reprinted from Issue 24, Spring 2017 of Frontiers of Medicine (PDF)
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What if the human body possessed a powerful weapon against cancer, honed by millions of years of evolution? That’s the idea behind immunotherapy, one of the most promising new approaches to fighting cancer. Instead of directly trying to poison cancer cells with chemotherapy, immunotherapy boosts the body’s own immune system to attack cancer cells – the same way it kills viruses and bacteria.
Long before cancer immunotherapy made headlines by helping former President Jimmy Carter achieve remission from metastatic melanoma – a disease which often kills people within months – UCSF Department of Medicine faculty members had been working to translate an intriguing idea into remarkably potent therapies.
“Cancer immunotherapy has been something that people have thought about for decades, but the real excitement now is we’ve made the transition from pre-clinical studies and animal models to actually treating patients,” said oncologist Lawrence Fong, MD, Efim Guzik Distinguished Professor in Cancer Biology. He leads the UCSF Cancer Immunotherapeutics Program, established in April 2016, which includes both a clinic that offers the latest immunotherapy drugs to patients through clinical trials as well as a laboratory that studies each patient’s response to these agents. He is also co-director of the Parker Institute for Cancer Immunotherapy at UCSF.
Uncloaking Tumor Cells
In the 1890s, a New York surgeon named William Coley, MD, began injecting cancer patients with bacteria, reasoning that an immune system stimulated to fight an infection would also be primed to attack cancer. He reported good results from using “Coley’s Toxins,” especially in patients with bone and soft tissue sarcomas. However, this controversial approach fell out of favor as radiation and chemotherapy advanced.
But a few tenacious researchers – including Fong and his UCSF colleagues – kept investigating the idea, playing pivotal roles in winning approval from the U.S. Food and Drug Administration (FDA) for novel immunotherapy drugs in 2010 and 2011.
“We’ve recognized over the last few years that carefully unleashing the immune system can have profound effects on tumors, an approach that was dismissed by most people for many years,” said Alan Ashworth, PhD, FRS, president of the UCSF Helen Diller Family Comprehensive Cancer Center, E. Dixon Heise Distinguished Professor in Oncology and Senior Vice President for Cancer Services, UCSF Health. “This has revolutionized the way we think about treating cancer.”
The immune system is built to attack invaders such as bacteria. But to prevent the body from attacking itself and causing autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, the immune system has developed many brakes, also known as checkpoints. In part because cancer arises from the body’s own cells, it has found ways to exploit this loophole, lulling the immune system into lowering its guns through mechanisms that are not yet fully understood.
“Cancer cloaks itself from the immune system and becomes invisible, so the immune system ignores it,” said Ashworth. “The recent successes in immunotherapy harness the notion that you can uncloak cancer. UCSF has worked in this area for a long time.”
Bringing Immunotherapy to Patients
The development of some of the first immunotherapeutics illustrates UCSF’s important role in the field. In the 1990s at UC Berkeley, immunologist James P. Allison, PhD, discovered that the CTLA-4 gene could tamp down the immune system, functioning like an off switch. One of Allison’s graduate students, Matthew “Max” Krummel, PhD, now a professor in the UCSF Department of Pathology, conducted several experiments that applied this finding to prostate cancer.
In the mid-1990s, Jeffrey A. Bluestone, PhD, then an immunologist at the University of Chicago, discovered that CTLA-4 could restrain the immune system from causing autoimmune diseases and rejection of transplanted organs. Bluestone joined the UCSF faculty in 2000, and is now the president and chief executive officer of the Parker Institute for Cancer Immunotherapy and A.W. and Mary Margaret Clausen Distinguished Professor at UCSF.
Bringing these discoveries to patients, Fong and Eric Small, MD, now the chief of the Division of Hematology and Oncology, Doris and Donald Fisher Distinguished Professor in Clinical Cancer Research, Stanford W. and Norman R. Ascherman Endowed Chair, and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center, led the first-in-human trials of the CTLA-4 inhibitor ipilimumab (also known as Yervoy), now an FDA-approved immunotherapy for melanoma. It functions by releasing the CTLA-4 “brake pedal,” allowing the immune system to respond more aggressively to cancer.
Similarly, UCSF oncologist Adil Daud, MD, led trials of another checkpoint inhibitor that targets the PD-1 and PDL-1 antibodies. One of these agents, pembrolizumab (also known as Keytruda), has received FDA approval for use against advanced melanoma, non-small cell lung cancer and head and neck squamous cell cancer. It’s the drug that former President Carter later received.
“One of the big turning points for the field of immunotherapy was learning the way these anti-CTLA-4 and anti-PD-1 antibodies each targeted just one molecule,” said Fong. “By teasing apart different molecules that are important for controlling the immune system, you can hit specific molecules, rather than coming in with a sledgehammer that might hit multiple targets.
“Another watershed moment was when anti-PD-1 antibodies were approved for lung cancer, a disease which is essentially incurable and which kills people fairly quickly,” said Fong. “We saw a clinical response with immunotherapy that is relatively free of side effects. Immunotherapy is absolutely now one of the pillars of cancer therapy, and, in the United States, the vast majority of lung cancer patients are now getting these immune checkpoint inhibitors. It has really transformed medicine.”
In yet another groundbreaking investigation, Fong and Small led development and clinical trials of sipuleucel-T (also known as Provenge), the only FDA-approved cancer vaccine. It exposes a prostate cancer patient’s white blood cells to an antigen – a molecule that causes the immune system to produce an antibody against it – found in prostate cancer. These enhanced white blood cells are then re-infused into the patient, where they hunt down and destroy prostate cancer cells.
‘We’re Just Getting Started’
While many patients experience fewer side effects with immunotherapy than with conventional chemotherapy, others may suffer potentially life-threatening toxicities that require management in the intensive care unit. The UCSF Cancer Immunotherapy program has developed the expertise to manage patients through these challenging situations.
For example, one particularly potent immunotherapy approach is called chimeric antigen receptor (CAR) T cell therapy. It involves extracting a patient’s T cells, genetically engineering them to recognize an antigen found in their cancer, multiplying these souped-up T cells and reinfusing them into the patient. In some cases, this approach can produce severe side effects, including high fever, nausea and organ failure. This is partly because CAR T cells can attack not only cancer cells but normal tissues that contain the target antigen. Moreover, they can also stimulate so-called cytokine release syndrome, in which a patient’s highly activated immune system releases a storm of immune molecules.
“It really speaks to the strength and power of the immune system,” said Fong. “We walk that fine line of trying to suppress the immune response, while allowing the immune response to target the cancer cells. We have a team of investigators who manage patients across different clinical trials and are accustomed to identifying and treating cytokine release syndrome, for example, rather than assuming it’s an infection that requires an antibiotic.”
Immunotherapy has been incredibly effective for some patients, but is far from a silver bullet. When used as monotherapy, many immunotherapies lead to significant clinical responses in only 10 to 20 percent of patients. Yet some of these patients have extraordinary responses, living for years when most patients treated with conventional therapies only survive for months.
Fong and his colleagues in the UCSF Cancer Immunotherapy Program are working hard to determine why some patients have astonishing responses to a particular immunotherapy, while others have little or no response. One component of this investigation involves neoadjuvant immunotherapy – giving patients immunotherapy prior to surgery, then intensively studying the genetic and immune profiles of tumor, lymph node and blood samples obtained during surgery.
“We use state-of-the-art immune assays and leverage the incredibly strong immunology community at UCSF to profile patient samples by multiple means,” said Fong. “One of our visions is to create a precision immunooncology clinic. If we understand mechanistically why some patients respond and some do not, we could use that to help guide treatment selection or patient selection for a particular treatment.”
“We’re moving to this holistic analysis of not just the tumor cell and its genome, but the microenvironment in the tumor and then the circulating immune environment,” said Ashworth. “That provides a much more compre-hensive picture of what’s going on in the person with cancer. It may be that only by modulating all of those effects do you get the best therapeutic effects.”
This approach may also yield clues about ways to effectively combine different kinds of immunotherapy drugs, or specific immunotherapy agents with conventional chemotherapy drugs, in a way that targets a patient’s specific type of cancer.
“So far, we’ve been targeting two molecules, but there are probably 30-plus molecules that are relevant for the immune system that we could target,” said Fong. “I tell people that we are just getting started with immunotherapy.”
From Cold to Hot
Cancer is an incredibly sophisticated foe, and it is likely that effectively administering immunotherapy is not as simple as removing a bottleneck in the immune system. “The crucial problem today, especially with PD-1, is that 40 percent of melanoma patients will respond to it, but the rest won’t,” said Daud, the UCSF oncologist who led clinical trials of PD-1 inhibitors and directs the Melanoma Program at the UCSF Helen Diller Family Compre-hensive Cancer Center. “For most cancers, like colon, breast, lung and prostate cancer, PD-1 inhibitors only work about 10 to 20 percent of the time, and CTLA-4 has almost no activity at all.”
To better determine which patients are likely to respond to PD-1, Daud has teamed up with UCSF dermatologist and immunology researcher Michael Rosenblum, MD, PhD. Together they devised a novel way to extract, isolate and study T cells from patients’ tumors – something that had been done in mice, but not previously in humans.
T cells are the immune system’s foot soldiers, scouting out and destroying invaders. By interrogating T cells that specifically target cancer, Daud and Rosenblum found that many of these tend to be “exhausted” – meaning that they were able to find enemy tumor cells, but for some reason lost the ability to kill them. They hope to discover ways to revive these exhausted T cells, restoring their natural ability to fight cancer.
Daud and Rosenblum also found that patients with “hot” tumors – those that were crawling with T cells – tend to respond well to a PD-1 inhibitor like pembrolizumab, while patients with “cold” tumors – those with few T cells on them – tend to be unresponsive.
“The question is, how do you take a cold tumor and make it hot?” asked Daud, noting that just revving up the entire immune system by giving more immunotherapy drugs doesn’t work. “It’s like trying to cook an egg in your kitchen. You can turn up the heat in your apartment, but the heat needs to be more targeted – otherwise you might burn your house down before the egg is cooked. What we’re trying to induce is immune rejection of the tumor, without causing collateral damage to your skin, colon and other organs.”
Daud had previous success with making tumors more visible to the immune system in the early 2000s, when he worked at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. He and colleague Richard Heller, PhD, injected a gene called plasmid interleukin-12 (pIL-12) directly into melanoma tumors, then used electrical pulses to drive the gene through the tumor cell membrane. Once inside the tumor cell, pIL-12 caused the tumor cells to crank out a signaling protein that the immune system usually produces in response to emergencies like an infection. “It’s like a Code Blue that says, ‘Hey, something is seriously wrong – you’d better get over here quick!’” said Daud.
He recently launched a clinical trial that combines injections of pIL-12 with pembrolizumab, with the idea that the pIL-12 makes the tumor visible to the immune system, and pembrolizumab boosts the immune system’s ability to attack the cancer.
Daud, who joined UCSF’s faculty in 2008, leads a number of other immuno-therapy trials, and is excited about the way that cancer immunotherapy has transformed the field. “It’s a time of incredible promise,” he said. “In 10 years, I think the basic treatment for cancer will be immunotherapy, and that we will add chemotherapy or targeted therapy to that as needed. Immunotherapy potentially offers a way out for some cancers that have been hard-core resisters, recalcitrant to whatever you can throw at them. It’s pretty amazing to be able to look people in the eye and say, ‘Hey, we think we can get rid of this tumor.’”
‘Just Living My Life’
One of those patients is Bonnie Grear, a retired X-ray technologist who spends a lot of time doing yard work. In October 2015, she noticed what looked like a mosquito bite on her left calf. When it grew to the size of a dime, she showed it to her primary care physician at UCSF.
After undergoing several diagnostic tests, Grear was shocked to learn she had metastatic melanoma, which had spread to a lymph node in her groin. “It was very scary,” said Grear, now 75. “I felt like someone hit me on the head with a brick, and I went into panic mode.”
Her doctor referred her to the UCSF Melanoma Center, where she met with Daud and his team. They invited her to participate in the pembrolizumab and pIL-12 combination trial, which had shown early promise with other melanoma patients. “They answered every question, and I said, ‘Let’s take a chance,’” said Grear.
Since April 2016, she has received an intravenous infusion of pembrolizumab every three weeks. She also received injections of pIL-12 directly into the tumor on her leg. After two injections, however, the lesion shrank and became undetectable, so her doctors discontinued the injections. Her latest positron emission test (PET) scan showed that the tumor in her groin has regressed.
“Dr. Daud is very positive and has a sense of humor,” said Grear. “He always explains things in a way that I can understand. He told me, ‘I expect this PET scan to be a big fat zero,’ and it was. The groin lesion is there, but it’s like it’s dead. I’m responding well to the treatment, and the results are pretty wonderful.”
Grear initially lost her appetite when starting treatment, but regained it after a few months. Now she sometimes goes out to lunch after her infusions. She does experience fatigue, joint pain in her hip, and occasional light-headedness. “Those side effects are pretty common, but are really minor,” she said. “If that’s all I have, I’m grateful.”
Grear will continue receiving pembrolizumab infusions for another year, then will be monitored every three to six months for life. The hypothesis is that after two years of treatment, Grear’s immune system will be sufficiently trained to keep the cancer in check on its own.
“It’s a different paradigm from chemotherapy, where you always worry that the tumor may come back if you stop the chemotherapy,” said Daud. “Immunotherapy is more like vaccination – it either works or it doesn’t, but you don’t just keep giving people more pneumonia shots. Once the T cells are running around, killing tumors, we’re not inclined to keep giving a PD-1 inhibitor forever, because it does increase the chances of autoimmune side effects.” The trial’s initial results are promising: 18 months after stopping both the pembrolizumab and the pIL-12, 97 percent of patients who responded to the treatment remain in remission.
“I want to thank Dr. Daud and his team for making me part of this study,” said Grear. “His expertise and enthusiasm keep my attitude very positive. There are patients who kick this, and they live for years after treatment. Hopefully I’m in that category. I’m just living my life, one day at a time, and am happy to be doing so well.”