Denny Stratton spent 45 years working outdoors, climbing utility poles and making repairs for the Rochester Telephone Co. In 2014, a mass the size of a baseball swelled near his elbow, on the same arm that used to hang out the open window of his utility truck.
Alarmed, the fair-skinned Irish-American saw a dermatologist and then an orthopedic oncologist, Wakenda Tyler, M.D. A biopsy confirmed that he had Merkel cell carcinoma, a rare, aggressive skin cancer. After surgery and 26 radiation treatments, he was ready to move on, cancer-free. But early this year a routine imaging scan showed the cancer had returned, this time with tumors on his pancreas and prostate gland.
His care team at the Wilmot Cancer Institute cautioned Stratton that metastatic cancer cannot be cured but they also suggested a promising way to extend his life: Immunotherapy.
They recommended that Stratton consider taking the same drug that wiped out former President Jimmy Carter’s metastatic melanoma. Known as Keytruda (pembrolizumab), the drug is in a class of groundbreaking medications that harness a patient’s own immune system to attack malignancies. Keytruda is used to treat melanoma and Merkel cell, lung cancer, and head-and-neck tumors.
And just like President Carter, Stratton is reaping the benefits. After four infusions, his pancreas tumor disappeared completely and only a speck remained on the prostate gland. Stratton continues to take the drug and experiences almost no side effects.
“Me and Jimmy Carter — hopefully we'll live long!” says Stratton, 77, of Penfield, N.Y. “And most importantly, this drug is helping a lot of other people, too.”
Excitement around immunotherapy exists for many reasons — not the least of which is that patients like Stratton, who respond well to the treatment, are able to live fully. A retiree and former Marine, he visits Wilmot every three weeks for treatment. He also hunts and goes fishing, meets his buddies for breakfast twice a week, and spends time with his children and grandchildren. After the holidays, he and his wife plan to drive their RV to Florida for the winter. His Wilmot physicians have arranged for him to receive Keytruda infusions while there.
“I know how lucky I am,” Stratton says.
‘Everything is Changing Now’
Immunotherapy has been around for more than 100 years. The approach aims to boost, restore, or improve the body’s natural defenses to fight cancer.
It was pioneered by William Bradley Coley, M.D., who used cocktails of toxic bacteria to stimulate the immune systems of his patients in 1891. Coley’s procedure, however, eventually took a back seat to advances in surgery, radiation, and chemotherapy. But scientists continued to study the immune system’s response to cancer, and several drug makers showed a renewed interest in Coley’s toxins during the 1990s. In the 21st century, immunotherapy was still on the radar but many scientists shifted their attention to targeted therapies that attack very specific mutations on cancer cells.
Most recently, scientists exploring immunotherapy began experiencing several new eureka moments, according to Hucky Land, Ph.D., Wilmot Cancer Institute’s director of research. The immune system usually has the ability to balance its reaction to foreign invaders while also remaining tolerant enough that it doesn’t become hyper-stimulated. For the first time, Land says, scientists started to understand how to manipulate immune cells to kill cancer while preserving the healthy balance.
“That’s why this moment is so important,” Land says. “We’re learning how to use immunotherapy appropriately to fight cancer.”
Science magazine declared in 2013 that immunotherapy was the “Breakthrough of the Year,” and at the 2016 American Society of Clinical Oncology annual meeting, the immunotherapy buzz was palpable among the 30,000 attendees. Pharmaceutical companies are investing heavily in the treatment as well.
Bone marrow transplants (BMTs) have ranked among the most reliable, modern forms of immunotherapy. The procedure involves implanting well-matched, healthy immune cells from a sibling or unrelated donor’s immune system into eligible cancer patients, potentially offering cures or prolonged remissions. Wilmot recently celebrated its 3,000th BMT. New research, however, has uncovered even better transplant techniques that could benefit patients without 100-percent-matched donors. In fact, Wilmot is taking part in a national clinical study testing the effectiveness of immune cells from parents, siblings, children, or other donors who are at least a 50-percent match.
Other discoveries have led to additional new immunotherapies, such as Keytruda. It works by shutting down a protective mechanism on cancer cells (known as PD-L1), clearing the way for the immune system to control cancer growth and lengthen the life of the immune cells that target cancer.
CAR T-cell therapy, the most radical of the latest developments in immunotherapy, involves removing a patient’s own fighter T-cells, re-engineering them in a laboratory to boost their ability to hunt down cancer, and then injecting the modified immune cells back into the patient. It’s being tested in a limited number of people with lymphoma and leukemia at Wilmot and at a select number of academic institutions across the country.
“I’ve spent 20 years doing immunotherapy research and frankly, I was met with a lot of skepticism in the past,” says David Linehan, M.D., clinical director at Wilmot and a surgeon who also runs a research laboratory focusing on pancreatic cancer. “Everything is changing now and we’re finding a lot of enthusiasm.”
Based on his own painstaking bench science, Linehan and Marcus Noel, M.D., are conducting a clinical trial to find out if chemotherapy combined with an experimental immunotherapy drug can help people with advanced pancreatic cancer, which often has a poor prognosis. The drug targets a receptor on pancreas cancer cells known as CCR2, which prevents the immune system from properly attacking the disease.
One of their patients, Jason Anderson, 41, who lives about 40 miles west of Rochester in Knowlesville, Orleans County, N.Y., had a pancreatic tumor that was surgically removed and another tumor the size of an orange on his liver, where the cancer had spread. He entered their immunotherapy study nearly a year ago, and the liver tumor shrank to the size of a peanut. Anderson continues to receive the treatment and has been stable for months.
“I was 40 years old when all of this happened and I was thinking, ‘Whatever I can handle, give it to me. I’ve got to fight,’ ” says Anderson, whose passions are car shows, swap meets, and watching drag racing. He was feeling well enough last summer to travel all over western New York for his favorite events. “I’m definitely happy with the direction everything’s been going. I feel good.”
Oncologists are energized by seeing extremely sick patients go into complete or partial remissions.
“It’s a very exciting time in cancer research, both in terms of what’s hot now and what’s next,” says Wilmot’s director, Jonathan Friedberg, M.D., M.M.Sc., who is spearheading the CAR T-cell study in upstate New York. “And with the support of the National Cancer Institute and the federal Cancer Moonshot program, we are encouraged that scientists at Wilmot and elsewhere are leveraging new discoveries and working together to bring these therapies to many more patients.”
Stimulating the immune system to fight cancer has a lot of merit and seems logical. In fact, a healthy immune system quashes cancer cells that emerge regularly in most people before the cancer proliferates and does harm.
But when cancer takes hold and treatment is required, the response to immunotherapy is far from perfect despite many inspiring patient stories.
Individuals with melanoma have some of the best outcomes, although immunotherapy only works well in 25 to 40 percent of those cases, estimates John Frelinger, Ph.D., a professor of Microbiology and Immunology at the University of Rochester and a Wilmot investigator. He and Minsoo Kim, Ph.D., also a professor of Microbiology and Immunology, are working toward improving the odds to something above 50 percent.
They believe that three underlying issues challenge immunotherapy:
- Cancer cells are smart and evasive. They can hide from the immune system’s T-cells, which normally are good at fighting disease.
- Aggressive tumors suppress the immune system, preventing super-fighting T-cells from doing their job.
- Some types of immunotherapy come with serious or life-threatening side effects, a result of the immune system being overstimulated and unable to shut itself down after treatment. Earlier this year, for example, one national CAR T-cell study was temporarily halted due to patient deaths from side effects.
Frelinger and Kim are each using different approaches to investigate ways to bypass all three obstacles.
Kim’s lab is finding practical ways to use light or optics to guide T-cells toward tumors, exposing cancer when it hides and minimizing side effects.
With National Institutes of Health funding, he invented a tiny implantable LED chip that can steer genetically modified T-cells (like those used in CAR T-cell therapy) toward the cancer. A wireless signal from a small battery pack directs the LED beam to shine light onto the tumor, sending the T-cells racing in that direction.
“It’s like sending light on a spy mission to track down cancer cells,’ Kim says. He tested his hypothesis in mice, with success.
Other applications are possible. For example, the light can be activated or inactivated in a millisecond with a safety switch that he also invented. If the immune system gets too revved up, the light source can induce T-cell suicide to slow it down.
Another drawback to immunotherapy is that doctors have no way of knowing if it’s working until several weeks later when a patient gets an imaging scan. By tracking the T-cells and the tumors with light, doctors would be able to see in real time whether the immunotherapy reaches its target, Kim says.
“This approach is also appealing because light is non-toxic, inexpensive, and it can be personalized for an individual patient’s needs,” he says. One patient might need light therapy to guide the immunotherapy to the cancer, whereas another might need it solely to minimize side effects.
Light therapy in medicine is still a bit of a fantasy, but Kim likes to picture the future: “Imagine that a patient could walk into a chamber and colored lights would scan the body and direct healthy T-cells to kill whatever ails you,” he says. “That would be really cool.”
A Throwback to the Past
Like Kim, Frelinger’s goal also involves unleashing T-cells as serial killers for cancer in a controlled manner. But instead of using optics, Frelinger’s weapons are recombinant proteins—molecules engineered in his laboratory to perform specific duties.
His work is best described using the analogy of Pac-Man, the popular 1980s arcade game.
In Frelinger’s world, Pac-Man stands for Protease-Activated Cytokines. Cytokines are proteins that act on immune cells, causing them to expand in number and also making them more effective at killing tumor cells. Proteases "chop up" other proteins (chewing them like Pac-Man) and are over-expressed by cancer cells as they invade surrounding normal tissues.
Frelinger and other scientists have known for years that a cytokine called interleukin-2 (IL-2), a growth factor that spurs T-cells into action, can prompt tumor killing. Indeed, some patients receiving IL-2 therapy experience long-lasting remissions and apparent cures. But IL-2 treatment often comes with dangerous side effects; IL-2 stimulates legions of immune cells at once, which can cause a "cytokine storm," producing a violent immune-system reaction.
To circumvent the storm, Frelinger engineered proteins that contain a form of IL-2 that remains inactive until it reaches the tumor. Once at the site of the cancer, overactive proteases then “chop up” the recombinant protein, releasing IL-2 precisely where it’s needed, he says.
This stimulates the killer T-cells in the tumor without triggering a dangerous immune-system reaction in the rest of the body. Frelinger’s approach has been supported by the NIH.
He and a postdoctoral fellow in his lab, Denise Skrombolas, Ph.D., are now working on expanding the potential of PAC-MAN, testing it with different cytokines and investigating whether it can work in tandem with other immunotherapies.
Scientists utter the word “revolutionary” to describe today’s immunotherapy research—in part because they believe immunotherapy has the potential to cure some cancers.
“It’s a 30-year, overnight success,” Frelinger jokes, thinking back on decades of study that led to major progress in modern times.
And yet many steps remain before immunotherapy will be routinely offered alone or in combination with other treatments. The next big initiative, according to Wilmot investigators, is to outsmart relapsing cancer cells that sometimes linger in the body despite their best efforts to uproot the disease.
"This is a golden age," Frelinger says. "People use the term 'tipping point' because scientists really believe immunotherapy can work, even those who are outside of the field of immunology. I'm keen on the future."