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Turning the Tables

  T-lymphocytes, or T cells  
 

T-lymphocytes, or T cells (round), play an important role in the body’s immune system, tracking down and destroying foreign bodies and infected cells. Now, the evolving science of immunotherapy seeks to unleash the power of T cells against cancer.
Image: Stefan Diller/Science Photo Library

By Shari Roan • Photography by Amanda Friedman

In the spring of 2012, Tom Stutz was a man without a future. Just getting through the day took all of his energy and determination. The retired attorney from Sherman Oaks, California, had been diagnosed with metastatic melanoma the previous year. He had tumors in his lung, liver, spine and shoulder. He could no longer walk. His wife Sophia had just died after a long illness, and Stutz, at age 71, was depressed and hopeless. Struggling to breathe, nighttime became almost unbearable. “I had to sleep sitting up and could only get cat naps,” Stutz recalls. “I used to dread the night.”

But in the midst of this misery, Stutz had the good fortune to meet with Antoni Ribas, MD (FEL ’98, ’01), PhD, professor of medicine, surgery and pharmacology at UCLA, and secure one of the last spots in a Phase 1 clinical trial Dr. Ribas was conducting on an experimental medication for advanced melanoma. The study was designed to assess the drug’s safety at various doses and look for some signs of effectiveness. Stutz, wheelchair bound and tethered to an oxygen tank, had tried every other available therapy, but the disease had progressed relentlessly. “I figured this was my last shot,” he recalls. “I wasn’t optimistic.”

Today, Stutz is in excellent health. He travels, plays tennis and cycles. What’s remarkable is that he’s not an exception — one of those rare cases of someone who survives seemingly terminal cancer for reasons unknown. Rather, Stutz is among a growing number of cancer patients who are being snatched from the precipice by novel immunotherapy treatments. Immunotherapy is the catchall word for treatments that enlist the body’s own immune system to fight cancer. Unlike chemotherapy, which poisons cancer cells but also can damage healthy tissue, immunotherapies provoke the body into doing to cancer what it does naturally to viruses, bacteria and other foreign invaders: attack and destroy.

  Tom Stutz  
  When Tom Stutz began undergoing treatment for
metastatic melanoma in 2012 with the immunotherapy drug pembrolizumab, “I figured this was my last shot,” he says. “I wasn’t optimistic.” Today, he travels, plays tennis, cycles and enjoys excellent health.

Because of its stunning success, the medication that Stutz received, pembrolizumab, received “fast-track” approval by the U.S. Food and Drug Administration (FDA) last fall and now is prescribed under the brand name Keytruda. It’s among the first in a new class of immunotherapies known as checkpoint inhibitors. Another drug, nivolumab (Opdivo), was approved by the FDA in December 2014 for metastatic melanoma and, two months later, for patients with metastatic squamous non-small-cell lung cancer. Several other drugs with similar mechanisms are in the pharmaceutical pipeline.

Pembrolizumab and nivolumab represent a jaw-dropping burst of progress in the field of cancer immunotherapy. Today, many experts believe immunotherapies will emerge as primary treatment modalities for many types of cancer, perhaps, in some cases, even relegating chemotherapy to the sidelines. “I’ve been working in the field of immunotherapy for lung cancer for 25 years,” says Steven M. Dubinett, MD, chief of the Division of Pulmonary and Critical-care Medicine and director of UCLA’s Jonsson Comprehensive Cancer Center’s lung-cancer-research program. “I think we had all hoped that there would come a point where our knowledge about human immunotherapy would be sufficient to overcome critical obstacles. That has come to pass, and, although many questions remain to be addressed in further research, optimism is certainly warranted.”

The checkpoint inhibitors “have been one of the biggest stories in cancer in the last 10 years, and they are the biggest advance in cancer immunotherapy ever,” adds John Timmerman, MD, associate professor of medicine in the Division of Hematology/Oncology.

UNTIL RECENTLY, SCIENTISTS DEBATED whether or not the finely balanced immune system could be harnessed to kill cancer. For many years, James P. Allison, PhD, now chair of immunology at the University of Texas MD Anderson Cancer Center in Houston, studied why the immune system, so efficient at protecting the body from microbes and chemicals, was no match for cancer. “Immunotherapy has gone through a lot of peaks and valleys,” he says. “In the 1960s, the notion was that the reason we had an immune system was to kill early cancers arising in our bodies. But then, people began to doubt that.”

  Dr. Antoni Ribas  
  Dr. Antoni Ribas: “The problem was that we were trying to turn on the immune system against the cancer. What we realized afterward was that we needed to take off the brakes instead of trying to turn it on.”
Photo: Ann Johansson

In the 1980s, the hope that immunotherapies could conquer cancer rose with the advent of two drugs: interferon and interleukin-2. Both are cytokines, proteins secreted by immune cells that communicate and coordinate the immune response. During a normal immune response, cells called lymphocytes are summoned into action; B-cell lymphocytes manufacture antibodies, proteins that bind to the surface of the foreign invader, while T-cell lymphocytes attack the target.

But excitement over those inaugural immunotherapies faded. A decade’s worth of studies showed the drugs benefited fewer than 10 percent of people with kidney cancer and melanoma and had little impact on other cancers. Another immunotherapy approach — cancer vaccines to propel the immune system into action — also did not pan out at that time. Dr. Allison remembers the pall over the field. After he submitted a research paper on cancer immunotherapy to a scientific journal, a peer reviewer wrote on the paper: “Immunotherapy has never worked, will never work and we shouldn’t waste pages in these precious journals on it,” he recalls.

In 1997, however, the FDA approved a drug called rituxumab for patients with non-Hodgkin’s lymphoma. The drug was an antibody that targeted a specific protein on the surface of B cells and unleashed the immune system to fight some types of cancer. Meanwhile, Dr. Allison and another group independently showed that a molecule on the surface of T cells performed like a brake, or checkpoint, on the immune system’s attack cells. This T-cell braking mechanism serves an important function by preventing the immune system from becoming overactive, attacking healthy tissue. But it also allows cancer to thrive. Dr. Allison’s next insight was a game-changer: Could blocking the checkpoint free the immune system to attack cancer?

“Both interferon and interleukin-2 were approved for the treatment of melanoma, but they had low activity and a lot of side effects,” Dr. Ribas explains. “The problem was that we were trying to turn on the immune system against the cancer. What we realized afterward was that we needed to take off the brakes instead of trying to turn it on.”

Dr. Allison’s work ultimately led to the first immune checkpoint inhibitor, ipilimumab (Yervoy), which was approved in 2011 for metastatic melanoma. The drug, which binds to the CTLA-4 molecule on the surface of T cells, helps about 22 percent of patients. Pembrolizumab works on a different tumor-defense mechanism, called programmed cell death 1 (PD-1). Cancer hides by expressing a protein, programmed death-ligand (PD-L1), that applies a brake to the body’s immune response. Pembrolizumab, a PD-1 inhibitor, disables this brake, allowing T cells to attack cancer cells.

  Dr. Steven M. Dubinett  
  Dr. John Timmerman  
 

Top: Dr. Steven M. Dubinett: “I’ve been working in the field of immunotherapy for lung cancer for 25 years. I think we had all hoped that there would come a point where our knowledge about human immunotherapy would be sufficient to overcome critical obstacles. That has come to pass.”

Bottom: Dr. John Timmerman: “For the majority of common cancers ... chemotherapy is still very important. We’re not ready to replace the conventional treatments yet. But given this huge, quantum leap in immunotherapy ... we feel we can get away from chemotherapy for some forms of cancer.”

When he launched his clinical trial, Dr. Ribas was hopeful the drug would work in 10-to-15 percent of patients with advanced melanoma.

AT FIRST, TOM STUTZ CONCLUDED that the infusions of pembrolizumab he received every three weeks at UCLA weren’t working. “I got quite a lot worse,” he says. “I couldn’t turn over in bed without being out of breath,” and he had to undergo a procedure to drain fluid from his lungs.

Then, one night, one of his fitful cat naps stretched into a blissful 16 hours of uninterrupted sleep. Gradually, he found he could breathe easier. He took small walks outside his house, adding a few more steps every day. By June, he no longer needed oxygen therapy. In July, a scan showed the two main tumors in his liver and lung had shrunk by half.

Stutz continues to receive pembrolizumab infusions every three weeks. There is a shadowy spot in his lung that may be a small tumor, the remnants of a tumor or scar tissue. He doesn’t really care what it is; he’s alive and thriving, spending precious time with his children and grandchildren.

“In the beginning, I was stunned. I would say to myself: I can’t believe I’m still here,” he says. “The wonderful thing about this treatment, besides the result, is you can live pretty much a normal life. The side effects are minimal.”

Dr. Ribas’s clinical-trial data, published in the July 2013 issue of the New England Journal of Medicine, showed that one-third of patients with advanced melanoma experienced long-term responses to pembrolizumab. Another third had some tumor shrinkage, but the disease eventually progressed. Only 12 percent of patients had a significant side effect, such as fatigue or joint pain.

“I honestly didn’t think it would work this well,” Dr. Ribas says. “When we started the clinical trial, sometimes we tried to select patients who we thought would be more likely to benefit. Then we started giving it to patients with more aggressive metastatic melanoma, even patients who were at the limit of eligibility for the clinical trial, where a day or two more and they wouldn’t have been eligible. Some of those patients responded. Those were patients where, if we didn’t do anything, life expectancy would have been weeks.”

The therapy also appears to attack cancers that have spread throughout the body, including the brain. “If you get an immunotherapy that works really well, it can work all over,” Dr. Ribas notes.

Now, similarly stunning results are being seen with other checkpoint inhibitors and in other types of cancer. Thirty-two percent of melanoma patients receiving nivolumab experienced a reduction in tumor size, and more than one-third had an effect that lasted for more than six months. In people with advanced squamous non-small-cell lung cancer, nivolumab produced tumor shrinkage or the complete disappearance of the tumor in 15 percent of patients, many with long-lasting results.

And, in a highly anticipated presentation in April at the American Association for Cancer Research annual meeting in Philadelphia, Pennsylvania, UCLA researchers reported evidence of positive responses to pembrolizumab in about 20 percent of patients with non-small-cell lung cancer. The study — which will be published in the New England Journal of Medicine — also demonstrated the potential for measuring the expression of PD-L1 to help select patients who are most likely to respond to the therapy; nearly half of patients with high-level staining for PD-L1, a target of PD-1, responded to the drug.

“These results have the potential to very substantively change the way that lung cancer is treated”, says Edward B. Garon, MD (FEL ’06), director of the thoracic oncology program at UCLA, who presented the data. “The prolonged duration of the response with this class of drugs has been particularly appealing to patients. It’s quite exciting.”

  Dr. James P. Allison  
  Dr. James P. Allison: “Immunotherapy has gone
through a lot of peaks and valleys. In the 1960s, the notion was that the reason we had an immune system was to kill early cancers arising in our bodies. But then, people began to doubt that.”
Photo: Scott Dalton/The New York Times/Redux

THERE ALSO IS EVIDENCE that checkpoint inhibitors are most effective in tumors with a high number of genetic mutations, such as lung cancer in cigarette smokers, says Dr. Garon, who also co-authored a study published recently in the journal Science on tumor mutations and immunotherapy.

Melanoma also is a cancer with many mutations. “Melanoma has the highest instance of DNA aberrations of any cancer,” Dr. Ribas says. Usually, if patients have a lot of alterations in the cancer, that’s bad. But, for this therapy, a lot of gene alterations may allow the immune system to differentiate normal from disease.”

The question of how well the checkpoint inhibitors may work on other types of cancers, including those with fewer mutations, has emerged as one of the most pressing issues to resolve. Clinical trials are underway around the world to assess the drugs on a number of cancers. In January 2015, Dr. Timmerman and his colleagues published data in the New England Journal of Medicine showing a whopping 87 percent of patients with Hodgkin’s lymphoma responded to nivolumab. Moreover, at a December meeting of the American Society for Hematology, the group reported a response rate between 30 and 40 percent in patients with non-Hodgkin’s lymphoma.

Some cancers, such as colon cancer, appear less responsive to immunotherapies, but researchers are studying those cancers to understand the less-robust response and how potential barriers might be circumnavigated. “We’re still trying to understand why some of these cancers are resistant,” Dr. Timmerman says. “There are plenty of theories. These cancers could be using a different set of checkpoints.” About a half-dozen other checkpoints are being explored, he adds.

Researchers also are examining whether or not checkpoint inhibitors should be used for earlier-stage cancers. Dr. Dubinett is exploring how the immune system responds to early abnormalities in the lung. “The assumption is that as the tumor moves from premalignancy to cancer, the immune system has missed the ability to kill the cancer,” he explains, adding that the key “is to learn when to intervene.”

Work also is underway to evaluate immunotherapies used in combination with drugs that target specific mutations, such as the BRAF mutation that allows cancer to become resistant to drugs. Dr. Ribas and his colleagues have already demonstrated the success of such combinations in patients with advanced melanoma.

MANY OTHER HIGHLY CREATIVE IMMUNOTHERAPIES are under investigation. For example, only about half of lung-cancer patients have lymphocytes in the tumor. That’s a problem because lymphocytes must be present for drugs like the checkpoint inhibitors to work. To get around that obstacle, Dr. Dubinett and his team are injecting molecules called chemokines into tumors. Chemokines are signaling molecules; they attract immune-system cells to the site of infected or damaged tissue. In this case, the chemokines shepherd T cells and dendritic cells (cells that also help induce an immune response) into the tumor.

In a Phase 1 trial in patients with advanced lung cancer, Dr. Dubinett and his UCLA colleague, Jay M. Lee, MD ’97, chief of thoracic surgery, injected a chemokine called CCL21, a protein that is typically found in human lymph nodes, into the tumor via a bronchoscope or a needle through the chest wall.

The protein was able to draw lymphocytes to the tumor. The therapy was safe, and some patients’ tumors stabilized. “The therapy is intended to activate the immune response not just at the local site but is designed to work systemically — all over the body,” Dr. Dubinett says. “Thus the therapy is designed to treat metastatic disease as well as the local tumor.”

Meanwhile, Dr. Dubinett is collaborating with Leonard Rome, PhD, associate director of UCLA’s California NanoSystems Institute, on a treatment that combines CCL21 with nanotechnology drug delivery. The drug is packaged in biological particles called vaults, which were discovered by Dr. Rome in the 1980s. The CCL21-vaults are injected into the tumor to allow the slow release of the chemokines. Last fall, the researchers received a $1-million grant from the National Cancer Institute’s Small Business Innovation Research Program to advance the project.

The therapy may be most effective when used with a drug like pembrolizumab, Dr. Dubinett says. “We think that by getting lymphocytes into the tumor, more patients will have a durable response.”

Researchers also are studying immunotherapies that target specific tumor targets. Madhuri Wadehra, PhD, assistant professor of pathology and laboratory medicine, is studying a protein called EMP2 that is present in a number of cancers affecting women, especially breast cancer, with the goal of making an antibody to target that protein. “What the PD-1 story tells us is we can use a specific subset of the immune system to target cancer,” Dr. Wadehra explains. “We don’t want to elicit a massive inflammatory environment. We need to just tap into the part of the immune system we need to use.”

  Joyce Brandman  
 

Joyce Brandman
Photo: Courtesy of Brandman University

Why I Give
As president of The Saul and Joyce Brandman
Foundation, Joyce Brandman has provided
vital support to hundreds of medical, educational
and Jewish communal causes and organizations. She and her late husband Saul provided longstanding support for the UCLA Division of
Pulmonary and Critical Care Medicine.

“I’ve been impressed with Dr. Steven Dubinett and his innovative approach to research. I appreciate how he keeps me updated on all the latest developments, and he frequently invites me to visit his facility, allowing me to ask questions and see how my money is being spent.”

– Joyce Brandman

Other promising immunotherapies include adoptive cell therapies in which cells taken from a patient are engineered in the lab to recognize and attack tumors and then returned to the patient. In another variation, called chimeric antigen receptors therapy (CARs T-cell therapy), T cells taken from a patient’s blood are genetically engineered to produce receptors on their surfaces. CARs receptors allow T cells to recognize cancer and destroy it. In a study at Children’s Hospital of Philadelphia, CARs T-cell therapy eradicated leukemia in 27 of 30 patients treated, according to a study published in October in the New England Journal of Medicine. Dr. Ribas is among the UCLA researchers who are working on adoptive cell therapies.

It may not be long before immunotherapies begin to take the place of chemotherapy in some cases, Dr. Timmerman says. For lymphoma, care is turning toward targeted therapies in combination with checkpoint inhibitors. “Those treatments are looking to be just as effective as traditional chemotherapy,” he says. “For the majority of common cancers, such as breast and gastrointestinal cancers, chemotherapy is still very important. We’re not ready to replace the conventional treatments yet. But given this huge, quantum leap in immunotherapy, which continues to move at a faster and faster pace, we feel we can get away from chemotherapy for some forms of cancer.”

Immunotherapy is emerging as the “fourth pillar” of cancer treatment, joining surgery, radiation and chemotherapy, says Dr. Ribas. “I don’t think there’s much research going on in the development of new chemotherapy drugs — which are nonspecific toxins — without knowing why they work or not,” he says “The majority of cancer drugs in development now are based on understanding specific targets.”

That means that cancer patients today, perhaps more than ever before, need to ask questions about emerging treatments, even therapies that are still in clinical trials. “In many communities, doctors are not aware of how fast this is moving,” Dr. Timmerman notes. “Patients need to be aggressive and be aware that some new medications are available.”

“Mutational Landscape Determines Sensitivity to PD-1 Blockade in Non-small-cell Lung Cancer,” Science, March 2015

“PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma,” New England Journal of Medicine, January 28, 2015

“Anti-programmed-death-receptor-1 Treatment with Pembrolizumab in Ipilimumab-refractory Advanced Melanoma: a Randomised Dose-comparison Cohort of a Phase 1 Trial,” The Lancet, September 20, 2014

“Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma,” New England Journal of Medicine, July 11, 2013

Shari Roan wrote about healthcare and medicine as a staff writer for the Los Angeles Times.

 

 

 





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