RxPG News : Glioblastoma Multiforme

Signaling pathway discovered which may help find treatment for glioblastoma multiforme

Sat, 14 Aug 2010 21:28:59 PST

( from http://www.rxpgnews.com ) Malignant gliomas are the most common subtype of primary brain tumor – and one of the deadliest. Even as doctors make steady progress treating other types of solid tumor cancers, from breast to prostate, the most aggressive form of malignant glioma, called a glioblastoma multiforme or GBM, has steadfastly defied advances in neurosurgery, radiation therapy and various conventional or novel drugs.

But an international team of scientists, headed by researchers at the Ludwig Institute for Cancer Research (LICR) at the University of California, San Diego School of Medicine, reports in the August 15 issue of Genes & Development that they have discovered a new signaling pathway between GBM cells – one that, if ultimately blocked or disrupted, could significantly slow or reduce tumor growth and malignancy.

More than other types of cancer, GBMs are diverse assemblages of cell subtypes featuring great genetic variation. Anti-cancer therapies that target a specific mutation or cellular pathway tend to be less effective against such tumor heterogeneity.

"These myriad genetic alterations may be one of the primary reasons why GBMs are so lethal," said Frank Furnari, PhD, associate professor of medicine at the UCSD School of Medicine and an associate investigator at the San Diego branch of the LICR.

Even with maximum treatment effort, the median patient survival rate for a diagnosed GBM is nine to 12 months – a statistic that has not changed substantially in decades.

However, Furnari, along with postdoctoral fellows Maria-del-Mar Inda and Rudy Bonavia, and Webster Cavenee, PhD, professor of medicine and director of the San Diego LICR branch, and others noted that in GBMs only a minority of tumor cells possess a mutant form of the epidermal growth factor receptor (EGFR) gene. These cells drive the tumor's rapid, deadly growth. "Most GBM tumor cells express wild-type or normal EGFR," said Furnari. "Yet when expressed by itself, wild-type EGFR is a poor oncogene."

The scientists discovered that tumor cells with mutant EGFR secrete molecules that cause neighboring cells with wild-type EGFR to accelerate their tumorigenic growth. "The mutant cells are instructing other less malignant tumor cells to become more malignant," said Furnari.

This signaling pathway between GBM tumor cells was not known and presents a new and potentially promising chink in the armor of glioblastomas. "If we can inhibit or block this cellular communication, the tumor does not grow as quickly and may be more treatable," Furnari said. Researchers have already identified two molecules that appear to trigger EGFR activity on non-mutant tumor cells.

The findings may also provide clues in the bigger picture of how GBMs and other cancers survive and thrive. "There are other types of mutations and growth factor receptors in tumors," Furnari said. "We need to look at how they communicate. Historically, brain tumor research has focused upon the most abundantly expressed mutations, but this research suggests minority mutations play very important roles as well."

The researchers' next step will be to create a mouse model with mixed cell glioblastoma that can be used to test different therapeutics, inhibitors and blocking agents.

Significant vaccine-enhanced immune response in malignant brain tumour

Tue, 15 Jul 2008 01:21:44 PST

( from http://www.rxpgnews.com ) Researchers conducting a clinical trial of a dendritic cell vaccine designed to fight malignant brain tumors called glioblastoma multiforme (GBM) have found a correlation between the "intensity" of a patient's immune response and clinical outcome, according to an article in the July 15 issue of the journal Cancer Research.

While other studies have suggested a link, this is believed to be the first to show direct and continual proportionality between the strength of anti-tumor responses and clinical benefits in cancer patients. This also may be the first documentation of a definite immune response/patient outcome correlation that can be credited to tumor-altering therapeutic interventions.

"Fifty-three percent of patients in our study exhibited a significant vaccine-enhanced immune response. Compared to non-responders or those with limited responses, the vaccine responders had significantly longer times to tumor progression and longer survival," said Keith L. Black, M.D., chairman of Cedars-Sinai's Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute. Black is one of the article's authors.

The study also substantiates a finding previously reported by the researchers: Dendritic cell vaccination and chemotherapy work synergistically to improve treatment. Time to tumor progression increased significantly when vaccination was followed by chemotherapy, compared to vaccination alone.

"No other vaccine trial in cancer patients has shown the kind of progressive correlation between immune responses and clinical outcomes that we found," said Christopher J. Wheeler, Ph.D., research scientist at the MDNSI and the article's first and corresponding author. "We looked at whether the correlation was present after vaccination alone or after post-vaccine chemotherapy. It was evident only after post-vaccine chemotherapy. This leads us to believe that while T-cell activity may not result in net destruction of the tumor it is fundamentally changing the tumor into one that is predominantly comprised of chemosensitive cells rather than chemoresistant cells."

The findings also appear to give scientists a way to more quickly evaluate future vaccine-related research.

"The demonstration that the magnitude of immune response is directly related to survival of patients gives us a very good tool or 'surrogate marker' for clinical benefit. If we can improve the immune response of our vaccine, we can anticipate that the clinical benefit will be improved as well. This allows us to fine-tune our vaccine in more of a real-time way," said John S. Yu, M.D., director of Surgical Neuro-oncology at Cedars-Sinai, principal investigator of the clinical trial and senior author of the article.

This study centered on the immune responses of 32 patients enrolled in a Phase II clinical trial. Seventeen patients had a significant positive response after three vaccinations; 15 showed no such responsiveness. Average time to tumor progression (based on when tumor volume increased by about 25 percent on MRI scans) was about 308 days among responders, compared to 167 days for non-responders. Average length of survival (based on date of death or date of last contact with surviving patients) was about 642 days (about 21 months) among responders, compared to 430 days (about 14 months) for non-responders.

Forty-one percent of vaccine responders, compared to seven percent of non-responders, survived at least two years. All patients in the trial had longer time to progression and longer time of survival, on average, than patients undergoing standard treatment without vaccination, although their pre-vaccine disease courses were similar.

The vaccine was first used experimentally in patient treatment in May 1998, and numerous studies have been conducted to fine-tune the therapy and combine it with other cancer-killing treatments.

Upon founding the Maxine Dunitz Neurosurgical Institute in 1997, Black led the development of the dendritic cell vaccine because gliomas and other cancer cells are not readily detected or attacked by the immune system. Dendritic cells are the immune system's most powerful antigen-presenting cells – those responsible for helping the immune system recognize invaders.

When a tumor is surgically removed, proteins are collected, cultured and introduced in a Petri dish to dendritic cells taken from the patient's blood. The new, "educated" dendritic cells are then injected into the patient where they are intended to recognize and destroy lingering tumor cells. Patients receive three vaccinations at two-week intervals. A fourth vaccination is given six weeks after the third.

Simultaneous implantation of radioactive seeds and chemotherapy wafers promising in glioblastoma multiforme treatment

Sun, 20 Jan 2008 09:31:57 PST

( from http://www.rxpgnews.com ) In the battle against malignant brain tumors, dual implantation of radioactive seeds and chemotherapy wafers following surgery showed promising results in a study led by specialists at the Neuroscience Institute at the University of Cincinnati (UC) and University Hospital.

The study, published in the February issue of the Journal of Neurosurgery, revealed that patients treated with simultaneous implantation of radioactive seeds and chemotherapy wafers following removal of glioblastoma multiforme (GBM) experienced longer survival compared with patients who had implantation of seeds or wafers alone.

The study was the first ever to explore the combination treatment in patients suffering from recurrent GBM. The early phase trial involved 34 patients, all of whom underwent the same treatment. No patients received a placebo. The study’s purpose was to assess the safety and effectiveness of the highly localized, combination therapy.

The median survival was 69 weeks, and nearly a quarter (eight) of the study’s patients survived two years. In comparison, patients with recurrent GBM who undergo conventional treatment (chemotherapy) have a median survival of approximately 26 weeks.

“Treatment of recurrent GBM presents a major challenge to neurosurgeons and neuro-oncologists,” said investigator Ronald Warnick, MD, chairman of the Mayfield Clinic and professor of neurosurgery at UC. “Glioblastoma is an aggressive, highly malignant tumor with unclear boundaries. Because of its diffuse nature, surgeons are unable to remove it completely, and it regrows in the majority of patients. Our aim is to find a way to keep the infiltrating glioblastoma cells from growing into adjacent, healthy tissue.”

Because most GBM tumors recur within two centimeters of the initial tumor margin, Warnick and his team have focused their efforts on highly localized treatment.

Previously they studied the implantation of permanent, low-activity iodine-125 seeds following the surgical removal of the tumor. The seeds, housed in a titanium casing filled with iodine-125 (a radioisotope of iodine) are the size of grains of rice. The seeds are left in the brain cavity permanently, and radiation is delivered for six months.

Other institutions have studied implantation of chemotherapy wafers, which are the size of a nickel. The wafers contain BCNU (carmustine), a standard form of chemotherapy. The wafers are placed along the surface of the brain following removal of the tumor.

Combining radiation seeds and chemotherapy wafers was a logical next step, Warnick said. The combination of seeds and wafers “appears to provide longer survival” compared with studies of seeds and wafers alone, he said, and “disease progression also seems to be further delayed.”

Warnick cautioned that the effectiveness of the combination therapy is not definitive, because the study did not include a control group.

In the most notable downside to the dual therapy, brain tissue death developed in nearly 25 percent of patients and appeared to be higher than in treatment with seeds or wafers alone. The tissue death was treated successfully with surgery or hyperbaric oxygen therapy, however, and did not affect survival.

Future studies will involve using a combination of seeds and wafers to treat patients newly diagnosed with GBM, Warnick said.

New vaccine to fight glioblastoma multiforme developed

Tue, 02 May 2006 22:40:00 PST

( from http://www.rxpgnews.com ) A vaccine to fight an aggressive form of brain tumour has been developed by US scientists, who say it can delay progression of the cancer.

Scientists say the vaccine increased survival rates by at least 18 months for the 23 patients of glioblastoma multiforme that it was tested on, reported the online edition of BBC News.

One in four brain tumours are glioblastoma multiforme (GBM), the most aggressive form of the primary brain tumours known collectively as gliomas.

These tumours arise from the supporting glial cells of the brain. These growths do not spread throughout the body like other forms of cancer, but cause symptoms by invading the brain.

The developed vaccine, an easy-to-use "off-the-shelf" treatment, could potentially help half of all patients with glioblastoma multiforme (GBM), said Amy Heimberger, assistant professor of neurosurgery at the MD Anderson Cancer Center, Texas.

Trial results showed that the vaccine significantly delays the progression of tumours until the cancer finds a new way to grow. A larger trial of the vaccine, which works by targeting a protein thought to drive the tumour's spread, is now planned.

Discovery could change the way doctors treat glioblastomas

Fri, 11 Nov 2005 00:46:00 PST

( from http://www.rxpgnews.com ) Researchers at UCLA's Jonsson Cancer have identified key characteristics in certain deadly brain tumors that make them 51 times more likely to respond to a specific class of drugs than tumors in which the molecular signature is absent.

The discovery of the telltale molecular signature the expression of a mutant protein and the presence of a tumor suppressor protein called PTEN will allow researchers to identify patients who are likely to respond to the drug treatment before they undergo therapies that are not likely to work, said Dr. Paul Mischel, a UCLA associate professor of pathology and laboratory medicine and a Jonsson Cancer Center researcher.

Mischel and his colleagues write in an article in the Nov. 10 issue of the New England Journal of Medicine that the discovery could change the way doctors treat glioblastomas, the most common type of malignant brain tumor and one of the those lethal forms of cancer.

"In a biologically aggressive disease like glioblastoma, it's vital to be able to stratify patients up front so we can treat them with drugs that they are more likely to respond to," Mischel said. "This will help prevent patients from having therapies that are much more toxic and less beneficial. With the short survival times associated with glioblastoma, that is critical."

Between 8,000 and 10,000 new cases of glioblastoma will be diagnosed in Americans this year. Average survival is less than a year, according to the American Cancer Society. Although treatment may prolong life, most malignant brain tumors are not curable, making the search for better treatments even more urgent, Mischel said.

A protein called epidermal growth factor receptor (EGFR) is commonly amplified in glioblastoma, making it a prime focus for therapies. Drugs such as Tarceva and Iressa target EGFR, blocking the cell signals that drive amplification of the protein and speed cancer growth. A subset of glioblastoma patients responded to Tarceva and Iressa, but it was not clear what characteristics made them respond to these drugs. There had to be critical molecular factors that determined response, Mischel said.

He and his team set out to find the molecular determinants that indicated which patients would respond best to EGFR blockers. Previous UCLA research in brain and other cancers suggested that the key might be the interaction of the PTEN protein and a mutant protein called EGFRvIII. About half of patients with amplified EGFR also have this mutant protein.

The UCLA team and their collaborators studied a subset of 26 glioblastoma patients who either responded very well or very poorly to EGFR-blocking drugs and developed a way to test their brain tumor tissue for the presence of both the mutant and PTEN proteins. Mischel's team found that patients with both genetic variations were 51 times more likely to respond to EGFR blockers. They also lived five times longer after initiating therapy than those without the variation, surviving 253 days versus 50 days.

To confirm their promising work, Mischel and his team obtained tissue samples from 33 brain cancer patients treated at another facility without knowing who the responders were. They were able to replicate their results independently, confirming that those with both genetic variations were more likely to respond to EGFR-blocking drugs.

The study shows that glioblastoma patients can respond to targeted agents, and suggests that patients likely to benefit from treatment can be identified by molecular testing. The study also raised the possibility that patients whose tumors lack the genetic variations in the molecular signature could possibly be treated with drugs to make them more sensitive to EGFR blockers.

Of the 8,000 to 10,000 glioblastoma patients diagnosed each year, about 10 percent to 20 percent have the combination of the mutant and PTEN proteins, Mischel said. The next step is a prospective study determining the molecular signature of patients' tumors and directing those with the right protein combination to EGFR-blocking therapies. Mischel's team also is working to uncover the molecular signatures in the tumors of non-responders so they can determine what therapies might be most effective for them.

"This is a much more hopeful period now in cancer research," Mischel said. "Genomic and proteomic technologies are helping us begin to understand the underlying molecular features of disease, and new drugs are making it possible to safely and specifically target pathways that are altered in cancer cells. This was impossible five years ago. Glioblastoma is still a difficult disease, but the idea that it may be possible to induce long-term disease suppression gives us reason for hope."

The study, Mischel said, also may have important implications in other cancers.

"Many cancers have a similar combination of a mutant cancer-causing protein and either the expression or loss of the PTEN protein," Mischel said. "The interactions of the two may be important in determining response to targeted agents."

Glioblastoma Gene Variations Can Predict Treatment Response

Fri, 11 Nov 2005 00:20:00 PST

( from http://www.rxpgnews.com ) Screening glioblastoma brain tumors for two gene variations can reliably predict which tumors will respond to a specific class of drugs, a new study shows. The findings may lead to improved treatment for this devastating disease. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), and appears in the November 10, 2005, issue of the New England Journal of Medicine.*

Glioblastomas are the most common malignant brain tumors in adults, and they are notoriously difficult to treat successfully. "The survival with glioblastoma is usually a year on average, and that hasn't improved in a while, so this is a very serious and challenging disease," says Paul Mischel, M.D., of the David Geffen School of Medicine and Jonsson Comprehensive Cancer Center at the University of California , Los Angeles (UCLA), who led the study. While drugs are available to help treat glioblastoma, they often have minimal effect, and doctors usually have time to try only one or two treatments before the disease causes severe impairment. Glioblastomas feature many genetic variations that affect their response to different treatments. Researchers are trying to identify these genetic factors and to tease apart how they affect the disease in order to determine which patients are the most likely to benefit from specific drugs.

In the new study, Dr. Mischel and his colleagues performed genetic analysis on tissue from recurrent malignant glioblastoma patients, 26 of whom responded either very well or very poorly to the drugs erlotinib (Tarceva®) and gefitinib (Iressa®). These two drugs belong to a class called EGFR (epidermal growth factor receptor) kinase inhibitors, and both are currently approved by the by the U.S. Food and Drug Administration (FDA) to treat advanced lung cancer that has not responded to other treatments.

Based on results from other studies, the researchers hypothesized that variations in several different genes might play a role in the tumor's response to EGFR inhibitors. They looked for mutations in genes called EGFR and HER2/neu, and they analyzed the activity of EGFR, an EGFR variant called EGFRvIII, and a gene called PTEN. Many tumors not just brain tumors have mutations or abnormal activity of one or more of these genes, which help to control cell growth and other functions.

Glioblastomas that produced both EGFRvIII and PTEN were 51 times more likely to shrink when treated with EGFR inhibitors than tumors without this combination of proteins, the researchers found. Patients whose tumors expressed these proteins and who received an EGFR inhibitor went almost 5 times longer on average before their tumors progressed (243 days vs. 50 days) than those whose tumors did not express both of the proteins. In contrast, EGFR and HER2/neu activity had no effect on how tumors responded to these drugs. Similar results were found in tissues from another group of 33 glioblastoma patients who had taken part in a clinical trial of erlotinib at the University of California , San Francisco .

The findings suggest that both EGFRvIII and PTEN proteins are important for tumors to be susceptible to EGFR inhibitors, Dr. Mischel says. Their data further suggest that EGFRvIII may act to sensitize glioblastoma cells, while PTEN loss may act as a resistance factor. The researchers tested their results in several different cell models and repeatedly found that expression of these two proteins made the cells sensitive to EGFR inhibitors and that PTEN loss promoted resistance in those models.

The study shows that genetic analysis of glioblastomas can predict the tumors' sensitivity to specific drugs. Adjusting treatment based on each tumor's genetic activity could significantly prolong life for a subset of glioblastoma patients, Dr. Mischel says. It also may prevent patients from undergoing unnecessary and expensive treatments, and it could allow some people to be treated with the most effective therapy immediately, before the tumors can grow and develop new mutations that make them more difficult to treat.

Kinases are enzymes that play key roles in cell proliferation, metabolism, and other functions, and they are often overactive in cancer cells. Because cancer cells may become dependent on the persistent signals created by altered kinases in a way in which non-cancerous cells do not, kinase inhibitors such as EGFR inhibitors can often target cancer cells without seriously affecting the rest of the body. Therefore they cause fewer side effects than most other cancer drugs. The drug imatinib (Gleevec®), which is FDA-approved to treat chronic myeloid leukemia, is one of the early success stories for this kind of treatment.

The study also reveals important information about how glioblastomas and other tumors develop, Dr. Mischel says. Knowing that EGFRvIII and PTEN play critical roles in tumor response to treatment could lead to new combination therapies that target both proteins. Such therapies might also be beneficial for other types of cancer.

Screening for these factors also might allow researchers to better determine a treatment's effects in clinical trials, Dr. Mischel adds. Traditional clinical trials that do not take into account each tumor's genetic makeup often fail to show enough of an effect to warrant FDA approval for a drug because only a subset of patients respond well to the treatment.

The researchers are now planning prospective clinical trials to determine whether selecting treatment based on each tumor's genetic activity can lead to better patient survival. They also plan to continue looking for other tumor susceptibility factors, to develop new treatments that target those factors, and to try to learn how some patients become resistant to treatment. Researchers also need to develop their genetic screening techniques into a diagnostic test so that it can be available to all people with glioblastoma, Dr. Mischel says.

P-gp system let JV-1-36 pass into the brain to treat malignant glioblastomas

Tue, 23 Aug 2005 19:56:00 PST

( from http://www.rxpgnews.com ) A compound that kills cancer can sneak past the blood brain barrier, which protects the brain from foreign substances, to do its work in fighting a particularly invasive brain cancer, according to a new Saint Louis University animal study published in the Proceedings of the National Academy of Sciences Online Early Edition the week of Aug. 22.

"The bottom line is, if you can get drugs into the brain, you can cure brain cancer," says William A. Banks, M.D., professor of geriatrics in the department of internal medicine and professor of pharmacological and physiological science at Saint Louis University School of Medicine and a member of the research team.

The compound JV-1-36 is an antagonist of the hypothalamic growth hormone- releasing hormone, which has been found to cause cancerous tumors, such as malignant glioblastomas, to grow. The main known purposes of the hypothalamic growth hormone-releasing hormone usually are to trigger the hormone that makes children grow and affect how glucose is used in adults.

Researchers found that the P-gp system, an extra guardian located at the blood brain barrier that usually keeps anticancer drugs out of the brain, intercepted some of the JV-1-36 that was injected into mice but let much of it pass into the brain to treat cancer.

"The blood brain barrier is set up to very carefully patrol what it lets into the brain and what it keeps out. It makes these decisions based on the physicochemical properties," says Dr. Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.

"Most of our drugs that fight cancers are toxic to cancer cells and to other cells, too. That's why the blood brain barrier locks them out of the brain."

The research was done in collaboration with investigators at Tulane University School of Medicine in New Orleans, including Nobel Laureate Andrew V. Schally, Ph.D.

Dr. Banks said the findings are promising because they show a way to get drugs into the brain to treat cancer.

"There are times when there's a big difference between an animal model and the human condition. In terms of getting drugs across the blood brain barrier to fight cancer, there's not such a big difference. There's pretty much the same rules in any blood brain barrier be it in a mouse or human."

Laura Jaeger, the lead author of the study and a doctoral student in the department of pharmacological and physiological science at Saint Louis University, calls the findings "very positive and a good first step."

Combined gene therapy can eliminate glioblastoma multiforme

Mon, 15 Aug 2005 17:44:00 PST

( from http://www.rxpgnews.com ) Despite aggressive treatment, glioblastoma multiforme (GBM) the most common and deadly of brain cancers usually claims the lives of its victims within six to 12 months of diagnosis. Because GBM is so aggressive, the disease has been the target of a number of laboratory and clinical studies investigating the effectiveness of gene therapy to deliver novel therapies to the brain. In laboratory studies, this type of gene therapy has proved almost completely effective. But in clinical trials, it has had limited effectiveness.

To overcome these limitations, researchers at Cedars-Sinai Medical Center developed a large brain tumor model in laboratory rats that would more accurately predict the outcome of gene therapies in patients. In addition, they tested a genetically engineered virus to deliver two proteins directly to the brain. Their findings, reported in the August 15th issue of the journal Cancer Research, show that the majority of rats bearing large tumors were still alive six months after combined treatment with two proteins: RAdTK, a protein that kills cancer cells, and RAdFlt3L, which stimulates immune or dendritic cells in the brain.

"Our study shows that GBM tumors were completely eliminated in lab rats, likely because the two proteins increase the production of fully mature immune cells within the brain," said Maria Castro, Ph.D., co-director of the Gene Therapeutics Research Institute at Cedars-Sinai Medical Center and the senior author of the study. "This suggests that combined RAdFlt3L and RAdTK gene therapy may ultimately provide an effective treatment for patients undergoing clinical trials with GBM."

GBM tumors derive from brain astrocytes, a cell that normally supports and nurtures the brain's neurons. GBM grows quickly, often becoming very large before any symptoms are experienced. Once GBM is diagnosed, conventional treatment begins with surgery to remove as much of the tumor as possible and is then followed with radiation and/or chemotherapy to slow progression of the disease. But despite aggressive treatment, the tumors recur and patients usually die within a year's time.

To find another way to more effectively treat GBM, scientists have begun investigating the use of gene therapy to deliver novel therapeutic agents directly to the brain. Typically, these studies have tested the use of the suicide gene from the herpes simplex virus to develop a gene therapy approach that kills cancer cells in the presence of the antiviral drug gancyclovir. In laboratory studies, this type of gene therapy has proved almost 100 percent effective. But in clinical trials, it has had limited effectiveness, suggesting that the tumor mass is too large for the gene to effect long-term.

"Because we haven't seen the same positive results with gene therapy in clinical trials that we've seen treating GBM in laboratory rats, we realized that we needed to design a better model that more closely mimicked these tumors in patients," Castro said. "We also wanted to test whether a combined gene therapy strategy using proteins known to kill cancer cells or promote an immune response would work to eliminate these larger tumors in the rats."

Gene therapy is an experimental treatment that uses genetically engineered viruses to transport genes and/or proteins into cells. Just like a viral infection, the viruses work by tricking cells into accepting them as part of their own genetic coding. To make them safe, scientists remove the genetic viral genes that cause infection and engineer them so that they stop reproducing after they have delivered the therapeutic genes.

In this study, the researchers first developed a large GBM tumor model and implanted them in rats, allowing the tumor to grow for 10 days, when they were at their largest. Secondly, the investigators tested the effectiveness of various gene therapies used in combination or individually to see whether they would shrink or eliminate tumors.

To determine whether the size of the tumor significantly affected survival, the researches implanted both large and smaller GBM tumors in rats. The investigators then treated rats bearing GBM tumors with single or combined gene therapies (RAdTK and/or RAdFlt3l), or a saline placebo, as a control. They found that RAdTK treatment was 100 percent effective when delivered into small tumors, but only 20 percent effective when injected into large tumors. RAdFlt3L, on the other hand, was 60 percent effective if delivered into small tumors, but failed completely if injected into the large tumors. But when both RAdTK and RAdFlt3l were given in combination, the investigators found 70 percent of rats were still alive after six months of treatment and that the large GBM tumors had completely disappeared or shrank significantly.

"Just as with patients, our results emphasize that tumor size at the time of treatment is critical to predict clinical outcome," said Pedro Lowenstein, M.D., Ph.D., director of the Gene Therapeutic Research Institute at Cedars-Sinai. "Our model reproduces more closely the human disease condition where tumor size at the time of treatment determines how well the patient will respond to therapies."

"Our results show for the first time, that we could elicit a potent and stable anti-tumor immune response in the brains of rats bearing large GBM tumors," Castro said. "In these pre-clinical studies, combined gene therapy treatment with RAdTK and RAdFlt3L dramatically increased survival, without adverse immune reactions in the brain."