and therapeutic immunology at the John Wayne Cancer Institute. “Dr. Morton thought he’d try the BCG vaccine since she had nothing to lose. Her melanoma went away, and she was still sending him Christmas cards decades later. From that experience, he was instilled with a fervor to make immunotherapy work, while others remained doubtful.”
“I’ve been saying all along that the immune system is the key in fighting cancer. It has taken a while for the concept to prove itself. But we, at the Institute, were always looking at the immune system.” – Delphine J. Lee, MD, PhD
Dr. Morton continued to study cancer immunotherapy after he moved on to the University of California, Los Angeles, and then started the John Wayne Cancer Institute at Saint John’s Health Center, says Leland J. Foshag, MD, a surgical oncologist who later moved with Dr. Morton to Saint John’s. “Back then people thought immunotherapy was both a revolutionary and crazy idea. The feeling was, ‘Why are you fooling around with the immune system? It’s all about chemotherapy.’”
BANKING ON THE FUTURE
But Dr. Morton stuck to his guns, and took another prescient action when he decided to begin freezing blood, tumor and other tissue samples from cancer patients that could be used to study immune system response. His foresight convinced Dr. Lee to join the Institute’s immunotherapy team.
“It was his vision and ability to collect specimens that enticed me,” she says. “It’s one thing to ask an interesting scientific question. It’s another thing to have the tools to answer it.” The Institute’s specimen repository is exceptional because it includes patients’ records with outcomes—data that can be correlated with their tissue samples.
“Everyone is jumping on the bandwagon with tissue banks now. But Dr. Morton carefully collected immune cells from blood and froze the samples,” Dr. Lee explains. “I’ve been able to thaw them 30 years later and study their live function. I do something with them and learn. That is beyond visionary.”
Saint John’s has remained steadfast in its support of this kind of basic science, which—while painstaking and slow and seemingly impractical—is the basis for extraordinary discoveries such as the recent burst of new cancer immunotherapy drugs like ipilimumab and pembrolizumab, which are dramatically improving long-term remission rates for melanoma and other types of cancers, says Dr. Lee. “There is this focus on clinical research and clinical trials, but the findings that led us to ipilimumab and pembrolizumab started from basic research,” she says. “You can’t fix something if you don’t know how it works. That’s where progress starts.”
AN EARLY CANCER VACCINE
[MortonGupta_SJMagWinter15] In 1998, Dr. Morton was convinced enough of the potential success of immunotherapies that he created an experimental vaccine for melanoma. Called CancerVax, the vaccine was based on the knowledge that the BCG vaccine could, in some patients, cause melanoma tumors to vanish.
CancerVax consisted of live cells from three melanoma cell lines grown in culture. The study participants either received the vaccine or BCG injections. Ultimately, CancerVax was considered ineffective because the patients receiving BCG had outcomes similar to those who had received the vaccine.
But Dr. Morton and his Institute colleagues continued to use BCG injections, much to the gratitude of patients like Anita Semjen, 71, who lives in Washington, D.C. An international arts consultant, Anita was born in Hungary but moved to the United States in 1988. In 1989, she noticed a growth on the back of her right calf. An immigrant without health insurance, she didn’t consult a doctor until 1990, when she learned the growth was melanoma. The tumor was removed, but three years later Anita learned the cancer had returned and spread.
Anita had surgery and chemotherapy and even tried several experimental therapies at Memorial Sloan Kettering Cancer Center in New York City. “Four or five tumors came back on my leg,” she says. “After a while the doctor at Sloan Kettering said, ‘Sorry, that is all we can do for you.’”
At that time, Anita learned she also had breast cancer and was successfully treated. However, the melanoma persisted. She turned to the National Institutes of Health in Bethesda, Maryland, near her home, and had an experimental treatment called isolated limb perfusion, which involves infusions of chemotherapy directly into the limb with the tumors.
The treatment didn’t work and left her with a weakened leg and in severe pain for a year. By 1998 she had about 200 small melanoma tumors in her right leg, but none of the cancer centers she had seen on the East Coast had anything more to offer her. One group of physicians even recommended amputating the leg.
Years earlier, however, a dermatologist had told Anita about BCG injections for treating melanoma. She began searching for someone who offered the treatment, found Dr. Morton and underwent BCG injections at the John Wayne Cancer Institute for five years, first flying out every two weeks and then stretching out her trips for injections as she responded to the therapy. The tumors had completely disappeared around the third year of treatment.
Anita still visits Saint John’s from D.C. twice a year, seeing Dr. Foshag at the Institute. “I remember during one of my first visits, seeing this little sign in the waiting room that said to be patient because the doctors will spend as much time with each patient as the patient needs. It was like I had arrived home.”
“Don Morton was a pioneer in the development of early immune treatments for cancer, initially with BCG and then tumor cell vaccines. He was fearless, tireless and an out-of-the box thinker,” says Steven J. O’Day, MD, professor of medical oncology at the Institute. “Don’s colleagues around the world often thought he was crazy, injecting BCG into human tumors. But it’s come full circle. All the naysayers are now jumping on board.”
MELANOMA: A WILD OPPORTUNITY
Unlike other skin cancers, melanoma is highly aggressive, with the ability to move rapidly into the bloodstream and fan out along the highways of the circulatory system, setting up camp wherever it likes, from the lymph nodes to the internal organs. It also mutates easily. All of this means that traditional treatments such as surgery, chemotherapy and radiation have little to no effect.
“Melanoma has been a prime candidate for immune therapy investigation because these traditional therapies could never be established as standard treatments,” says Dr. Faries. “The two most promising categories of advancement in melanoma treatment today are immune therapies and targeted therapies.”
Current immune therapies include drugs such as ipilimumab, which strengthens the body’s immune system by boosting the number and effectiveness of the body’s T cells, and two new drugs (pembrolizumab and nivolumab) that bind to a pathway on the cancer cells called PD-1 receptors. In addition to these immune therapies, the nascent and growing field of targeted therapies uses melanoma’s own mutations against it, preventing the cells from growing and eventually killing them.
“Up until now, treatments for advanced cancers were merely ways of buying time for patients and extending survival,” says Dr. Faries. “But these new therapies are game changers because they have the potential of fixing a cancer in a more long-term way.” And while the new medications used to treat melanoma have shown the most promise, researchers at the Institute are now testing them against a host of other types of cancer, including colon, bladder, kidney, breast, Hodgkin’s lymphoma and multiple myeloma.
Specific genetic mutations such as the BRAF mutation, which accounts for about half of melanoma patients, can be targeted quite effectively. “We can easily test for it,” explains Dr. O’Day. “Someone with widespread melanoma can see their tumors melt away within a week.” The downside is that, currently, targeted therapies on their own may only work for a limited time before the cancer becomes resistant to them as well. So these medications are primarily used for patients with advanced cancer who need a fast response and temporary remission that gives doctors time to find a long-term plan.
PAST MISSTEPS LEAD TO PROGRESS
While CancerVax was considered unsuccessful by some, it hinted at the immune system’s complexity, a concept that today is understood much better, Dr. Lee says. Researchers have learned that turning on the immune system to fight cancer won’t work on its own. The immune system also needs to be strategically manipulated to shut off some mechanisms and allow other key functions to recognize and attack cancer, she says.
Research on cancer vaccines is undergoing a renaissance today, and the Institute’s researchers are front and center. Two melanoma vaccine trials are underway under the direction of Dr. Faries. “Both use patients’ own tumors as sources of vaccines,” he explains. “The tumor is removed, then a vaccine is created from the tumor to give back to patients. What’s different is they are given with different immune stimulation alongside the vaccine. The context in which the vaccine is given affects the response. Both trials use dendritic cells created from patients’ own blood to steer immune response in more beneficial directions.”
Dr. Faries’ research on tumor-infiltrating lymphocytes (TILs) is also a type of immunotherapy. After a metastatic tumor is removed, it’s taken to the lab and put into a culture to assist growth of immune cells. Very large numbers of those cells are injected into the patient. “With vaccines,” Dr. Faries says, “We rely on a patient’s body to stimulate immune cells on their own within the patient. Part of the problem with melanoma is the immune system is not so strong, so the response from the vaccine may not be strong enough, whereas the massive response generated in lab can be given back fully formed.”
NEXT UP: THE MYSTERIOUS MICROBIOME
In Dr. Lee’s lab, several innovative immunotherapy projects are underway. Researchers continue to study how BCG can be used to enhance the immune response. She is also on the leading edge of research exploring how microbes that naturally cover our bodies and populate our intestines can influence cancer development through an immune system response.
“We’re living with the bacteria all over us. They mold and shape all of our organ systems and, more importantly, our immune system,” she says. “We’re undertaking a big effort to understand how the microbes in the breast contribute to breast cancer in its development or contribute to it reoccurring.”
She is working with Susan Love, MD, MBA, the renowned breast cancer expert, and NASA researchers to study the breast microbiome. The group is seeking funding to expand their work to study how bacteria in the intestinal tract may influence breast cancer development.
Likewise Dr. Lee is working with Anton J. Bilchik, MD, PhD, and Providence researchers in Portland on the role of the intestinal microbiome in colon cancer development. Dr. Bilchik is chief of medicine and the gastrointestinal research program at the John Wayne Cancer Institute.
“The progress being made in immunotherapy at the Institute is truly inspiring,” says Carole Schwartz, a Saint John’s Health Center Foundation trustee and a member of the cancer committee. “So many patients, families and future generations will benefit from the incredible findings and discoveries made by Institute researchers. This is just one of the reasons why I am so motivated to raise awareness and funds to support cancer research at the John Wayne Cancer Institute.”
Unlike many other research groups that are gearing up to study cancer immunotherapy, the researchers at the Institute are continuing their work. “It’s nice to know that we’re on the right track,” Dr. Lee says of the cancer immunotherapies that are now making headlines around the world. “It’s sort of a confirmation: We’re not out here in left field. We’ve been digging in the right area.”