Through Thick and Thin: Institute scientists championed cancer immunotherapy long before its current success

December 22, 2015
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In 2013 the prestigious journal Science designated cancer immunotherapy its Breakthrough of the Year, citing stunning progress in strategies to harness the body’s immune system to attack cancer. In just the past two years, a handful of potent new anti-cancer drugs have received “fast-track” approval from the Food and Drug Administration while researchers flock to the field to look for more immunotherapies.

Just a short time later, the co-founder of the John Wayne Cancer Institute, Donald L. Morton, MD, died after a long illness. The irony of the two events was not lost on some of Dr. Morton’s oldest and closest colleagues. While immunotherapies had, over the course of four decades, fallen in and out of favor among medical researchers, Dr. Morton and his colleagues at the Institute 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 pioneering legacy in the revolutionary development of cancer immunotherapies, says Delphine J. Lee, MD, PhD, director of translational immunology and director of the Dirks/Dougherty Laboratory for Cancer 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 researchers here were always looking at the immune system. Dr. Morton was a pioneer in this.”

Dr. Morton became an early advocate of immunotherapy research around 1960, while working at the National Cancer Institute. He had been struggling to design a vaccine for melanoma using modified melanoma cells. Vaccines are a type of immunotherapy; they take advantage of the body’s natural ability to recognize and attack harmful substances.

“People are sometimes reluctant to support basic science because they can’t see that connection. You can’t fix something if you don’t know how it works. That’s where progress starts.” – Dr. Delphine J. Lee

One day he saw a patient with melanoma lesions all over her arm. There were no treatments for such an advanced case, so Dr. Morton decided to give the patient an injection of the 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 offered 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 director of therapeutic immunology. “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. When you see a patient who has been told elsewhere there’s nothing to do, but then the cancer goes away, it’s like a religious conversion experience. From that experience he was instilled with a fervor to make immune therapy work, while others were doubtful.”

Dr. Morton continued to study cancer immunotherapy after he moved on to the University of California, Los Angeles, and started the John Wayne Cancer Institute, says Leland J. Foshag, MD, a surgical oncologist at the Institute who later moved with Dr. Morton to Saint John’s Health Center. “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.’ No one really believed in the immune system. There wasn’t much interest or belief in the ability of the immune system to have any major impact.”

IF AT FIRST YOU DON’T SUCCEED . . .

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 the immune system response. His foresight convinced Dr. Lee, who was studying leprosy at UCLA, to join the Institute’s immunotherapy team.

“It was his vision and ability to collect specimens that enticed me,” she says. “He said, ‘Why do you want to study leprosy; why don’t you study BCG that can treat cancer?’ 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. We learn from patients’ living cells, after they are long gone. That is beyond visionary.”

The Institute has remained steadfast in the belief that this kind of basic science, 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. “People are sometimes reluctant to support basic science because they can’t see that connection. But you can’t fix something if you don’t know how it works. That’s where progress starts.”

Basic science can be discouraging, Dr. Foshag adds. “Many times research is a matter of: If you don’t succeed the first time, keep trying. But the basic science is what has led to the immunotherapies we see today. It’s an outgrowth of that research.”

AN EARLY CANCER VACCINE

By the start of the new century, however, 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, the vaccine was considered ineffective because the patients receiving BCG had outcomes similar to those receiving CancerVax.

“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 O’Day, MD, professor of medical oncology and director of immuno-oncology and clinical research at the Institute. Dr. O’Day was recruited by Dr. Morton to the Institute from Dana Farber Cancer Institute in Boston in 1994 and worked alongside Dr. Morton for two decades. “His 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.”

And although it was not in vogue as a therapy, Dr. Morton and his Institute colleagues continued to use BCG injections, much to the gratitude of patients like Anita Semjen, 71. 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.

“Back then people though immunotherapy was both a revolutionary and crazy idea. The feeling was, ‘Why are you fooling around with the immune system?” – Dr. Leland J. Foshag

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.

She had surgery, 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. 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, 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, in 1990, a dermatologist had mentioned BCG injections for treating melanoma. She began searching for someone who offered the treatment and found Dr. Morton.

“When nobody wanted to do anything for me, I found the John Wayne Cancer Institute,” says Anita, who is the founder and president of the Cultural Exchange Foundation, a nonprofit organization that showcases works of art that promote the themes of freedom, civil liberties and cultural diversity. “It became an obsession; I thought if I found a BCG program, it would save me.”

She underwent BCG injections at the 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.

“Everybody at the John Wayne Cancer Institute was so fantastic,” says Anita, who still visits the Institute twice a year, seeing Dr. Foshag. “It was such a big difference from the East Coast. 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.”

LESSONS LEAD TO PROGRESS

While CancerVax was considered a failure 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.

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“Everything we do now all stems from that work,” Dr. Faries says about the early research performed by Dr. Morton and some of his colleagues. “Today it seems clear that the vaccine he used wasn’t what caused the positive outcomes, but there was something about the immune response, possibly from the BCG. We now understand the immune system in much greater detail. It has many components, and the characteristics of peoples’ responses can be very different.”

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.” [Dendritic cells play a key role in immune system function by controlling several types of immune responses.]

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 culture to assist growth of immune cells. Very large numbers of those cells are injected into the patient.

“The immune response is something we generate in lab with an army of immune cells to give back,” he says. “With vaccines, 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.”

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 instructing our immune system response.

“It’s taken a while for the concept to prove itself. But researchers here were always looking at the immune system. Dr. Morton was a pioneer in this.” – Dr. Delphine J. Lee

“We’re living with the bacteria all over us. They mold and shape all of our organ systems and, 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, 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 chief of the gastrointestinal research program.

Unlike many other research groups that are gearing up to study cancer immunotherapy, the Institute’s researchers are soldiering on.

“It’s nice to know that we’re on the right track,” Dr. Lee says of the cancer immunotherapies 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.”

To support groundbreaking research in immunotherapy, please contact Michael Avila in the Office of Development at 310-829-8351 or michael.avila@stjohns.org.