Ron Warnick, MD
July 28, 2009
FOR IMMEDIATE RELEASE
CONTACT: Tom Rosenberger, APR
CONTACT: Cindy Starr, MSJ
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Future Advances in Brain Tumor Therapy
A Conversation with Ronald Warnick, MD, Chairman of the Mayfield Clinic and
Director of the Brain Tumor Center at the UC Neuroscience Institute
CINCINNATI -- Ronald Warnick, MD, Chairman of the Mayfield Clinic, Director of the Brain Tumor Center at the University of Cincinnati Neuroscience Institute, and Co-Director and a developer of the Precision Radiotherapy Center in West Chester, Ohio, is one of America's leading experts in the treatment of brain tumors. He is a past Chairman of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Tumors and is currently a co-investigator in nine clinical trials underway at the Brain Tumor Center.
During a recent interview, Dr. Warnick discussed advances in brain tumor therapy that are likely to have an impact on treatments in the years ahead. Select a question below to review answers.
Q: Where will the next major advances in brain tumor therapy come from?
A: The next advances in brain tumor therapy are going to come from the laboratory, where scientists are studying the molecular aspects of brain tumors. Some of these laboratory experiments will lead to potential therapies, and we will then test them in clinical trials. We will then take the results of those clinical trials back to the laboratory and refine those treatments. This cycle of transferring findings from the laboratory to the clinic and back to the laboratory is what I call the discovery-to-recovery phase and the recovery-to-discovery phase. We need physicians and scientists to work together to translate laboratory findings into the next major advances in brain tumor therapy.
Q: What is brain tumor profiling, and what is the current status of this technique?
A: An important aspect of brain tumor treatment and management of patients relates to something that we call brain tumor profiling. I liken this concept to an FBI agent who profiles a criminal. The FBI agent studies crimes the criminal has committed, correlates those crimes with a personality type, and then tries to anticipate the individual's future criminal behavior. We're doing the same thing when we take a sample of tumor and we look at it under the microscope and look at certain features and then try to predict how that tumor will act in a particular patient.
In the past we had only one way of doing this: We acquired the tissue through a biopsy or operation, stained it, and then looked at it under a microscope. We would make a diagnosis and then tell the patient his or her average prognosis. But now we can be much more sophisticated. We can take that tissue and conduct a molecular analysis of it. I like to think of this as a gene fingerprint. Just as you have specific fingerprints on your fingers, each tumor also has a specific gene fingerprint. From this we can not only obtain the diagnosis of the tumor, but we can also begin to start categorizing the prognosis of patients and their tumors.
For example, during the last six months a diagnostic test called Decision Dx-GBM has become available. We can take a sample of the tumor and send it to a central laboratory. Pathologists look at nine separate genes and, based on those results, they can determine which of five prognosis groups the patient falls into. This is helpful in itself; but even more helpful is the ability of that gene fingerprint to tell us which treatment would work best for each individual patient.
In the past, we were forced to take a cookie-cutter approach. If the tumor was diagnosed as a glioblastoma, we used a standard treatment, which is radiation combined with chemotherapy. What brain tumor profiling offers is not only a sophisticated prediction of outcome, but also a selection of appropriate therapy for a patient with that tumor. A gene fingerprint of a patient's tumor might reveal that a particular marker, such as EGFR, is positive in that patient, for example. This means, then, that we need to use a treatment that is anti-EGFR. If the patient has this marker, we want to attack that particular marker in order to kill the tumor cell. Some patients might be EGFR-positive, some might be VEGF-positive, and some might be positive for both. So their treatments will be different. This is also what is meant by the term “personalized medicine.” It means that we are personalizing, or tailoring, the treatment approach to a particular patient and his or her tumor. It is no longer a cookie-cutter approach; it is more like getting a custom-tailored suit.
While the test that allows us to determine the initial gene fingerprint has been available for about six months, the ability to tailor treatment based on that gene fingerprint is in progress, in patients and in clinical trials. It is not accepted as standard treatment yet.
Q: What is immunotherapy and its potential to fight brain tumors?
A: It is helpful to understand that every one of us is reliant on our immune cells to detect and kill cancer cells that may spontaneously form in our bodies. And the immune system generally does a good job of that. However, in patients who have glioblastoma, the number of those cancer-fighting immune cells is decreased by 75 percent. These patients only have 25 percent of the normal number of immune cells. We are not sure whether the glioblastoma causes this situation or whether these patients have an impaired immune system that has led to the glioblastoma. The latter is a strong possibility.
The reduced number of immune cells is not the only problem for patients with glioblastoma. A second problem is that the remaining cancer-fighting immune cells are impaired. They try to recognize and kill the tumor, but for some reason they are unable to get the job done. So we have to boost the numbers of cancer-fighting immune cells as well as their activity, their strength.
We do that by using a vaccine to re-educate these immune cells to be stronger cancer-fighting cells. And, luckily, there is a type of white blood cell in the body called the dendritic cell. This immune cell, which resembles an octopus, likes to digest tumor cells, and in so doing it pushes fragments of the tumor out onto its branches, or arms. When the arms of this dendritic cell – or teacher cell -- come in contact with inactive immune cells – or student cells – the student cells become activated and can home in on the tumor and kill it. When we re-educate these cells to become active, they then divide and produce children and grandchildren, which all have the same characteristics, because they have been educated and taught to fight and recognize the tumor. It is as if you had trained a pack of guard dogs.
A Phase II study of a dendritic cell-based vaccine (the DC Vax trial) involves taking dendritic cells from a patient newly diagnosed with glioblastoma and sending them to a central laboratory, where they are then incubated with tissue from the patient's own brain tumor. During the incubation, or fermenting, process, the dendritic cells chomp up and digest the tumor and become primed to be “teachers.” The dendritic cells are then sent back to the patient's hospital, where they are injected under the patient's skin. The cells educate the body's immune cells, which move from that site under the skin to the brain and attack the tumor.
The UC Brain Tumor Center was one of the early centers involved in this therapeutic clinical trial, whose patients also underwent surgery and received radiation therapy and chemotherapy. The trial is currently closed to enrollment, but we have acquired some promising information from the results of the first 20 patients. The therapy seems to be well tolerated; and of the 20 patients who received this therapy, 19 have lived longer than the average for this tumor. As such, DC Vax has a real potential to become a standard therapy for glioblastoma.
Q: What can you tell us about the CDX-110 vaccine?
A: Immunotherapy refers to the harnessing of the body's immune system to fight the tumor. One way to accomplish this is through a vaccine. We all know that vaccines are used to prevent infection, hepatitis, influenza, polio. Vaccines are made by taking the virus and weakening it so that it cannot cause infection. Then that weakened virus is injected into a patient or person, where it causes an immune response and prevents the person from getting the true infection if it is ever encountered. Medical scientists have long dreamed of developing a vaccine for brain tumors. The ideal solution would be a vaccine that would prevent you from ever getting a brain tumor. A second-best option would be a vaccine that could rev up a patient's immune system so that he or she that could fight the tumor. This is the kind of vaccine that is currently being studied and developed.
During our research we have discovered that glioblastoma cells have little switches on their surface. When these switches are turned on they send a signal to the cell's command center, and the cell is stimulated to grow and divide. We know that in about 40 percent of glioblastomas the switch is stuck in a permanent “on” position. So the goal of a new brain tumor vaccine is to turn off these switches and thus kill the cell. This treatment is called CDX-110, although the trial is often called the Celldex trial after the name of the drug manufacturer (Celldex Therapeutics). A Phase II trial involving this vaccine is underway here in Cincinnati and at 30 other centers.
The trial represents one of our first applications of tumor profiling, or gene fingerprinting. We take a sample of brain tumor tissue from all patients who are newly diagnosed with glioblastoma and test for the presence of the “on switch.” The 40 percent of patients whose genes test positively for the “on switch” should, theoretically, respond positively to a vaccine that seeks to turn the switches off. These patients (who also undergo radiation and chemotherapy) receive regular injections of the on-switch vaccine under the skin. The vaccine actually causes an immune reaction, and you can see a rash forming. Those cells are then basically activated, revved up to attack the “on switch” of glioblastoma. The cells migrate to the brain and turn off the glioblastoma cell and prevent it from dividing. Results of this study will become known sometime in 2010.
Q: What is an angiogenesis inhibitor, and how might it help in the fight against brain tumors?
A: Brain tumor angiogenesis is another “near-future” strategy – one that is in clinical trials and, if successful, is five years away from becoming standard therapy. Brain tumor angiogenesis is a complicated terminology, but it comes down to something very basic: glioblastomas are tumors that tend to have a very significant blood supply from the brain. For example, if you look at an angiogram of a patient with a glioblastoma, you will see a huge number of new blood vessels that have formed. These vessels are important to the tumor because they feed it oxygen, glucose, and other nutrients. The glioblastoma is a smart tumor that has figured out a way to trick the brain's blood vessels into giving it more of what it needs. The tumor's cells do this by sending out a signal that stimulates the blood vessels to form new blood vessels. These new blood vessels feed the tumor, bring it more nutrients, allow it to grow and divide, and cause more problems. This cycle continues unless we can stop those false signals.
We have a recently approved therapy, called Avastin, which can do just this. It is an intravenous medication that blocks at least one of tumor's signals. This leads to a decrease in the number of blood vessels that form and the amount of blood that is feeding the tumor. Eventually, the tumor shrinks. Avastin was approved by the FDA because of very promising results in patients who had exhausted other therapies. After being given the drug, these patients saw their tumors shrink dramatically.
The UC Brain Tumor Center and 34 others are currently studying a similar angiogenesis inhibitor called Recentin, an oral medication that is manufactured by AstraZeneca. The study is comparing the results of three groups of patients: 1) those who take Recentin alone; 2) those who take Recentin in combination with an oral chemotherapy agent (CCNU); 3) and those who take only CCNU. The centers expect to collectively enroll 300 patients, and the trial will close in the summer of 2010. The advantage of Recentin over Avastin is that it is oral. Eventually, down the road, the standard treatment for glioblastoma could consist of oral Temodar (our most common chemotherapy agent) and oral Recentin.
Q: What is the latest news about neural stem cells?
A: First, I'd like to clarify that the stem cells we're talking about with glioblastoma are not embryonic stem cells. These are stem cells that we all have in our bodies. These particular stem cells are found deep in the brain, around the fluid space called the ventricle, and are responsible for producing various types of brain cells, or neural cells. Stem cells are normal and good, but occasionally they get knocked akilter. That happens when a neural stem cell undergoes a mutation or permanent change. It could be from some external stimulus, like radiation. But whatever the cause, this neural stem cell becomes a cancer stem cell, and we know, from previous studies, that glioblastoma starts and grows from cancer stem cells.
I liken cancer stem cells to the queen bee of the hive. They live forever, they produce the worker bees or the worker tumor cells, and they're very difficult to kill. Normally, our treatments are very effective at killing the worker bees. But for a variety of reasons, about 1 percent of tumor cells are very resistant to radiation and chemotherapy and do not die. These remaining cells are the cancer stem cells, the queen bee. We have found that they will be suppressed for about 24 hours after chemotherapy, but they very quickly revive themselves and begin growing and dividing again. This is our major problem. Over time, this 1 percent of remaining cells will produce more worker bees, and, before you know it, the tumor has returned.
So, what we need to do is study why cancer stem cells are resistant to radiation and chemotherapy. That is being done in the laboratory right now. Scientists in the laboratory are asking how can we change this cancer stem cell, how can we modify it, so that it will become sensitive to radiation or chemotherapy. Therapies involving the sensitization or modification of cancer stem cells could go into clinical trials in five years and could become standard treatments in 10 years.
There are other ways we might attack cancer stem cells, however. We know that stem cells have certain markers on their surface. Some of these markers are specific to cancer stem cells, and CD 133 is one of them. If we have a specific immunotherapy, like an antibody, or a vaccine that could recognize CD 133, this could be used to selectively eliminate cancer stem cells, like a surgical strike in a war. The other possibility that is being studied involves injecting a modified herpes virus that would infect only cancer stem cells. The herpes virus would divide and grow and finally kill the cell.
Q: Does nanotechnology hold promise for brain tumor therapy?
A: Nanotechnology is a technology that focuses on the development of machines that range in size from 10 to 100 nanometers. One nanometer is 1 million times smaller than the head of a pin. These machines cannot be seen with a naked eye or even a regular microscope. You need a scanning electronic microscope to see them. These nanomachines are not constructed from metal or plastic but from the body's building blocks, whether DNA, RNA, or protein. They can navigate through tissues and they can sense objects. They can smell tumor cells, for example, and they can be designed to perform certain tasks. There are some whose job is to form a channel through the membrane of a cell to allow chemotherapy agents to flow through.
Some nanomachines truly exist, and some exist only in scientists' minds. So how would we use nanomachines to treat brain tumors? Well, one possibility is to deliver nanomachines made of iron oxides into brain cells. Because MR imaging is based on magnetic fields, and since iron is magnetic, then we might be able to visualize individual tumor cells that contain the magnetic particles. Right now we can only see large tumor masses. If we could image every tumor cell that exists in the brain, we might be able to treat them more effectively.
Another possibility is that nanomachines could deliver a drug that sensitizes the tumor cell to radiation or chemotherapy. They could also help drugs pass through the blood brain barrier. Or the nanomachine could enter the cell and disrupt the command center machinery of the cell. Some of these uses are in the minds of scientists and some are in experiments right now. But they certainly are not in clinical trials. Those that exist are only being tested in animal models.
Q: In summary, how optimistic are you about the future of brain tumor therapy?
A: I believe that in 10 or 15 years the field will be quite different. I believe that when we do imaging of a patient with a brain tumor, we will use a much more powerful form of MRI than we currently use. It will not only show structural images of where the tumor is and what it is pressing against, but the MRI itself – even without a biopsy -- will tell us the gene fingerprint of the tumor. And from this fingerprint, we will be able to know the type of tumor and its grade.
With knowledge of a patient's gene fingerprint, we will be able to provide optimal treatment that is tailored to that individual patient. If there are seven common fingerprints in glioblastoma, for example, we may well end up with a particular therapy for each type. This treatment could come in the form of immunotherapy or a vaccine, or it could involve nanotechnology. It will probably be delivered intravenously. And whether it is involves immunotherapy or nanotechnology, it will be very specific for the tumor and will deliver some kind of anti-cancer agent only to the tumor cells.
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The UC Brain Tumor Center treats hundreds of patients from the Greater Cincinnati region and beyond each year. The multidisciplinary center, which includes specialists in neurosurgery, radiology, radiation oncology, otolaryngology, internal medicine and physical medicine and rehabilitation, is committed to evidence-based medicine, compassionate care, research, and the utilization of emerging therapies and technologies.
The UC Neuroscience Institute, a regional center of excellence, is dedicated to patient care, research, education, and the development of new treatments for stroke, brain and spinal tumors, epilepsy, traumatic brain and spinal injury, Alzheimer's disease, Parkinson's disease, multiple sclerosis, disorders of the senses (swallowing, voice, hearing, pain, taste and smell), and psychiatric conditions (bipolar disorder, schizophrenia, and depression).
The Mayfield Clinic is recognized as one of the nation's leading physician organizations for clinical care, education, and research of the spine and brain. Supported by 20 neurosurgeons, three neurointensivists, an interventional radiologist, and a pain specialist, the Clinic treats 25,000 patients from 35 states and 13 countries in a typical year. Mayfield's physicians have pioneered surgical procedures and instrumentation that have revolutionized the medical art of neurosurgery for brain tumors and neurovascular diseases and disorders.