Once a stepchild of cancer research, immunotherapy is taking a leading role with new approaches to attack and kill tumors.
The story of today’s hottest science in the battle against cancer was, up until fairly recently, one of “failure and futility.” “Immunotherapy was considered to be a backwater of cancer research,” says John A. Glaspy, MD ’79 (RES ’82, FEL ’83), Estelle, Abe, and Marjorie Sanders Endowed Chair in Cancer Research at UCLA’s Jonsson Comprehensive Cancer Center. “It was not prime time.”
For some four decades, researchers who dedicated their lives to finding the key to unlock the immune system to battle cancer toiled in obscurity and struggled to get funding for their work as other scientists dismissed their efforts. Even though early animal studies showed some promising results, translating those findings to human trials was painstakingly slow. At oncology conferences, the sessions on immunotherapy usually were an afterthought, and few people bothered to attend.
“All of cancer research was focused on figuring out what was the difference between cancer cells and the tissues within which cancer arose and developing targeted treatments for those differences,” Dr. Glaspy says. “So we focused on the cancer’s biology and not on the biology of the host tissues.”
That has changed. Today, the evidence is indisputable: The immune system can battle cancer. Sometimes, it just needs a little help. We can see videos, for example, that show a dark red T cell attacking and destroying a blue cancer cell, setting its membrane ablaze with poisonous proteins. With Food and Drug Administration (FDA)-approved treatments for 17 different cancers and more than 1,000 new clinical trials, immunotherapy has emerged as the most promising area of cancer research in many, many years — a tribute to persistent scientific and medical investigation. It has come so far, in fact, that on October 1, 2018, two cancer researchers — James P. Allison, PhD, of MD Anderson Cancer Center in Houston, Texas, and Tasuku Honjo, MD, PhD, of Japan’s Kyoto University — won the Nobel Prize in Physiology or Medicine for their work in immunotherapy.
Dr. John Glaspy: “All of cancer research was focused on figuring out what was the difference between cancer cells and the tissues within which cancer arose and developing targeted treatments for those differences. So we focused on the cancer’s biology and not on the biology of the host tissues.”
Dr. Antoni Ribas: “For many years, the majority of patients I treated would die within weeks to months because none of the therapies were working. We were just observing the cancer win the battle every time.”
Getting to such a landmark was not easy. Antoni Ribas, MD (FEL ’98, ’01), PhD, director of the Tumor Immunology Program at UCLA’s Jonsson Comprehensive Cancer Center, has been a leader in the drive to alter the direction of immunotherapy research. “Changing minds to get to this point has depended on understanding the biology,” he says.
Dr. Ribas always felt drawn to immunotherapy rather than chemotherapy. “The immune system was always puzzling to me, and it seemed promising,” says Dr. Ribas, who won the 2018 Lloyd J. Old Award in Cancer Immunology from the American Association for Cancer Research as a scientist whose “innovative research in cancer immunology has had a far-reaching impact on the cancer field.” In addition, Dr. Ribas is director of the Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA, which is part of a consortium of 11 of the nation’s leading cancer centers that is focused on advancing new immunotherapies to turn cancer into a curable disease.
His explorations began in the early 1990s, when he spent three months in a San Diego lab researching tumor vaccines and immunotherapy. That led to his PhD dissertation on tumor immunology. In 1996, he came to UCLA, which was receptive to research in immunotherapy. Yet, in the early days, when he sat on a grant-review panel for the National Cancer Institute, colleagues routinely rejected applications for immunotherapy research. “They’d say, ‘It just doesn’t work,’” he says, with a hint of lingering sadness still in his voice.
SCIENTISTS, AT LEAST SINCE THE LATE 19TH CENTURY, HAVE EXPLORED WAYS TO BOOST THE IMMUNE SYSTEM to fight cancer. In the 1890s, a New York surgeon named William Coley injected patients with sarcomas with the Streptococcus bacteria, called “Coley’s Toxins,” to stimulate an immune reaction. Sometimes it worked; often it did not. Throughout most of the 20th century, surgery, radiation and chemotherapy dominated cancer treatments. That started to change in the 1970s, when bone marrow transplantation, which boosted T cells, was used to treat leukemia. In the 1980s, recombinant DNA technology enabled researchers to clone proteins such as interferon and interleukin-2, which mimic stimulants in the immune system. Interferon had success in treating hairy cell leukemia and kidney cancer. High-dose interleukin-2 had a modest impact in treating melanoma and kidney cancer, but it also had severe side effects. The few patients who did respond, however, had durable remissions, a positive sign.
“In those days, some benefit was the best we’d ever seen,” Dr. Glaspy says. The FDA approved the first monoclonal antibody, rituximab, in 1997, and UCLA has employed it since to treat lymphomas. But scientists had yet to realize that there were natural suppressors to turn off the immune system.
“We were focusing everything on making the immune system stronger. What we did not really appreciate was this whole area of the defenses that the cancer cells were using, the immune checkpoints, the brakes on the immune system,” says John M. Timmerman, MD, professor of medicine in the UCLA Division of Hematology & Oncology. “We were stepping our foot on the gas; however, as you know, you can step your foot on the gas all you want, but if the brake is on, the car won’t move.”
By the beginning of the 21st century, armed with powerful scientific tools, researchers gained a better understanding of how the immune system is regulated. Researchers came to understand that the immune system has accelerators and inhibitors, or “checkpoints,” to prevent it from attacking normal tissue. And cancer cells can take advantage by expressing proteins that activate those checkpoints.
The first breakthrough was the discovery, by a scientist then at UC Berkeley, of the immune checkpoint effect of a protein called CTLA-4. That led to the development of the first checkpoint inhibitor, a monoclonal antibody called ipilimumab, which blocks the CTLA-4 receptor. Blocking CTLA-4 allowed the immune system to respond to cancers.
Drs. Glaspy and Ribas were involved in clinical trials of ipilimumab beginning in 2001. After trials involving 5,000 patients, the FDA approved the drug in 2011, which led to a 10 percent response rate in melanoma. More important, it encouraged investigators to look for additional checkpoints. Soon, scientists identified an even more potent checkpoint, the protein PD-1 and its ligand PD-L1, resulting in the development of several new monoclonal antibodies, including pembrolizumab and nivolumab, for treating advanced melanoma.
Treating melanoma was Dr. Ribas’s life’s work, but it had been a heartbreaking endeavor. “For many years, the majority of patients I treated would die within weeks to months because none of the therapies were working. We were just observing the cancer win the battle every time,” he says.
But in 2011, Dr. Ribas began clinical trials of pembrolizumab, and he immediately experienced a rare aha! moment. “We treated the first seven patients. These were patients with metastatic melanoma, melanoma spread throughout their bodies and multiple organs, some of them in the brain, liver, the bones, the lungs. These were patients who would have weeks to months of life expectancy.” After treatment, “six of the seven patients had positive responses!” The FDA approved pembrolizumab in 2014 for treatment of melanoma.
With the addition of several hundred other patients, it became clear that the response rate for melanoma — 40 percent — turned out to be a significant improvement. But it still left 60 percent of patients who didn’t respond. Dr. Ribas now is focusing on devising treatments, using several immunotherapy approaches for those patients.
The ability of cancer cells to resist assault mounted by the immune system remains an ongoing challenge. “Cancer cells are stupid, but they grow fast and they’re very strong,” Dr. Timmerman says. “Just like Darwinian selection, a few cancer cells will survive these treatments. It only takes one cell for the whole cancer to come back.”
Sean Parker Photo: Courtesy of The Parker Foundation
WHY I GIVE
In 2016, entrepreneur and philanthropist Sean Parker and The Parker Foundation founded the Parker Institute for Cancer Immunotherapy with a $250 million grant that was the largest contribution ever made to the field of cancer immunotherapy. The Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA is among 11 leading centers nationwide brought together under the Parker umbrella to maximize the potential of cancer immunotherapy research.
“We are at an inflection point in cancer research, and now is the time to maximize immunotherapy’s unique potential to transform all cancers into manageable diseases, saving millions of lives. We believe that the creation of a new funding and research model can overcome many of the obstacles that currently prevent research breakthroughs.”
— Sean Parker.
THE DEVELOPMENT OF CHECKPOINT INHIBITORS REPRESENTED A PAYOFF AFTER DECADES OF FRUSTRATION. Unlike targeted treatments that work in one tumor type, the checkpoint inhibitors have proven effective in a broad array of cancers: lymphoma, lung, bladder, kidney, stomach, head and neck and some types of colon and endometrial cancers. “It is a more global potential solution,” Dr. Glaspy says.
Dr. Timmerman led the first trial of nivolumab, another anti-PD-1 antibody, in lymphoma in 2015, and he was astounded by the 87 percent response rate in Hodgkin’s lymphoma. “It was the most exciting thing I’ve seen in my career,” he says. “Tumors were just melting away. There were almost no side effects. For those patients with Hodgkin’s lymphoma, it has been a complete lifesaver.”
In 2012, Dr. Ribas approached Edward B. Garon, MD (FEL ’06), director of thoracic oncology at UCLA’s Jonsson Comprehensive Cancer Center, with the idea of testing pembrolizumab in patients with non-small-cell lung cancer, which represents 85 percent of lung cancer cases. Twelve patients out of an initial cohort of 38 were enrolled at UCLA. The initial response rate was between 20-to-25 percent in patients whose disease had worsened after multiple prior therapies, which, Dr. Garon says, “was obviously not what we were used to seeing in this disease.”
Dr. John M. Timmerman (left): “Cancer cells are stupid, but they grow fast and they’re very strong. Just like Darwinian selection, a few cancer cells will survive these treatments. It only takes one cell for the whole cancer to come back.” Dr. Edward B. Garon (right): “Our hope, obviously, is that with continued understanding at the basic science level, and additional clinical testing, we will have more effective immunotherapies — ideally without a significant increase in toxicity.” Photo: Jessica Pons
When this trial was expanded to include a total of 550 patients with lung cancer, approximately 100 were treated at UCLA, requiring UCLA to overhaul its lung cancer clinical research team to run the study. Dr. Garon was the lead author when the findings were published in the New England Journal of Medicine in 2015. The study showed an approximately 20 percent response rate overall, and patients with a high expression of the protein PD-L1 had about a 40 percent response rate and lived much longer than other patients. More recently, he was part of a group that published a report in the New England Journal of Medicine in 2018 that showed the benefits of adding pembrolizumab to frontline chemotherapy in treating lung cancer. Today, patients with lung cancer who have a high-level of PD-L1 often receive pembrolizumab rather than chemotherapy, and those without a high-level of PD-L1 generally receive a combination of chemotherapy and pembrolizumab. This experience has served as a proof of concept that the management of a common malignancy such as lung cancer can be overhauled by immunotherapy, Dr. Garon says.
Dr. Deborah Wong: “We know our immune system has memory, which is why the saying goes, ‘You never get the same cold twice.’ [In immunotherapy} it’s this idea that, perhaps, the immune system can remember this particular cancer that the patient has is foreign and continue responding to kill off this cancer.” Photo: Ann Johansson
When she was completing her fellowship training at UCLA, Deborah Wong, MD (RES ’09, FEL ’13), PhD, got a firsthand look at Dr. Ribas’s research while working in his lab during the phase-1 studies of pembrolizumab. “I got to see the field of immunotherapy unfold,” says Dr. Wong, now an assistant professor of medicine with a specialty in head and neck cancers. “It’s really revolutionized treatments for patients with incurable cancer.”
Among Dr. Wong’s patients with head and neck cancers, the response rate to checkpoint inhibitor therapy is about 15 percent. But for those patients who do respond, the results are enduring, lasting two to three years, or more. “We know our immune system has memory, which is why the saying goes, ‘You never get the same cold twice,’” Dr. Wong says. “It’s this idea that, perhaps, the immune system can remember this particular cancer that the patient has is foreign and continue responding to kill off this cancer.”
THE REVOLUTION OF CHECKPOINT INHIBITORS ALSO HAS PAVED THE WAY for other immunotherapy treatments. CAR T-cell therapy (CAR stands for chimeric antigen receptor) received FDA approval in 2017 for treatment for two forms of blood cancers: acute lymphoblastic leukemia and diffuse large B-cell lymphoma. UCLA, which was involved in the CAR T-cell clinical trials, is one of the few centers in the country capable of administering CAR T-cell therapy, which involves genetically modifying a patient’s T cells to add claw-like receptors that seek out and destroy the CD19 protein in those two blood cancers.
“Once the CAR T cells are infused back into the patient’s veins, they migrate around the body, and whenever they encounter a cell that expresses CD19, it ignites an inflammatory reaction inside the cancer cells, eradicating them,” explains Joshua P. Sasine, MD (RES ’13, FEL ’17), clinical director of UCLA’s CAR T-cell program.
“It is like a GPS to find cancer cells,” Dr. Ribas says.
Dr. Joshua P. Sasine: “The precision of CAR T-cell therapy really is limited only by the proteins that are expressed on the surface of the target cells. While that does impose more of a limit than we would like, it still is a degree of precision that we’ve never had before.” Photo: Ann Johansson
Dr. Sasine notes that about one-third to two-thirds of the patients who receive the innovative new therapy are having durable remissions. “There are patients who had large volumes of tumors all over their bodies who are now, as far as we can tell, free of cancer,” he says. But it is not a perfect cure. While side effects most often mimic flu-like symptoms such as fever, mild nausea or malaise, Dr. Sasine does note that a significant percentage of patients — 10-to-30 percent — do experience serious and potentially life-threatening inflammation.
Last fall, UCLA treated a 40-year-old patient with a high-risk lymphoma that did not respond to chemotherapy. “We knew he was in trouble right away,” Dr. Sasine says. Initiating CAR T-cell therapy, physicians extracted millions of white blood cells from the patient, which were sent to be genetically engineered and grown to a sufficient number to be infused back into the patient. In March 2018, he received the treatment. Although he experienced treatable inflammation, the patient’s cancer was in remission within a month following therapy.
“The precision of CAR T-cell therapy really is limited only by the proteins that are expressed on the surface of the target cells. While that does impose more of a limit than we would like, it still is a degree of precision that we’ve never had before,” Dr. Sasine says. “The ability to genetically engineer a cell to kill any other cell that expresses protein X, Y or Z is new. We’ve never had that degree of flexible accuracy.”
To which Dr. Timmerman adds: “We’ve turned the body’s natural killers into something that’s going to target the patient’s lymphoma or leukemia. When these cells are given back to the body, they are a living therapy; they circulate through the body and hunt down these tumors and attack them wherever they are.”
Such successes have made it impossible for the medical community to ignore immunotherapy. “One can no longer say immunotherapy is not going to have a role,” Dr. Glaspy says. “It does have a role. And it is not an insignificant role. Whether or not it will be 20 percent or 80 percent of the ultimate solution — stay tuned.”
While there are many obstacles that still need to be overcome — immunotherapy can lead to inflammation in the lungs, liver, kidneys, colon, brain, and even the heart — the benefits of treating the cancer with immunotherapy most often outweigh the risks of the autoimmune toxicity. “Our hope, obviously, is that with continued understanding at the basic science level, and additional clinical testing, we will have more effective immunotherapies — ideally without a significant increase in toxicity,” Dr. Garon says. “We’ve been fortunate at UCLA to have a wealth of investigators who put seminal work into this area that hopefully will continue to expand even further over the coming years.”
A patient’s dendritic cells (DCs) are stimulated to develop from their own blood cells and then strengthened with CCL21, which attract other cancer-fighting immune cells. The enhanced DCs are injected into the tumor, alerting the immune system to find and fight the cancer cells. Graphic: Courtesy of Dr. Steven M. Dubinett
On the Horizon
Beyond CAR T cells and checkpoint inhibitors to turn the body’s own immune system against cancer, UCLA is working to bolster the arsenal of weapons in the fight, testing combinations of drugs, studying tumor biopsies and pioneering new treatments.
Dr. Antoni Ribas, for example, received a $20 million grant from the California Institute for Regenerative Medicine (CIRM) to use stem cells to treat cancer. His team will genetically modify a patient’s bloodforming, or hematopoietic, stem cells and T cells and add receptors to redirect them to biomarkers for melanoma and other forms of resistance-prone cancers. Dr. Ribas recently treated the first patient with this new approach; he says he will have a better idea of its potency after treating six or seven patients.
Steven M. Dubinett, MD (RES ’84), director of the UCLA Lung Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center, has long studied inflammation and immunology in lung cancer. He is experimenting with a novel treatment by genetically modifying a person’s own dendritic cells — the most potent antigen presenting cells — and injecting them back into a patient’s tumor. The goal of the clinical trial, which is supported by a $12 million grant from CIRM, is to more effectively present a patient’s own tumor antigens to their immune system. A checkpoint inhibitor also will be given in an effort to enhance the power of the immune system to destroy the tumor.
And Sherie L. Morrison, PhD, Distinguished Research Professor of Microbiology, Immunology and Molecular Genetics, together with Dr. John M. Timmerman, is studying antibody-interferon fusion proteins, which can target interferon to tumors to help shrink tumors and sensitize them to the effects of checkpoint inhibitors and CAR T cells.
— Lyndon Stambler
FOR ALL THE PROMISE OF IMMUNOTHERAPY, cost of treatment remains a not-inconsequential issue. The price tag for CAR T-cell therapy to treat lymphoma is about $373,000, and it is $475,000 to treat leukemia. That doesn’t include hospitalization, follow-up care and autoimmune toxicity management. Checkpoint inhibitors, which require infusions every three weeks, cost about $20,000 per dose. In a practical sense, “It is going to have to morph into something that is a lot cheaper and more accessible for the broader population,” Dr. Glaspy says.
Still, “It is hard to put a price on keeping people alive and getting people to live normal lives after having had a metastatic cancer,” Dr. Ribas says.
The science of immunotherapy is fascinating, but the evolution of this revolutionary treatment modality from fringe to mainstream medicine is all about helping patients. One of the many beneficiaries of the new immunotherapy era is Wayne Parker, 61, a retired electronics technician with the U.S. Postal Service, who found a mole on the back of his neck in October 2017. The Salem, Oregon, resident was diagnosed with Stage IV metastatic melanoma. Tumors had spread to his liver and lymph nodes. His prognosis was dire. Oncologists in Oregon recommended surgery on his liver and lymph nodes.
Instead, Parker (no relation to Sean Parker, founder of the Parker Institute for Cancer Immunotherapy) sought a second opinion, from Dr. Ribas. In November 2017, Dr. Ribas told Parker that surgery would be futile. Instead, he enrolled Parker in a clinical trial combining pembrolizumab with an immune-activating molecule injected into his lymph nodes. In January 2018, Parker began treatments every three weeks, driving his motor home more than 900 miles south, to Los Angeles, to get injections, 30-minute infusions and biopsies. Initially, he experienced side effects: 24 hours of nausea, sudden diarrhea and intense shivering. The side effects subsided, and within a few weeks, his tumors started to shrink. By August, a CT scan revealed that Parker’s tumors had all but disappeared.
“When Dr. Ribas said, ‘You’re in remission,’ that was like a million bucks right there,” Parker says.
Such treatments were unimaginable just a few decades ago. No longer. “We are using a host of approaches to attack cancers from many different angles,” Dr. Timmerman says. “Momentum is growing faster and faster toward finding cures for so many different kinds of cancers.”
Lyndon Stambler is a freelance writer and associate professor of journalism at Santa Monica College.
“Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer,” New England Journal of Medicine, May 2015
“Pembrolizumab Plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer,” New England Journal of Medicine, May 2018
