Immune therapy is recognizably different from all conventional cancer therapies. Imagine a cancer treatment that works without making patients sick or causing their hair to fall out. Doctors and nurses agree it is unlike anything they have ever witnessed in the world of cancer medicine. Gone are the iconic bald heads that immediately identified a person—inside or outside of the hospital—as a cancer patient. Like no other disease, cancer has traumatized the human population with its lethality and toxic treatments. That’s all changing now, as therapies that empowers the body’s own natural defenses are at last becoming a reality and providing unparalleled, long-lasting responses across many cancer types, and even in the most advanced and treatment-resistant cancers.
Patients are saying they don’t feel like they have cancer. Knowing what cancer treatment is “supposed” to be like—many having already experienced it—they worry that they feel too well. Many ask: “If I feel this healthy, could the treatment really be working?”
The answer, experts say, is a resounding “yes,” and the Kimmel Cancer Center is leading the way with its unprecedented findings echoing through the laboratories and waiting rooms of medical institutions, community hospitals, and cancer clinics all over the world.
“This is oncology of the future,” says William Nelson, Kimmel Cancer Center Director, “and the future is now.”
A Game Changer
As long as cancer has been a recognized disease, doctors have believed the power to eliminate it existed within the immune system, but attempt after attempt to unlock this potential has largely failed. The potential always existed, but the key information needed to turn this promise into real treatments was locked away inside the DNA of tumor and immune cells. Researchers and clinicians at the Kimmel Cancer Center have worked together with experts throughout Johns Hopkins, using science to follow the clues and bring the world what may be a universal treatment for cancer. Cancer immunology and melanoma expert Suzanne Topalian calls immunotherapy “the common denominator.”
Immune-based therapies reflect a different approach to treatment. Instead of targeting cancer cells, the new therapies target immune cells in and around cancers. Some treatments increase the number of immune cells summoned to the tumor, and others unleash the commands that send the immune cells to work against it. These types of immune therapies have had success alone, but perhaps their greatest power will come in combining them, and through precision medicine, using the biological clues within each patient’s cancer to guide treatment.
Leading the way are scientists, like Drew Pardoll and Elizabeth Jaffee, who have been at work for more than 30 years deciphering the mechanisms of the immune system, how it works and why it all too often does not work against cancer. As students of the immune system, Pardoll, Jaffee, and others understood that the characteristics of the immune system should make it the perfect anticancer weapon, but if the cancer cell was complex in its molecular construction, the intricacies of the immune system were equally complicated.
Unlike viruses and bacteria that are easily recognized by our immune system because they are so different, cancer originates from our own cells. As a result, it has all of the cellular mechanisms that are used by normal cells at its disposal. Cancer co-opts them selectively, using them like superpowers to grow, spread, and cloak themselves from the immune system.
It took time for the technology to catch up with the scientific ideas, but the invincible cancer cell may have finally met its match. This Kimmel Cancer Center team of multispecialty collaborators—seasoned investigators and young clinician-scientists—have figured out how to reset the cellular controls hijacked by the cancer cell and restore power to the immune system. In a convergence of immunology, genetic, and epigenetic findings, the secrets of the cancer cell’s ability to dodge an immune attack are being revealed, and the results, though admittedly early, are like nothing that has ever been seen in cancer medicine. Utter destruction of the most resistant, lethal tumors is occurring across many cancer types and with few side effects. Patients who were months, even weeks, from dying are alive and well, some five years or more after treatment.
It was what Pardoll and Jaffee imagined three decades ago when they first began studying the immune system—perhaps even better.
Immune Checkpoint Blockades
More than 8000 practicing oncologists and clinical cancer scientists from all over the world filled the lecture hall at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO). It’s not the first time a standing-room-only crowd has come there to hear a Kimmel Cancer Center cancer expert discuss one of the most promising new cancer therapies in decades—immune checkpoint blockade. This time, cancer immunology expert Suzanne Topalian was there as the David A. Karnofsky Memorial Award and Lecture recipient for “outstanding contributions to the research, diagnosis, and treatment of cancer.” In 2012, Thoracic Oncology Program Director Julie Brahmer presented findings on an immune checkpoint blockade study in lung cancer. It marks a changing tide in clinical cancer research. Immunology studies had never before received this level of attention at ASCO meetings.
With remarkable and lasting results in about 20 to 40 percent of patients with advanced cancers that resisted all other types of therapy, oncologists wanted to know more. Scholarly journals and the news media alike were reporting on drugs that caused lethal melanoma skin cancers, kidney cancers, and lung cancers to melt away and stay away.
The therapies are so new—first tested in patients in 2006—that the Kimmel Cancer Center immunology team readily admits there is much left to learn. “We don’t know yet what the ultimate survival benefit will be, but for some patients in these first trials, the responses are still ongoing after many years,” says Pardoll. These long-lasting responses that continued even after therapy was stopped and caused few side effects are the reason the auditorium was filled to capacity with doctors anxious to learn how and when they could get this new therapy for their patients.
The source of the excitement is an immune target called PD-1 and a related partner protein on tumor cells called PD-L1. PD-1 is what immunology experts call an immune checkpoint. Pardoll stops short of calling it an immune system master switch, but the results in laboratory research and these early clinical trials point to it as one of the strongest influencers of an immune response to cancer identified so far. It—and likely some other similar proteins—is responsible for cancer’s ability to avert an immune attack.
There are two main actions at play in an immune reaction. The first is a “go” signal. “Our cells are constantly presenting our own proteins to our own immune system,” explains pathologist Bob Anders. One can think of DNA as the blueprint of a cell, and the proteins its genes encode are its building blocks. A protein from a mutated gene looks different than its normal counterpart. In the same way it recognizes bacteria and viruses, the patrolling immune system can recognize abnormal cells that don’t belong. “When immune cells come upon something that shouldn’t be there, they generate an immune reaction,” says Anders. This is the go signal. When the job is done and the invading cells are taken care of, the immune system issues a “stop” signal.
These stop signals are controlled by immune checkpoints like PD-1. In cancer, malignant cells hijack the “stop” signal to maintain their own survival. They send a deceptive message to cancer-killing immune cells that there is no problem. Immune cells arrive at the tumor, but they are duped with a false message that everything is OK. “Essentially, they’re told to go home. There is nothing to see here,” says pathologist Janis Taube.
Taube and Anders describe a scenario in which a tumor is spreading, and as immune cells come in to try to remove the cancer, the cancer turns up the volume on PD-1, a signal that turns the immune cells off. “The tumor cells use our own physiology against us,” says Anders.
The “volume” of the PD-1 stop signal is controlled in the cancer cell by the expression of one or both of two partner proteins called PD-L1 and PD-L2. In solid tumors, like melanoma and lung cancer, PD-L1 has received the most attention today, but PD-L2 appears to play an important role in cancers that start in the blood and lymph nodes, such as leukemia and lymphoma. “We see PD-L1 frequently in melanoma,” says Taube. “PD-L1 is expressed on the surface of the tumor cell. When you see it through the microscope, it looks like someone outlined the cells with a marker. It forms an armor that protects the cancer cell from the immune system.”
Giving patients a drug, known as an anti-PD-1 checkpoint blocker, for its ability to interrupt PD-1 signaling as well as the communication between PD-1 and PD-L1 and PD-L2, removes the stop signal and re-engages the immune system.
Among normal cells, PD-1 is not a bad actor, explains blood and bone marrow cancer expert and immunology collaborator Jonathan Powell. “It’s actually a good thing. It’s the means by which the immune system regulates itself. It makes sure the immune system doesn’t overdo its job,” he says. It’s the cancer cell that once again assumes the role of villain. PD-1 is an immune mechanism that has been usurped by the cancer cell. “Cancer cells take control of a valuable immune response regulator and turn it on its head,” he says. “Anti-PD-1 therapy allows us to seize that power back.”
Unbelievable Patient Responses
John Ryan is among the many patients who have benefitted from the anti-PD-1 therapy being discussed at ASCO.
Ryan, 71, began experiencing symptoms in 2013 when he coughed up a small amount of blood. The husband and father of eight thought it was strange, but with no pain or other symptoms he was stunned to learn he had the most advanced stage of a common form of lung cancer known as non-small cell lung cancer. The cancer had already spread to a rib.
There are few diagnoses worse than late stage lung cancer. The cancer kills more people than any other type of cancer, and few patients survive once it has spread. At this stage, the cancer is treatment resistant, responding for a brief time to chemotherapy or cancer-gene-targeted therapies, but almost always resurging even stronger.
Medically speaking, Ryan’s diagnosis was Stage 4 non small cell adenocarcinoma of the lung. “One of my sons was graduating from college, and my daughter was about to leave for a study abroad. I wondered if I would live long enough to see my son graduate or to welcome my daughter back home,” Ryan recalls.
For a time, the chemotherapy worked, but the treatment came at great physical cost, and these side effects were worsening. The simplest tasks became difficult. His body was weakening, and worse, he learned his cancer was no longer responding. Genetic testing of his tumor did not reveal any mutations that would make him a candidate for targeted therapies. It seemed he was out of options, until his doctor suggested he go to the Kimmel Cancer Center and meet with lung cancer expert Julie Brahmer.
Brahmer was one of the lead investigators on an experimental clinical study of the anti-PD-1 therapy in a variety of advanced cancers. Ryan’s form of lung cancer was among the cancers that showed unprecedented responses.
“Before I began treatment, I struggled to sit at my kitchen table. After just four treatments, the tumor shrunk by 65 percent and I felt like a human being again,” says Ryan. A few more treatments and Ryan’s rapidly growing lung cancer was nearly gone and the cancer that spread to his rib was eliminated. His only side effect was some minor skin irritations he compared to a mosquito bite.
Ryan is not an isolated case. Topalian and Brahmer say about one-quarter of the lung cancer patients in their studies responded to the treatment. The numbers are even higher for melanoma and kidney cancer patients.
Anti-PD-1 is not the first checkpoint blockade therapy, but it is the first to work beyond melanoma in as many as 14 other cancer types, and that’s the pivotal difference that has excited the cancer world.
The Lung Cancer Difference
The first clinical reports of checkpoint inhibitors in melanoma were exciting and peaked interest, but excitement was tempered because the few successes in immune therapy over the last three decades had also been primarily in melanoma and kidney cancer. There have been documented cases of these cancers occasionally going into spontaneous remission, so experts long maintained that, by nature, these types of cancers had a way of engaging the immune system. No other type of cancer was considered to be responsive to immune interventions. The new therapy was greeted with guarded optimism.
That all changed in 2012 when the Kimmel Cancer Center group published the results of anti-PD-1 therapy in lung cancer patients. Lung cancer had never before responded to an immune therapy, and the remarkable activity of anti-PD-1 in a small number of lung cancer patients proved what Pardoll and other cancer immunologists long believed—if understood, the immune system could be used to fight any cancer. “Anti-PD-1 has become a cancer juggernaut,” says Pardoll.
Pardoll first became interested in the protein in 2000 when he came upon PD-1’s second partner, PD-L2. Lieping Chen, a collaborator of Pardoll’s at the Kimmel Cancer Center who is now at Yale, had just discovered PD-L1 and showed that it’s expression in human lung cancer cells was highly elevated compared to normal cells. Although lung cancers had not responded to other past immune therapy attempts, this discovery provided new evidence that it had the potential to work and was the reason the Kimmel Cancer Center team included lung cancer patients in the first anti-PD-1 trial.
Powell is excited about the success of PD-1 in patients, but he is also enthusiastic about what he sees as a triumph of science. “What we have learned is so encouraging,” he says. “The mere fact that we can block a checkpoint and make a tumor go away is an incredibly important finding because it tells us that the human body—even without help from immunologists—has an immune response to cancer. The problem is that the response is being blocked. That concept, and the fact that it is true in people, is exceedingly important.”
“This is yet more evidence that well-thought-out, consistent and collaborative research pays off,” says William Nelson, the Kimmel Cancer Center Director. “Anti-PD1 is a triumph of team science.” It is this willingness to follow leads and seek out other experts that can inform the process that continues to position Johns Hopkins as a leader in transitioning laboratory science into pioneering cancer therapies, he says.
“We developed this one from scratch at the Kimmel Cancer Center,” says Pardoll. As soon as the components of the PD-1 pathway were discovered in 2000, Pardoll, Topalian, Brahmer, and immunology and genitourinary cancer expert Chuck Drake, saw the potential of blocking it. They began working with the small biotech company Medarex to develop the first anti-PD1 antibody in the laboratory and took it to patients. They too found strong responses in melanoma, but it was Brahmer’s lung cancer patients that were game changers.
This was the moment Pardoll and Topalian, who are not only research partners but also husband and wife, were waiting for. It was a belief Pardoll had staked his career on, and one that caused Topalian to change course from a career as surgical oncologist to immunology, working as a National Cancer Institute scientist alongside cancer immunology pioneer Steven Rosenberg for 20 years before coming to the Kimmel Cancer Center.
Rosenberg’s research of interferons and interleukins, cellular messengers critical to immune responses, garnered similar excitement in the 1980s as a potential broad-based immune treatment for cancer. The cover of Time magazine boasted the headline “Interferon: The Cure for Cancer.” When the celebrated treatment failed to live up to expectations—most of which had been generated by an eager news media desperately waiting for the grand-slam victory that had been promised when the “war against cancer” was announced in 1971—the field of cancer immunology was nearly crushed. To be fair, interleukin-2 treatment, while a difficult treatment for patients, continues to be used occasionally today and is highly effective in some patients with melanoma and kidney cancer. However, instead of being the blockbuster immune therapy people had hoped for, it was a start. “It was the first evidence that a drug that acted only through the immune system could fight very advanced cancer,” says Topalian. “That was important because it told us we were on the right track with immunotherapy and needed to keep working on this.”
In fact, many outside the field of cancer immunology had begun to doubt the promise of immune treatments in cancer. Immunotherapy discussions at the large national cancer meetings were sparsely attended, and research funding was hard to come by. The Kimmel Cancer Center immunology team remained undeterred. They knew the power of the immune system and their convictions were cemented in this truth. The challenge was channeling this power into real therapies.
The promise of immune therapy is changing the way new therapies are studied and evaluated. Chemotherapy poisons cells dividing quickly, including immune cells. This toxic effect is the cause of the common side effects like hair loss, nausea, and infection risk due to a compromised immune system. Immune therapies appear to work more slowly over time, and it’s looking now like they work better for longer. Some of this was learned almost serendipitously as cancers that initially looked like they were not responding to immune treatments, with more time began to shrink with more time. “The immune system has been living with cancer for years. To make it not be so happy living with the cancer takes some time,” says Drake.
Eventually, it all rested upon what was learned with science and technology—powerful new ways to look inside the DNA of cancer cells and computerized data mining that measures and quantifies the subtlest of changes and differences among seemingly similar cancers.
The mechanisms that make therapy work in one patient and not in another are now being teased out. Treatments that worked only in a small subset of patients were once deemed failures. Now, in an era of precision medicine that uses molecular markers to identify the right treatment for each patient, the options are much broader and the outlook is significantly brighter.
First There Were Cancer Vaccines
Cancer vaccines were one of the first immune treatments studied by Kimmel Cancer Center investigators. Early research on cancer vaccines by immunologist and pancreatic cancer expert Elizabeth Jaffee proved the ability to successfully recruit immune cells to tumors, and even had some therapeutic benefit. All too often, however, the immune cells—called to the tumor by the vaccine in large numbers—did not fully attack the cancer.
Vaccines can peak the immune response in days, calling immune cells to the tumor site. To reverse tolerance of the cancer—characterized by immune cells flooding to the tumor site but not taking action—can take time. It may also require additional kinds of immune therapies. Some patients’ immune systems are on the edge, requiring just a vaccine to make them respond. Others need more.
Jaffee and Daniel Laheru, co-directors of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care, are leading the way in cancer vaccine therapy, and their target is one of the deadliest of cancers.
Jaffee began working on a pancreatic cancer vaccine more than two decades ago. To make vaccine therapy a reality, she became an expert in FDA regulations and vaccine manufacturing, and she opened a GMP (good manufacturing practices) facility at the Kimmel Cancer Center to make vaccines for clinical studies.
Jaffee, Laheru, and young investigators Dung Le, Lei Zheng, Erik Lutz and others are testing various versions of the vaccine, built from pancreatic cancer cells that have been rendered dormant with radiation and engineered to recruit immune cells to track and attack malignant cells anywhere in the body and to continue to do it indefinitely.
In some patients, the original iteration of the vaccine has worked remarkably. Patients like nearly 20-year survivor Kathleen Dowell, 12-year survivor Donna Bender, and eight-year survivor Nancy Amato were given months to live when their pancreatic cancers persisted after surgery, chemotherapy, and radiation therapy. Jaffee’s vaccine continues to keep their cancers in check.
Because it is perhaps one of the only treatments that make any real difference in long-term survival for this most aggressive of cancers, the vaccine has attracted worldwide attention. Clinic coordinator and research nurse Barbara Biedrzycki receives more than 60 calls per month from patients who want to get the vaccine. Once after an appearance by Jaffee on The Dr. Oz Show, the clinic was flooded with more than 1,000 inquiries from patients all over the country. “There is no other cancer center doing this kind of work,” say Zheng.
With funding from the Skip Viragh Foundation, Laheru, Zheng, Lutz, and Le are working with Jaffee to optimize the effects of her pioneering vaccine. They are making tweaks in timing of vaccination and changes to its composition and delivery that they hope will boost its cancer-killing capabilities and make the vaccine a treatment option for many more patients.
One of their new approaches is to give the vaccine before surgery. “Pancreatic cancer is notorious for being in areas outside of the pancreas, and the vaccine allows us to get ahead of the disease and get microscopic cancer cells that surgery might miss,” says Laheru.
Other variations include combined treatments. In some patients, giving the immune-modulating drug cyclophosphamide before the vaccine causes immune structures to form inside tumors that help regulate immune cell activation. “These organized immune structures do not naturally appear in pancreatic cancers,” says Zheng. “This suggests that there has been significant reprogramming of immune cells within the tumor.” There is evidence that adding a checkpoint blockade like anti-PD-1 treatment to the mix could further enhance immune activity.
Another combined approach adds a second kind of vaccine, a weakened version of the bacterium listeria. The listeria is genetically modified to be safe for humans but stimulates an immune response against the protein mesothelin. Ralph Hruban, pathologist and Director of the Sol Goldman Pancreatic Cancer Research, found mesothelin in high levels on the surface of pancreatic cancer cells, and Jaffee and Le believe the protein helps pancreatic cancer cells to grow and spread. “The combination essentially trains the body to recognize and attack pancreatic tumors,” says Le.
Ongoing research has revealed that mesothelin is over-expressed in many cancers, including about one-half of lung cancers, mesotheliomas, ovarian cancers, and stomach cancers. As a result, the vaccine is now being tested in lung cancer and mesothelioma, and Kimmel Cancer Center immunology expert Leisha Emens will lead a trial testing it in ovarian cancer.
Sarasota internist Jonathan Greco, 58, is among 90 patients enrolled in a clinical trial to test the effectiveness of a cyclophosphamide, GVAX, listeria, and anti-PD-1 quadruple combination.
After nine weeks of chemotherapy at a cancer clinic near his home, Greco says he felt worse than he ever had his life. He told himself it was worth it because, as bad as he felt, his doctors told him it was causing his pancreatic cancer to shrink enough that it could be cut out with surgery.
As a physician, Greco knew of Johns Hopkins expertise in the Whipple procedure, the primary surgical treatment for pancreatic cancer. Johns Hopkins surgeons perfected the procedure, perform more of them, and train more new surgeons how do the procedure than any other institution in the world. With this in mind, Greco scheduled a consultation at the Kimmel Cancer Center’s Skip Viragh Center.
At his consultation, he learned the chemotherapy hadn’t worked. In fact, his cancer was quite advanced, and a Whipple procedure would not help him. “I’m so thankful I came to Johns Hopkins,” says Greco. “If I had listened to the doctors in Florida and went ahead with the surgery, I’m certain I would have died.”
Greco continued to do his research. He was familiar with immune therapy and went to the National Cancer Institute’s clinicaltrials.gov website to search for experimental treatments and information. “Johns Hopkins clearly had the most immunotherapy experience. It was evident they had been doing this longer than anybody,” says Greco.
He enrolled in a clinical trial designed and led by Elizabeth Jaffee and Dung Le that is the centerpiece of a Stand Up To Cancer pancreatic cancer dream team directed by Jaffee. It combines treatments with the vaccine-enhancing drug cyclophosphamide, the immune-activating GVAX vaccine, mesothelin-targeting listeria, and the immune checkpoint blockade with anti-PD-1. The pancreatic cancer GVAX vaccine was developed by Jaffee with Viragh funding and is manufactured at a GMP facility in the Kimmel Cancer Center that she opened and directs.
The combined therapy represents a culmination of immunology laboratory and clinical science, joining the strength of several immune-targeted therapies in an attempt to topple one of the most lethal cancers. Jaffee and Le hope the combination will pack the immune punch needed to break the resistance of pancreatic cancer.
“I feel fortunate to be one of the 90 patients participating in this trial,” says Greco. Le says it’s too early in his treatment to measure the effect the treatment is having on his cancer or to know what the long-term impact will be. After his experience with chemotherapy, Greco says he is grateful for a treatment that doesn’t make him sick. “I feel like myself again. I feel great. I swim everyday, and I’m still seeing patients. I feel like I’m cured.”
Jonathan Greco is currently in the GVAX phase of his treatment, and at this appointment nurse Angela Van Tassel administers the second of nine vaccinations to pancreatic cancer patient Jonathan Greco. Greco receives six total injections per vaccination—two in each arm, and one in each thigh. The vaccine is administered just under the skin, with each injection taking about a minute. “It feels like a bee sting,” he says. “In a couple of days, it will start to itch.” The itching is an immune reaction, says Van Tassel.
Then Came PD-1
The first patients were treated with anti-PD-1 in 2006 as part of a small clinical trial led by Brahmer and funded by Medarex, now part of pharmaceutical giant Bristol- Myers Squibb. The scientific studies to better understand how anti-PD-1 was working were supported by the Melanoma Research Alliance, the National Cancer Institute, and faculty support Topalian received from the Kimmel Cancer Center and the Department of Surgery when she came to Johns Hopkins.
Fast forward to 2015, and people were getting very excited again about immunotherapy when the attention of the cancer world—some 30,000 people attending the ASCO meeting—was fixed on the findings from the Kimmel Cancer Center cancer immunology team as Topalian explained this immune checkpoint that could be reset with a drug. In addition to igniting an immune response against cancer, the anti-PD-1 drug could be given in the outpatient clinic and caused very few side effects. The media, including Science, one of the world’s leading scientific journals, dubbed it a breakthrough. “The attention it was receiving and the number of people who wanted to learn about our work were signs that immune therapy was now part of mainstream oncology,” says Topalian.
Topalian, who has been there through many of the ups and downs in cancer immunology, prefers to call it an evolution. To the public and even scientists outside of cancer immunology, it may seem like an overnight sensation. In reality, it was the product of research that occurred over decades with many contributors, when all but the immunology diehards weren’t looking. “It’s been a long process,” she says. “Today, it’s celebrated, but over the last 30 years there have been many things that looked great in the laboratory that did not translate into patients.” Although cancer immunology experts had held steadfast to their convictions that they could figure out a way to make the immune system work against cancer, outside of the field there were whispers of defeat. “In 2012, with our publication in theNew England Journal of Medicine on a 300-patient clinical trial of anti-PD-1, everything came together. It was our moment,” she says.
A Milestone in Cancer Medicine
Remarkable responses were occurring in a significant number of patients, putting the framework for a potentially broad-based treatment for cancer in place. This glimmer quickly ignited into a spark and continues to gain momentum as collaborations across many specialties at Johns Hopkins are expanding its benefit to other cancers.
This success revealed that the immune system could be employed against cancers beyond melanoma and kidney cancer. As important, it provided definitive proof that there was a common force at work to shut down an immune response to cancer.
The most recent clinical study provides clear evidence that for lung cancer patients whose immune cells express PD-1 or whose tumor cells express PD-L1, immune therapy works better than the best chemotherapy drugs and with far fewer side effects. In addition, patients with late-stage lung cancers frequently become resistant to chemotherapy, but Brahmer says that patients who respond to immune therapy tend to continue responding. “In my 20 years in practice, I have never seen anything like this. We’re reporting three-year and more survival rates in lung cancer patients who honestly would not typically be around,” says Brahmer. “This is truly a milestone in cancer medicine.”
As for how long patients will continue to respond off treatment and whether there are any long-term effects of this type of immune therapy, it’s too soon to know. Pardoll, Topalian and collaborators are working to answer these questions. They also want to make sense of the varied responses. In some patients, tumors were held in check, neither growing nor shrinking. Other patients, like Ryan, experienced huge reductions in the size of their tumors, but they didn’t go away completely. Pardoll and Topalian have gone back to the laboratory to better understand the biology of these responses. In virtually all patients, however, the responses appear to be long lasting. Some patients from the original clinical studies continue to do well. Such responses are virtually unheard of in advanced cancers. “We don’t know yet what the ultimate survival benefit will be, but for these early trials and these patients, the responses are lasting a long time,” says Pardoll. “We don’t have to intervene anymore with therapy. The patients’ own immune systems have taken over the battle.”
“It is a cyclical process,” says Topalian. “We need to continue working between the laboratory and the clinic to advance the science and understand more about responses, how long the drugs need to be given, and how to make the treatment work in more patients.” To help gather these answers, she is turning to pathologists Anders, Taube, and Ed Gabrielson who are uncovering the biomarkers, the unique cellular characteristics and signals that differentiate cancers that respond to anti-PD-1 from those that do not.
The list of responding cancers continues to grow. Bladder cancer, Hodgkin’s lymphoma and a few difficult-to-treat cancers, like triple-negative breast cancer and mesothelioma are on it, with others like certain ovarian, endometrial, colon, head and neck, stomach, liver, and esophageal cancers, expected to soon be added.
Drake tells of a patient referred to him from fellow Greenberg Bladder Cancer Institute physician-scientist Trinity Bivalacqua. The patient was getting chemotherapy to shrink the size of his bladder cancer so that it could be removed with surgery. When Bivalacqua operated, he found the cancer had already spFread. Surgery would not cure him, so he left his bladder intact and referred the patient to Drake.
The patient had lost his hair and was underweight from the chemotherapy, and now it was no longer working. “He was not looking well when he came to see me in 2013,” says Drake. He recommended immune therapy with anti-PD-1. Almost immediately, the patient regained his appetite and put some weight back on and reported just generally feeling better. Over time, his cancer shrank by 80 percent. His only side effect was a small itchy rash on his shoulder. “He has three children and was able to witness important events in their lives that he honestly might not have otherwise lived to see,” says Drake.
On the other hand, there are cancers, including prostate and pancreatic cancers that remain largely resistant. “We need to address that on the research side,” says Topalian. Drake does not get a good response in all bladder cancer patients either. “In some patients it works quite well, but in others the cancer continues to grow,” he says. Understanding why some tumors do not respond is as important as learning why others do, he says. “If we can figure out when it works and how it works—what kinds of cells are involved and what is happening from an immunological standpoint—maybe we can take non-responders and make them responders,” Drake says.
There are currently about eight different types of antibodies that block PD-1 or PD-L1 on the market. The treatment is now FDA approved for melanoma and lung cancers, and Pardoll says approvals for kidney cancer, bladder cancer, and Hodgkin’s lymphoma are anticipated by the end of 2015 or early 2016. They aren’t cheap, costing about $100,000 or more per year for each patient treated.
Although there have been many news reports about the pricing of the drugs, immunology research nurse Alice Pons and colleagues say patients have not seemed concerned about the cost. That could be because some insurance companies are covering them even before final FDA approval. Nurse practitioner and immunology expert Barbara Biedrzycki says other insurance companies may resist approving immune therapy, requiring patients to first try less expensive drug therapies. To help ease the cost burden, the pharmaceutical companies making anti-PD-1 drugs say they have programs to provide free drugs for patients who cannot afford them.
Immune therapies are outpatient treatments, and although there have been some serious side effects, in most patients they have so far proven to be very safe. When hospitalizations, management of side effects, and the cost of drugs, are taken into consideration, Biedrzycki suspects the costs of chemotherapy and immune therapy will become much more comparable.
With improved responses and lower toxicities, which are clearly documented in common cancers such as non small cell lung cancer, withholding immune therapies from patients could intensify public ire aimed at the already battered reputations of the pharmaceutical and insurance industries.
“This research has completely changed the slow, conservative approval process for drugs,” says Pardoll. “Typically you would have phase I and II clinical trials and then a big phase III trial, and if a drug makes it all the way through, it gets approval.” Some of the anti-PD-1 drugs are getting approved right out of the gate in phase I trials. “They have such remarkable therapeutic effects and little toxicity that we don’t need phase III studies. There is an obligation to get the therapy to patients quickly,” he says.
Nelson says this is where Johns Hopkins leadership in precision medicine will play a leading role. The first anti-PD-1 trials were open to all patients with advanced cancers that were resistant to standard treatments, but as our scientists learn more about what cancers respond and what cancers do not, they can begin to use biomarkers to identify the cancers and patients most likely to benefit from immune therapy. Pharmaceutical companies have already begun developing biomarker tests for PD-L1 based on the work of Anders and Taube that demonstrated PD-L1 expression was the best predictor of response to anti-PD-1 treatment. “PD-L1 on tumor cells is the cloak that shields cancer from the immune system,” says Anders. “If the tumor is not expressing PD-L1, it is not likely to respond to anti-PD-1 therapy.” Some clinical trials already require the biomarker test for PD-L1 before treatment, says Topalian.
At the same time, the cancer immunology team continues to work in the laboratory to find other immune “stop” signals and learn how to transform immune therapy-resistant cancers into responsive cancers.
One of the ways cancer immunology experts are improving response is by combining immune drugs. “The notion of doing clinical trials with experimental drug combinations, even where none of the drugs have FDA approval, is becoming the norm,” says Pardoll. “These drugs are turning clinical therapeutics on its head,” he says. “This is a game changer.”
One of these combinations is anti-LAG-3 and anti-PD-1. LAG-3, was shown by Drake, Powell and others to shut down immune responses to cancer cells, similar to PD-1. Unlike PD-1, however, inhibiting LAG-3 did not create the same robust response that occurred with anti-PD-1 therapies. However, Drake found that combining two drugs—one that targets PD-1 and another targeting LAG-3—works in synergy to boost the immune response against cancers. Combined approaches using another checkpoint inhibitor known as anti-CTLA-4 and anti-PD-1 drugs also have been studied, and Drake believes that as more immune regulatory genes are identified, more combinations will be revealed.
“We know there are more checkpoints and that, in some cancers, we might have to block more than one,” says Powell. “Maybe in some patients PD-1 is not the relevant checkpoint, and we’ll have to find the one that is. In other cancers, we may have to block more than one checkpoint because both are relevant.”
Powell and colleagues are also having success using anti-PD-1 in combination with a drug that interferes with metabolism of cancer cells. Tumors kill by growing, and they require nutrients—lots of them—to sustain this growth. Blocking cell pathways that enable this growth by providing amino acids, glucose, and lipids that nourish tumor cells can have an antitumor effect.
“We think tumor cell metabolism can be considered a kind of immune checkpoint because it creates an environment that turns off the immune response,” says Powell. Surprisingly, blocking these nutrients is cancer specific. All cells need nutrients, but normal cells don’t require the extraordinarily high levels demanded by rapidly dividing cancer cells. “To be a really good cancer cell, it needs a huge amount of these nutrients,” he says. Cutting off the biological supply line of these nutrients slows the growth of cancer cells without harming normal cells. Adding a checkpoint blocker like anti-PD-1, allows the immune system to sweep in and finish the job on the weakened cancer cells.
Powell is also studying a group of failed Parkinson’s disease drugs that target a pathway known as adenosine that acts as an on/off switch for immune T cells. Studies in Powell’s laboratory found that the drugs were remarkably proficient at instigating an immune response against cancer cells. The drugs have already been studied in patients with Parkinson’s disease and proved safe, so with funding, he hopes to be able to bring them to clinical trials for patients with cancer in less than a year.
These new combinations will not be limited to immune agents. Animal research by radiation oncology fellow Andrew Sharabi and Drake found that focused radiation treatment, like that used in radiosurgery, stimulates an immune response against the cancer. Sharabi says cell damage caused by radiation deploys immune cells to the tumor site, and combining anti-PD-1 with radiosurgery unleashes an immune assault on the cancer. “Radiation opens the door, and anti-PD-1 therapy allows the immune cells to get to work,” says Sharabi.
Radiation oncologist Joseph Herman, Anders, and Taube find evidence that radiosurgery may be activating immune cells in pancreatic cancer as well, a cancer that currently does not respond well to anti-PD-1 treatment. Combining radiosurgery with the right immune-targeted drugs may increase responses in a variety of cancers. Anders is examining tumors that are traditionally treated with radiation, including head and neck cancers and esophageal cancers to look for expression of PD-L1 in tumor cells, an indicator that they might respond to an anti-PD-1 checkpoint blockade/radiation therapy combination.
Pardoll and Topalian are hopeful that combination therapies may be the key to converting currently nonresponding cancers like prostate cancer into responders. Similar to Sharabi and Drake’s work, Topalian believes that giving another kind of therapy up front, including radiation, chemotherapy or targeted therapies, and following with anti-PD-1 could provoke an immune response in currently resistant cancers.
She is working in her laboratory to see what therapies incite an inflammatory response in the tumor because inflammation draws the attention of immune cells.
These are the situations where adding anti-PD-1 has the potential to cause a synergistic immune response. She and others are compiling this laboratory evidence. This component is critical, she says. “There are endless possibilities of potential treatment combinations. We can’t test them all, and we can’t simply do combinations of convenience,” says Topalian. “We have to let the research lead us, and then move to the clinic only with combinations supported by scientific evidence.”
Some cancers will respond to anti-PD-1, but others will need more to get the immune system working. Pardoll offers an automobile analogy. “If a car is sitting at the top of a hill with the front pointing downhill, it may only need the parking brake released to start moving. Another car sitting on a flat road may need the brake released and a push to get going. A car sitting at the bottom of a hill and facing uphill will need the brake released and a lot of gas to get moving.”[potential graphic]
Distinguishing which cancer fits which of these automobile scenarios is the focus of laboratory investigators, and Pardoll is confident that working together over time Johns Hopkins experts will be able to figure out the right combinations to get the immune therapy moving against almost any cancer.
The Learning Curve
With Ryan’s cancer stable—no longer shrinking but not growing either—Brahmer has decided to stop anti-PD-1 treatment. “We think that over time the immune system creates a memory. The T-cell remembers how to attack the cancer and stop the cancer from shielding itself from the immune cells. We think the immune system can keep the cancer under control now, even without treatment,” says Brahmer.
If Ryan’s cancer begins to grow, she will start therapy again. Other patients whose tumors began to grow again after anti-PD-1 treatment was stopped have responded with treatment that was reinitiated. It’s all part of the learning curve. Ryan continues his regular trips from his home near Middleburg, Virginia, to the Kimmel Cancer Center to have his cancer monitored. He also participates in a Stand Up To Cancer-funded study providing blood samples that help researchers understand more about how immune checkpoint blockade therapy works against cancer. Not every patient whose immune cells express PD-1 or whose tumor cells express PD-L1 respond to immune therapy. Patients like Ryan are helping investigators solve those mysteries and leading them to ways to help more patients.
“I feel like this is about more than just me,” says Ryan. “Immune therapy saved my life, and I want to bring this message of hope to others. I know how fortunate I was to have this wonderful team of doctors and nurses at Johns Hopkins. They are my heroes,” he says. “Two years ago, in a very short period of time, I went from feeling fine to being in serious trouble. I thought I might have only months to live and that I would miss so many important moments in my children’s lives. Time was critical, and I was fortunate to get in the right hands quickly.”
Today, Ryan says, he feels better than he has in years. He recently provided around-the-clock logistical support as a crew chief to his son as he participated in a grueling 100-mile ultra-marathon through the Vermont mountains. “My friends and family were worried when I told them I planned to do this. They were shocked by how much energy I had.”
Pardoll sees the therapy as a true breakthrough in cancer medicine. This is not just hyperbole; he actually did the math. With 14 different cancer types responding at rates of between 15 and 40 percent, early studies in Hodgkin’s lymphoma reporting response rates of nearly 90 percent, and enduring cancer remissions, immune checkpoint blockade therapy has distinguished itself from chemotherapy and gene-targeted therapies. “By a factor of 30,” he says, “anti-PD-1 is the most powerful single agent in the history of cancer therapeutics.”
Another Road Leads to PD-1
Forty years ago as efforts to decipher the causes and cures for cancer intensified, many began looking to the laboratories of the fledgling cancer center at Johns Hopkins. From the beginning, the National Cancer Institute had named it a center of excellence. Among the main areas of research were laboratories focused on immunology, genetics, and epigenetics. One of them, experts hoped, would lead to a discovery that would conquer cancer. No one, including Pardoll, ever imagined the interconnection of these three areas of research or that it would result in some of the most significant cancer discoveries of our time.
In 1977, Bert Vogelstein, a young scientist concentrating on the nearly impossible task of cracking cancer’s genetic code, and Pardoll, his graduate student at the time, met monthly with senior cancer researcher Donald Coffey to toss around ideas about how to cure cancer. Ideas were about all anyone had at that time. Coffey remains an iconic figure at the Kimmel Cancer Center. The consummate teacher with an enthralling Southern drawl challenged talented young investigators then—as he continues to do today—to work together and look for creative solutions to a tough problem. Usually, they would talk casually over tea. Even then, the immune system was on their short list of ideas. Vogelstein continued to pursue genetics convinced it would yield greater insights into the cellular processes that result in cancer. In many ways, he was correct.
Vogelstein, the Clayton Professor of Oncology and co-director of the Kimmel Cancer Center’s Ludwig Center, went on to define cancer as a genetic disease. Starting with colon cancer, he, Kenneth Kinzler, and their Ludwig Center team developed a model for cancer initiation and progression that became the paradigm for much of modern cancer research.
Pardoll continued to pursue cancer immunology, in part inspired by the monthly meetings with Coffey. With his and Vogelstein’s encouragement, he soon joined the faculty and started his own cancer immunology laboratory. But that was not the end of the Vogelstein/Pardoll collaboration. As Vogelstein focused on the cancer genome, Pardoll began to explore the genetic mechanisms of immune cells. Neither anticipated an intersection of the two laboratories that would lead to an unusual discovery.
“This kind of collaboration is what makes us Hopkins,” says Vogelstein. “People share their ideas and results here. Drew [Pardoll] and Suzanne showed us what they found and asked for our ideas.”
Pardoll and Topalian were trying to figure out why one of the first colon cancer patients ever treated with anti-PD-1 had a complete response—with no detectable tumor six years later—but another 32 colon cancer patients did not respond. They hoped that the Vogelstein team’s expertise in colon cancer could shed light on what was unique about that patient and maybe what they learned could be used to turn the tide of strikingly poor responses for that disease. “We were happy to share any of our research that could help,” says Vogelstein. “It’s all done in the service of patients. There is no discussion of the usual academic kinds of things. We don’t do that in the Kimmel Cancer Center.”
The Mystery of the Single Responder
Cancer is a disease of genetic mistakes, so for all intents and purposes, the signals sent out by mutated genes should be an announcement to the immune system that they don’t belong. “Ironically, this very mechanism that the tumor uses to accelerate its genetic diversity creates and Achilles heel for immunotherapy,” says Luis Diaz, investigator in the Kimmel Cancer Center’s Ludwig Center. The more mutations that exist in the cancer, the louder the signal and the more likely it is that the immune system will take notice.
So it was not surprising when Kimmel Cancer Center investigators, including Diaz, had an idea. “It’s mutations,” they suggested, suspecting that the single patient who responded to anti-PD-1 treatment had Lynch Syndrome, an inherited form of colon cancer characterized by abnormally large numbers of mutations.
The research that formed the basis for their conclusion occurred some 20 years earlier, remarkably from the same Ludwig Center laboratory. In 1993 Vogelstein, Kinzler, and Nicholas Papadopoulos of the Kimmel Cancer Center and Albert de la Chapelle from The Ohio State University identified a genetic alteration linked to Lynch syndrome, a hereditary form of colon cancer that is caused by mistakes in mismatch repair genes.
The job of mismatch repair is to correct copying errors that occur when DNA replicates and cells divide. People who inherit a defective copy of the gene experience high rates of mutations and are at increased risk of developing colon cancer. Colon cancers in patients with mismatch repair deficiency have more than 1,000 mutations while those without typically have less than 100. Vogelstein, Kinzler, and Papadopoulos developed a test for mismatch repair gene mutations, so that families with a history of Lynch syndrome could be screened and their colon cancers detected in an early and curable stage.
They could have never envisioned the clinical application that Diaz and another young immunology investigator, Dung Le, would have for the test. It would prove instrumental. “What is the patient’s mismatch repair status?” Diaz asked Pardoll and Topalian about the single colon cancer responder. Using the test Vogelstein, Kinzler, and Papadopoulos developed two decades earlier, they proved their suspicion was spot on. The patient’s tumor was positive for mismatch repair alterations. The large number of mutations common to mismatch repair served as an alert to immune cells because they make the tumor look much more different from normal colon cells that don’t have this large number of mutations.
Imagine a crowd of people in a room. If one person is speaking a language different from the rest, it might go unnoticed. If many of them are speaking a different language, it will likely garner attention. In principle, this is the way the immune system should work, ignoring those things that are “self” and noticing those things that are different. This is called immune recognition; the next step is action. That’s the role of anti-PD-1, which works by shutting down the cancer cell’s ability to send false signals to commandeer and divert immune cells from reacting. With anti-PD-1, the immune cells alerted by the high number of gene mutations were put into action to kill cancer cells.
“For other treatments, including chemotherapy, the changing tumor biology due to accumulating mutations causes treatments to stop working, but it seems to make immune therapies work better,” says Le. It’s likely more about the quantity of mutations than the specific type of mutation. The investigators believe the good responses to anti-PD-1 that occur in a subset of melanoma and lung cancers are also related to the accumulating gene mutations caused by sun exposure in melanoma and smoking in lung cancer. “In theory, you only need one mutation to get the immune system’s attention, but larger numbers of mutations, shift the odds in your favor,” he says.
The only way to prove the hypothesis was to test it in patients, but these trials are expensive and a huge undertaking for young investigators, but Diaz and Le were undeterred. Merck agreed to donate the drug, but it was the generosity of private funders—Swim Across America, the Lustgarten Foundation, the Skip Viragh Foundation, the Banyan Gate Foundation, the Commonwealth Fund, and the Sol Goldman Pancreatic Cancer Research Center—that allowed Diaz and Le to make it happen.
Le and Diaz are two of the young rising stars of the Kimmel Cancer Center. Le is a Viragh Scholar focused on immunology and pancreatic cancer vaccines, and Diaz is a GI cancer and genetics expert and director of the Swim Across America Laboratory. The balance of cancer genetics/cancer immunology expertise each brought to the table was perfectly suited to this study.
“The success of the Kimmel Cancer Center is inextricably tied to our ability to attract the best and brightest talent,” says Nelson. “This trial is an example of the depth of talent we have in our young investigators. Unfortunately, as this study illustrates, it can be a challenge for them to find funding for their science because they may not yet have a large body of work or the notoriety of more senior investigators. It is one of the greatest shortcomings in research, but a priority at the Kimmel Cancer Center. It was our benefactor Sidney Kimmel’s vision—a vision he brought to life through the Kimmel Scholars Program—and vitally important to the future of cancer medicine.”
With funding in place and the drug acquired, Le and Diaz began a clinical trial in 48 patients. Le, the more subdued of the research duo, speaks calmly and straightforwardly about the significance of their findings. Even before accrual to the study was completed, the results were so dramatic that they were viewed as a major finding, warranting publication in the prestigious New England Journal of Medicine in 2015, featured at the American Society of Clinical Oncology, and setting the stage for potential FDA breakthrough status for anti-PD-1 immune therapy in patients with mismatch repair deficiency.
Roughly 60 percent of patients with mismatch repair deficiencies responded to treatment, pointing to the presence of other checkpoint blockades that work similarly to PD-1. This will be the focus of additional laboratory research. As critical of a finding, however, was that none of the 25 patients with normal mismatch repair responded to treatment. The investigators will need to replicate their findings in a larger number of patients, but it provides clear evidence that mismatch repair alterations in tumors predicts which patients are good candidates for immune therapy with anti-PD-1.
Additional laboratory research at the Kimmel Cancer Center has pointed to other immune checkpoints in these tumors which could be targeted in combination with anti-PD-1. Frank Housseau and pediatric cancer expert Nico Llosa found high expression of LAG-3 in mismatch repair deficient tumors.
Beyond colon cancer, the clinical study demonstrated that mismatch repair deficiency is a universal biomarker of response to immune therapy. They tested the treatment in a small number of other cancers marked by mismatch repair mistakes—including some rare, difficult-to-treat cancers—and the treatment worked. “If you have the mismatch repair signature, you should be treated with a checkpoint inhibitor,” says Diaz. “Defects in mismatch repair genes are found in a small percentage of many cancer types,” says Le. Vogelstein estimates that 2 to 4 percent of all cancers have mismatch repair mistakes, and when that is calculated across every cancer type, the potential to help a lot of people is very real. Le believes that similar biomarkers for immunotherapy response could be applied to cancers with errors in other DNA repair genes.
“There is a tsunami coming,” says Anders, who believes the mismatch repair test is the first of many that will be used to predict response to immune therapy.
This is what excites Diaz and Le. They witnessed it firsthand, and Diaz brims with enthusiasm when he speaks particularly of two young patients who were part of the clinical study.
Stephanie Joho, who has Lynch syndrome, had just graduated from college when she was diagnosed with colon cancer. Surgery and two different types of chemotherapy did nothing to avert the aggressive cancer. Out of options and in excruciating pain, Joho searched desperately for other treatments and had reached out to Diaz who, until the mismatch repair discovery, had tried everything available. Recognizing Joho would be a perfect candidate for his new study, he called her. She was distraught, sitting in a waiting room at another comprehensive cancer center after one more failed search for an experimental therapy when she got Diaz’s call. “Come down here. We’ll cure you,” he told her. After treatment with anti-PD-1, Joho’s tumor shrank, and her pain subsided. “I haven’t felt this well in four years,” says Joho, now 25.
Another patient was weeks from dying and being encouraged to enter hospice care when Diaz and Le learned his tumor was positive for mismatch repair. He was so sick that they had to get a special exception to get him enrolled in the trial. “Without any doubt, this young man’s life was saved by this treatment,” says Diaz.
Diaz recalls more patients. “We could fill this room with people who have benefitted,” says Diaz. The two recognize their study was small, and in science, numbers matter. Still, they have met every one of the patients in their study, and they also recognize that medicine is more than numbers. Behind every statistic is a human being.
“It is rare to get a response in colon cancer patients who have not responded to other standard therapies, and most of them had just months to live,” says Le. She is hopeful this discovery will very soon benefit thousands, but nonetheless, at this moment, they celebrate Joho and the 20 other lives that were saved.
“One of the things that put us at the forefront of clinical breakthroughs in cancer immunology is that we never forget the science,” says Pardoll. “Having the leading epigenetics and genetics researchers here gives us an edge. At most institutions, the different laboratories don’t interact at all. At Johns Hopkins, interaction among different disciplines is the norm, and these types of collaborations have led to some exciting immunology advances. “There is no other place I know of with these deep, intellectual roots in genetics and immunology and the support of the institution to carry out investigator-initiated trials,” says Vogelstein. “You can’t create that environment from scratch. It has to be built in from the ground up, and we’re very fortunate to have it here.”
“Dung and I are standing on the shoulders of many giants,” says Diaz.
The Epigenetic Connection
A number of the controls that turn the immune system on and off are epigenetic in nature. These chemically mediated on and off switches alter the function of genes without mutating the DNA, usually by adding chemical groups to the signaling portion of genes or by tightening or relaxing how the DNA is packaged within the cell. Epigenetic therapies that target these control mechanisms, can reactivate genes that have been turned off.
Stephen Baylin is one of the world’s foremost epigenetics experts. These Kimmel Cancer Center innovators have independently informed some of the most vexing problems of cancer initiation, spread, and treatment resistance. Their combined knowledge is the cancer world’s triple threat. By deciphering the inter-related complexities of genetics, epigenetics, and immunology, they are bringing forth some of the most encouraging cancer treatment strategies of our time.
As Baylin explored the effects of epigenetic-targeted drugs on lung cancer cells in his laboratory, he found that some of the genes that were being reactivated were connected to immune responses. Among them was PD-L1 which interacts with a key molecule on immune cells, PD-1.
Baylin and young investigator Cynthia Zahnow, working with him as part of the Stand Up To Cancer Epigenetics Dream Team, shared their findings with Pardoll. In some lung cancer cells, the PD-L1 gene was already active, and epigenetic therapy made its signal even stronger. Pardoll believed that adding anti-PD-1 therapy in conjunction with epigenetic therapy could activate an immune response right within the tumor.
Treated with epigenetic drugs, the ability of cancer cells to evade the immune system is broken and they send new signals, beckoning immune cells to come and get them. At the same time, they begin to express PD-L1 to shield against immune attack. Anti-PD-1 breaks off that communication, unleashing the immune system on the cancer cells.
Baylin, Zahnow, and team went back to the laboratory to decipher the immune evasion signature for lung, breast, colon, and ovarian cancers. To do this, they looked at all of the genes in lung, breast, and ovarian cancers that got turned on in cancer cells with epigenetic-targeted therapies. Lots of genes were switched on, they found, but what stood out were the 20 percent or so related to immune regulation. These genes were studied in depth by post-doctoral fellow Kate Chiapinelli and found to be epigenetically programmed to evade detection by the immune system.
They are now looking at tumor samples from patients receiving combined epigenetic and anti-PD-1 immune therapy to see if the epigenetic therapy turned on immune genes that would cause the cancer cells to respond to anti-PD-1 treatment. “Epigenetic therapy does not break immune tolerance, but it has the potential to sensitize cancers to an immune anti-PD-1 checkpoint blockade treatment,” says Baylin. “We think it brings in immune cells, so if we follow it with anti-PD-1, we can cause an immune reaction against cancer cells.” This theory is currently being studied in clinical trials funded by Stand Up To Cancer.
Baylin continued his research of epigenetic controls of immune response, collaborating with another epigenetics research giant, Peter Jones, director of research at the Van Andel Institute. Working together as co-leaders of the Stand Up To Cancer Epigenetics Dream Team, they uncovered a viral defense mechanism in tumors that mimics a viral infection. Epigenetic drugs cause it to simulate an infection and summon immune cells to tumors.
“Epigenetic drugs upregulate the viral defense pathway, activating interferon signaling, and this brings in immune cells,” says Chiappinelli. “When epigenetic therapy is followed by anti-PD-1 checkpoint blockade immune therapy, the immune cells go into action against the cancer.”
The viral defense pathway is an ancient human biological mechanism that allows cells to recognize when they have been infected by a virus and helps activate an immune response to the viral invader. Our DNA retains a record of our viral exposure, creating a history that becomes integrated into the genome. This viral record is rendered dormant through epigenetic signaling, but as Baylin and Chiappinelli found, it can be reactivated when epigenetic-targeted therapies are given. Since it is reactivating only a memory of viruses, it only mimics an infection in tumor cells. The fake infection is enough to generate an immune response.
When they examined the DNA of a variety of cancer types, including ovarian cancer, colon cancer, and melanoma, they found that tumors with high expression of the viral defense pathway were more likely to respond to immune therapy with anti-PD-1. Tumors with low viral defense expression could be coaxed into response if epigenetic-targeted drugs were given before immune therapy. The FDA-approved epigenetic drug 5-azacityidine (Aza) converted low viral defense expression to high expression.
“Our research findings are consistent with the previous notion that silencing viral sequences in the human genome is a major function controlled epigenetically,” says Baylin. Using drugs like Aza to remove the epigenetic controls that silence the noninfectious viral memory locked away within tumor cells activates interferon, a signal to the immune system released by cells when they are invaded by bacteria or viruses. In essence, Aza makes tumor cells think they are infected with a virus and causes them to sound the alarm to alert the immune system. In laboratory experiments when Baylin and Chiapinnelli blocked interferon in tumor cells, the Aza-induced immune response stopped.
To further test their theory, the two collaborated with experts at Memorial Sloan Kettering Cancer Center in New York to examine cancer cells from melanoma patients treated with anti-CTLA-4, another checkpoint blockade immune therapy similar to anti-PD-1. They determined the viral defense pathway expression for each tumor and matched it back to the patients. High viral defense expression matched with all of the patients who responded to immune therapy and low expression matched with those who did not respond.
In a mouse model of melanoma, adding an epigenetic drug to cancers that were not responding to immune checkpoint blockade triggered an immune response. Baylin says the true test will come from clinical studies, but he is energized by these laboratory results.
“This is the most exciting time of my entire career,” says Baylin. “Kimmel Cancer Center scientists have made seminal contributions to the basic science, and now what is happening is almost magical as we make unbelievable transformation to harness the immune system to attack tumors. Our latest findings further decipher the mechanisms that lead to this immune reaction and offer a novel way to potentially boost the success of immune therapies in cancer patients.”
Baylin, like all of the Kimmel Cancer Center researchers and clinicians who held firm to their belief in immune therapy, is most excited by the safe and durable responses it delivers.
“Many people still view cancer as a terminal disease, particularly advanced cancers, and look what we have to put patients through to treat them,” says Baylin. “Immunotherapy promises to change that. It’s already made a huge difference. We have patients now who, against all odds, are alive and living well even when we have not completely eliminated their cancer. I can only imagine what the next 10 years will bring. You have to be excited about this.”
Whispers of a Cure
These combined approaches are the newest adaptation of cancer immunology therapies. Pardoll, Topalian, Jaffee and their immunology teams are optimistic that the power of immune therapy and the right combinations will continue to expand the numbers of cancer patients who will see their immune systems engaged against their cancers. For the first time in the history of cancer, experts and patients alike are beginning to see in immune therapy, the potential for a universal cure for cancer.
Through the convergence of a wealth of expertise, the advancement of technology and in an environment where bench-to-bedside research flourishes, Kimmel Cancer Center experts have solved the puzzle of cancer immune resistance, or at least they have identified many of the pieces. The critical component—immune resistance, how the cancer cell turned escapes an immune attack—was revealed and therapies to undo cancer’s ability to manipulate the immune cells to its own benefit can now be developed.
“The success we have had so far is unlike anything we have ever seen in cancer, and consider that we have only mined about 5 percent of what the immune system can do in cancer. This is just the beginning,” says Pardoll. “As we learn about other immune signals and combined approaches, we think it will only start to look better. In 20 years, possibly less, immune therapy has the promise to completely change the face of cancer and make almost all cancers curable or controllable.”
Patients, even those who are not currently on immune therapy, seem to sense the changing tide, says veteran immunology nurse practitioner Tianna Dauses. “Everyday we get calls from cancer patients who want to come to the Kimmel Cancer Center for immune therapy. Current patients, including many who are on other types of therapies, express the hopefulness they feel from being at a cancer center that is engaged in this kind of paradigm-shifting research.” Her immunology nursing colleagues concur. “I’ve worked in oncology for a long time. It’s an exciting time to see these new therapies that work in the worst cancers and don’t cause terrible side effects,” says Onners. “One of the first questions I typically get from patients is, ‘Will it make my hair fall out? It’s so nice to be able to tell them it won’t.”
The patients who were on chemotherapy before treatments like anti-PD-1 were discovered say they feel like chemotherapy kept them alive, but immune therapy gave them their lives back, says Biedrzycki. “It is so exciting to be a part of this,” she says.
After decades of research, it is the patients that matter most to the Kimmel Cancer Center immunology researchers and clinicians. It is not seeing their scientific theories proven correct that they finds most gratifying. The real satisfaction, they say, comes from seeing these scientific theories actually help patients and without the terrible side effects that have defined cancer treatment for decades. “Immune therapy is a game changer,” says Pardoll. “We need more research to take us the rest of the distance, but we don’t think there is a single cancer that the patient’s own immune system ultimately can’t beat.”