Researchers have long suspected the immune system, so efficient at defending the body against foreign invaders, could be key to treating cancer.
“The immune system has properties that make it very effective in recognizing and fighting off certain germs. We are figuring out how to use some of those properties in redirecting the immune system to recognize and destroy cancer. It is innovative in that it makes use of and repurposes some of what we already have in a way that has the potential to fundamentally change how we treat cancer,” said Olalekan Oluwole, M.D., MBBS, MPH.
Immunotherapy is quickly emerging as the future of cancer treatment, and Oluwole and others at Vanderbilt are poised to help bridge the gap between research and remedy.
“It’s a big paradigm shift,” said Young Kim, M.D., Ph.D., associate professor of Otolaryngology and co-leader of the Translational Research and Interventional Oncology Research Program at Vanderbilt University Medical Center.
“Before immunotherapy, people were trying to make cancer into a chronic disease,” he said. “Now we are moving toward a cure. There is hope for patients because we can actually think about the word ‘cure’ in a substantial way.”
According to Kim, the response rate for immunotherapy is about 20 percent, including patients who have failed all other modalities of treatment. Prior to the newest approach to treatment, the response rate was near zero, Kim added.
Kim offers an alternative perspective to frame the impact immunotherapy is having in the field of cancer treatment.
“Let’s talk about years of survival,” he said. “The use of immunotherapy translates into 80,000 patient years saved. With other forms of cancer treatments, it is more like 8,000.
“As clinicians and scientists, we are grappling with how to push that number to 60, 70 or even 80 percent,” he said. “And the current 20 percent are durable responses, and that is a real game changer. We are not talking about a few months or even a year. Durable is more like five years and 10 years. That is strikingly different than cancer therapy advances in the past which saw more like a 5 percent response.”
How it Works
Immunotherapy uses biologic agents, which occur naturally in the body and can now be made in the lab, to empower the immune system to kill cancer cells. It works by slowing or stopping the malignancy, preventing the cancer from spreading, and helping the immune system work better to recognize and destroy cancer cells. This is done through several therapies: checkpoint inhibitors that put the brakes on T-cells, allowing them to attack the cancer; tumor vaccines that expose the immune system to cancer antigens to produce an immune response; and with T-cell therapies, which involve removing T-cells from the body and engineering them to recognize cancer cells.
The breakthrough therapy, a PD-1 inhibitor, worked for 39-year-old Kimberly Jessop, who completed her last immunotherapy dose in 2012 for treatment of metastatic melanoma.
“Where I thought I would be today (when I was first diagnosed) is definitely not where I am,” said a jubilant Jessop. “I always say that my story is one of science and faith—they intertwined and I am here.”
In December 2010, at the urging of her husband, Jessop went to the dermatologist for what she thought was a cyst on her back. It turned out to be metastatic melanoma. Doctors found nearly 20 tumors in her body. The then 33-year-old mother of two young children had few options to treat the stage IV melanoma for which the 5-year survival rate is about 15 to 20 percent, according to the American Cancer Society.
The first treatment started in early 2011. The 26 infusions of an early generation immunotherapy, Interlukin-2, shrunk some of the tumors, while others grew. She then entered a trial for a checkpoint inhibitor, an anti PD-1 drug called nivolumab. Every two weeks she would drive to Vanderbilt for the infusion and return home later that evening. She did that for nine months until an MRI showed a tumor in her spine that left her immobile. The tumor was removed. She regained her ability to walk and resumed her cancer treatments.
“I was willing to do whatever it took for me to be around for my babies,” said Jessop, who also continued to work as a pediatric physical therapist. “Every eight weeks I would get scans and the tumors were getting smaller.”
Her joy was tempered by yet another setback—a new diagnosis of chronic myeloid leukemia (CML). She had to stop the immunotherapy trial to begin the new regime for CML. Over time, the leukemia went into remission and the melanoma tumors continued to shrink.
“The wonderful thing—the experimental immunotherapy drug taught my body to fight melanoma,” said Jessop. “My body’s cells have memory and they continue to fight the cancer. That’s pretty cool isn’t it?”
In 2013 both cancers were in remission and continue to remain so. Jessop returns to Vanderbilt every four months for scans and checkups.
“The stars certainly lined up for me and I am thankful that this is the story I get to tell,” she said. “But it doesn’t work for everyone. It’s not 100 percent. I have a real responsibility to live my life to the absolute fullest.”
The scientific community is focused on identifying which individuals will benefit from immunotherapy as well as learning more about how best to utilize the newest tool in the cancer arsenal.
Kim said that immunotherapy is one of the platforms for cancer treatment and will become one of many agents working in conjunction with multiple treatments to combat malignancies for optimal effectiveness.
Cautious Optimism
At Vanderbilt several immunotherapy mechanisms are being studied in clinical trials. One trial involves collecting white blood cells from a patient and sending them to a special facility where they are engineered to produce receptors on their surface called chimeric antigen receptors (CARs). These CAR-T cells are able to recognize specific cancer cells and target them for destruction.
While the cells are undergoing this process, the patient receives chemotherapy to suppress the immune system in preparation for the CAR-T cells, so that when the cells are infused, they can quickly multiply, circulate throughout the body, and attack targeted tumor cells causing them to die. Some adverse events have been described in patients including cytokine release syndrome consisting of fever, fast heart rate, low oxygen and neurologic events which manifest as confusion, tremors and difficulty speaking. These occur early during treatment, are generally reversible, and patients are monitored in the hospital during that time.
Vanderbilt-Ingram Cancer Center (VICC) was the first cancer center in Tennessee to treat a patient with this new investigational technology. The Phase 1/Phase 2 trial, called ZUMA-1, targets patients with diffuse large B-cell lymphoma and is sponsored by Kite Pharma Inc. Several patients were enrolled and are being monitored per clinical trial protocol.
re-engineered immune cells to attack cancer cells. Photo by Daniel Dubois.
Daniel Einstein, 56, a Nashville businessman and former music industry executive, was the initial patient treated in the trial. Einstein has been dealing with cancer since June 2012 when he woke up one morning with a swollen leg. A CT scan revealed substantial disease in his lymph nodes, diagnosed as stage 3 non-Hodgkin lymphoma (NHL). In hindsight, Einstein realized he had been feeling lethargic for several months.
He was treated with seven previous chemotherapy regimens, but his aggressive form of NHL did not respond completely to the therapy. Eventually, Einstein sought treatment at VICC with Michael Savona, M.D., whom Einstein calls “my guiding light.” After undergoing CAR-T immunotherapy, Einstein was released from the hospital and has continued to do well. He is in complete remission and returns every three months for scans.
“I am a happy camper,” said Einstein. “I am feeling great. This is the best that I have felt in years. I am back working full time and learning my boundaries so that I don’t overdo it.
“I am just so excited that the immunotherapy is working, that it is moving forward, and it can hopefully help a lot more people.”
Today, Einstein is happy that his role as a patient has taken a back seat.
“I am a cancer patient much less of the time and back to having my own personal life be front and center.”
Oluwole, principal investigator for the VICC trial, called the therapy “innovative.”
“This system has the potential to change how we approach the treatment of lymphoma,” he said of the (CAR-T) therapy. “We are hoping that this becomes a treatment modality that will bring hope to many lymphoma patients.”
There is still much to learn about the cutting-edge therapy, he cautions.
Oluwole’s team will continue to gather data on the patients enrolled in the study that was initiated in early 2016. Some approaches to use engineered cells may see FDA approval as early as late 2017.
“Vanderbilt is establishing itself as a leader in cellular immunotherapy,” he said. “The more we do, the more we are learning, but it all takes time. We are cautiously increasing our capacity in a simple way to ensure that safety remains our top priority.”