New Vaccine, Research Shows Hope Against Deadliest Brain Tumors by Gina Shaw Over the past few decades, many types of cancer have been transformed from diagnoses that meant certain death to often-chronic diseases, manageable if not curable. From the 1960s through the 1990s, survival rates have climbed dramatically for cancers such as childhood leukemia, Hodgkinís disease, testicular cancer, melanomas and prostate cancer. One type of cancer that remains almost 100 percent fatal, however, is brain cancer. The most deadly, and most common, type of brain tumor is the malignant gliomaóa family of cancers that originate in the glial cells, supportive tissue that surrounds and insulates the brainís nerve cells. Of the approximately 17,000 new brain cancers diagnosed each year in the United States, about half are malignant gliomas. These tumors are also among the most difficult cancers to treat. ìEven with aggressive therapy, including surgical resection followed by radiation therapy and chemotherapy, the median length of survival is less than one year,î said Dr. Keith Black, director of the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles. But some promising new approaches, developed at the Dunit z Institute and other medical centers, may soon offer the best hope yet of extending the survival of people with malignant gliomas. Black and Dr. John Yu, who co-direct the instituteís Comprehensive Brain Tumor Program, have developed a ìbrain cancer vaccineî that has shown great promise in early trials. Brain Cancer Vaccine The vaccine uses dendritic cellsóimmune cells that scout out foreign proteins, clean them up, and tag them as invaders for the immune systemís T-cells to attackóto launch an immune response that kills the glioma cells. (Gliomas are particularly deadly because they appear to have multiple ways of flying under the immune systemís radar.) After introducing the dendritic cells to the patientís tumor cells in a laboratory culture, neurosurgeons inject the resulting vaccine and the dendritic cells recognize the tumor cells as invaders, sounding the alarm in the patientís immune system. Unlike traditional vaccines for things such as measles and flu, which immunize patients against a disease before they develop it, the brain cancer vaccine launches the bodyís immune response against a disease it already has. ìWeíve completed three out of four phase one/phase two clinical trials, treating high-grade gliomas with a dendritic cell-based vaccine,î said Black. ìAt this point, about half the patients show evidence that their immune system is developing the ability to recognize the tumor and attack malignant cells selectively. Thatís the hallmark of a cellular immune response.î And even in some patients whose disease has recurred, requiring further surgery, surgical intervention has revealed some promising signs about the vaccineís effectiveness. ìAbout half of the patients we took back into surgery showed a significant infiltration of T-cells into the tumor,î Black said. ìNormally when we look at recurrence of gliomas, we donít see any active immune cells infiltrating into the tumor.î Although itís far too early to say anything definitive, early evidence also looks promising for the most important result of the vaccine: patient survival. ìIn our phase one trials of patients with recurrent glioblastoma who received the vaccine, weíve found that the median survival for those patients is greater than four years,î said Yu. Thatís remarkable when you consider that survival time for these patients is often measured in weeks. ìBy contrast, patients with recurrent glioblastoma who were not treated with the vaccine had a median survival of only 33 weeks,î Yu said. These dramatic numbers, he hastened to add, were based on very small populations and were not done in the randomized setting of a phase three trial. ìStill, it was significant enough to pursue studies in a randomized phase three setting,î said Yu. ìWe havenít come to any conclusions, but the findings are encouraging.î Yu and Black hope to begin a multi-institutional phase three trial of the vaccine later this year. But what about the other 50 percent of patientsóthe ones whose immune systems didnít develop an ability to recognize and attack tumor cells after receiving the vaccine? That is another sign of just how tricky gliomas can be. ìThere are several mechanisms by which a tumor can subvert the immune system,î explained Yu. ìWeíre dicing out these mechanisms in the lab. Once weíve identified all the specific mechanisms gliomas use to hide from the immune system, we hope to be able to examine the patient population and determine which ones have which mechanisms of immunosuppressionóor perhaps all of themóand develop specific strategies of reversing those mechanisms.î Role of Neural Stem Cells One of the reasons why gliomas recur so persistently is that although surgeons can remove a large bulk of the primary tumor, these cancers have a natural tendency to expand, infiltrate surrounding tissue, and migrate widely into the normal brain, leaving satellites of tumor cells that elude radiation, chemotherapy and gene therapy. The Dunitz Institute is one of several medical centers now exploring the possibility that neural stem cellsóthe undifferentiated, immature progenitor cells that have the potential to develop into multiple types of human cellsócan be used to deliver chemotherapy agents directly to these tumor cell satellites. When implanted into the brains of mice with gliomas, neural stem cells migrate throughout the tissue, aggressively chasing down the infiltrating satellite tumor cells, while at the same time surrounding the border of the invading tumor. ìIn one study, we inoculated mice with neural stem cells engineered to express the anti-tumor agent interleukin-12, which made the tumor reservoirs more susceptible to destruction by the bodyís T-cell,î explained Yu. In the other study, the scientists used the neural stem cells to deliver a cell-signaling molecule known as TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) directly to the tumor, where it set off the process of programmed cell death known as apoptosis. Why do neural stem cells track down tumor cells in the brain anyway? One theory is that the cells that cause brain tumors may, in fact, be relatives of neural stem cells. ìPeople have noticed that some brain tumors appear to be undifferentiated and primitive, not yet designated to be a particular cell typeóas stem cells are,î said Dr. Harley Kornblum, a pediatric neurologist, associate professor of pharmacology and pediatrics at UCLA, and a researcher at UCLAís Jonsson Comprehensive Cancer Center. A doctoral medical student working with Kornblum, Houman Hemmati, found that cells taken from brain tumors behaved very similarly to neural stem cells when in culture, with two important differences: They divide much more rapidly, and they donít differentiate as readily. ìWhen you make a neuron in your brain, that cell doesnít divide again, but the neuron-like stem cells from a brain tumor do continue to divide,î said Kornblum. Although Kornblum was initially more interested in a brain tumor most commonly found in children called a medulloblastoma, research pointed him another way. ìThe data really showed us that the tumors that behaved most like neural stem cells were actually gliomas,î he said. ìThis was surprising at first because gliomas are associated with glial cells, which have been thought to be more differentiated. But what research is showing us is that many glial cells are actually neural stem cells in disguise, and they have the capability of being stem cells.î For example, if you culture the genes typical of an astrocyte, a particular type of glial cell, in the right conditions, they donít just form other astrocytesóthey can also be coaxed to form other cell types of the brain. In addition to providing a possible explanation for why neural stem cells are drawn to tumor cells in the brain, making them a promising delivery service for anti-cancer agents, the idea that neural stem cells bear a close relationship to the tumor cells found in gliomas may offer other potential avenues for treating brain tumors. ìWeíve learned a lot about what genes cause neural stem cells to proliferate,î said Kornblum. ìCould those same genes be responsible for glioma and other tumor cell proliferation? If so, we could try to inhibit the function of those genes. One way to do that would be to inject a virus into the area of the tumor thatís designed to destroy the messenger RNA that makes the protein.î The problem, of course, is that if the genes responsible for neural stem cell proliferation are the same genes that spark the growth of gliomas and other tumor cells, shutting those genes down would likely shut down the growth of both tumors and normal brain cells. ìThe question is, can you avoid this result by doing localized treatment, or can you get away with inhibiting the proliferation of normal neural stem cells for a short period of time until you get rid of the tumor?î Kornblum asked. ìWe donít know the answer to that yet.î Crossing Blood-Brain Barrier Another reason that gliomas and other brain tumors have proven so difficult to treat involves the brainís natural defense system that, for the most part, is a very useful thing. The so-called ìblood-brain barrierî is a network of capillaries embedded in the brain that act as a defense system, preventing foreign agents in the blood from getting through to the brain. In the case of things such as toxins and bacteria, the blood-brain barrier provides important protection against disease and infection, but because the barrier doesnít distinguish between bacteria and, say, a chemotherapy agent, many anti-cancer drugs have a hard time reaching the brain. According to Cedars-Sinaiís Black, as many as 98 percent of drugs targeted at brain tumors cannot reach the brain effectively. A pioneer in the understanding of the blood-brain barrier, Black has discovered an essential difference between the molecular structure of capillaries in tumors and capillaries in the normal brain. ìBy exploiting the biochemistry of the blood-brain barrier, we can selectively modulate delivery of drugs across that barrier to treat gliomas, without compromising the surrounding tissue,î he said. Black has developed a drug delivery system that opens the capillaries of the tumor, enabling anti-cancer drugs to enter the malignant cells without attacking the normal surrounding tissue. ìIn animal trials, weíve demonstrated that we can increase drug delivery between three- and 12-fold using this method,î Black said. A small phase one trial in humans is set to begin this summer. ìWeíre very excited about this method. We think it holds real promise in increasing the ability of therapeutic compounds to attack brain tumors.î Gina Shaw is the medical writer for The Washington Diplomat.