U.S. researchers advocate national strategic approach to therapeutic cancer vaccines

ScienceDaily (June 8, 2011) — Vaccines that save lives by preventing disease have been around for centuries. Now, new vaccines that treat cancer are being developed, but how they will be combined with existing treatments is not clear.

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Researchers at the University of Michigan Health System recommend that a national strategy be developed for bringing therapeutic cancer vaccines to patient care, so that cancers with less effective treatment options are priority targets.

"Vaccines that prevent disease have profoundly changed the lives of billions of people around the world," says Matthew M. Davis, M.D., MAPP, associate professor of pediatrics and internal medicine at the University of Michigan Medical School. "A national strategy for therapeutic cancer vaccines would help emphasize development and regulatory approval for vaccines targeting cancers that currently do not have other good therapeutic options."

Davis and co-author Elias J. Dayoub, a student at the U-M Medical School, published a commentary in the June 8 theme issue on cancer of the Journal of the American Medical Association.

When germs such as viruses or bacteria enter the body, the human immune system recognizes those germs as something abnormal and attacks them. Preventive vaccines use this natural response to prime the body's immune system so it can respond to bacteria such as pertussis (the cause of whooping cough) or viruses such as polio and measles.

With cancer cells, however, it is hard for the immune system to detect the "invaders," since they are the human body's own cells gone bad. Therapeutic cancer vaccines can enable the immune system to recognize undetected harmful cells and generate a response to fight back.

Lung cancer, pancreatic cancer and types of leukemia's all have lower survival rates than many other cancers because they respond poorly to currently available chemotherapy, radiation and surgery.

More than 200,000 Americans died from these cancers in 2010 -- more deaths than from breast, prostate and colon cancer combined. Davis suggests that therapeutic vaccines can be used to improve the survival rates of patients with leukemia, lung cancer and pancreatic cancer and also for less common tumors that have similarly poor survival rates.

In 2010, the first cancer therapeutic vaccine was approved for specific forms of prostate cancer. Davis calls it "a major milestone for the entire class of therapeutic cancer vaccines in the United States."

Current research suggests it may be easier for scientists to develop specific vaccines, but Davis emphasizes that what is scientifically easiest may not necessarily benefit the broadest and largest groups of patients.

"While pharmaceutical research and development clearly can lead to exciting advances in care, it may take a strategic plan to help channel creative energy and effort into certain products that maximize benefit for the greatest number of patients over the shortest time frame," says Davis.

A strategic plan could include targeted funding for research and clinical trials that test specific vaccine candidates, explains Davis.

With currently available treatments, two out of every three people in the United States who are diagnosed with cancer survive for at least five years, according to the National Cancer Institute. Complications from these treatments can reduce patients' quality of life, though. Vaccines may potentially offer fewer side effects.

"While it is too early to claim success for therapeutic cancer vaccines, they offer patients and families facing cancer a new ray of hope," concludes Davis.

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Mechanism discovered for health benefit of green tea, new approach to autoimmune disease

ScienceDaily (June 3, 2011) — One of the beneficial compounds found in green tea has a powerful ability to increase the number of "regulatory T cells" that play a key role in immune function and suppression of autoimmune disease, according to new research in the Linus Pauling Institute at Oregon State University.

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This may be one of the underlying mechanisms for the health benefits of green tea, which has attracted wide interest for its ability to help control inflammation, improve immune function and prevent cancer.

Pharmaceutical drugs are available that perform similar roles and have been the subject of much research, scientists say, but they have problems with toxicity. A natural food product might provide a long-term, sustainable way to accomplish this same goal without toxicity, researchers said.

"This appears to be a natural, plant-derived compound that can affect the number of regulatory T cells, and in the process improve immune function," said Emily Ho, an LPI principal investigator and associate professor in the OSU Department of Nutrition and Exercise Sciences.

"When fully understood, this could provide an easy and safe way to help control autoimmune problems and address various diseases," Ho said.

The findings have been published in Immunology Letters.

There are many types of cells that have different roles in the immune system, which is a delicate balancing act of attacking unwanted invaders without damaging normal cells. In autoimmune diseases, which can range from simple allergies to juvenile diabetes or even terminal conditions such as Lou Gehrig's disease, this process goes awry and the body mistakenly attacks itself.

Some cells exist primarily to help control that problem and dampen or "turn off" the immune system, including regulatory T cells. The number and proper function of those regulatory T cells, in turn, is regulated by other biological processes such as transcription factors and DNA methylation.

In this study, OSU scientists did experiments with a compound in green tea, a polyphenol called EGCG, which is believed to be responsible for much of its health benefits and has both anti-inflammatory and anti-cancer characteristics. They found it could cause a higher production of regulatory T cells. Its effects were not as potent as some of those produced by prescription drugs, but it also had few concerns about long-term use or toxicity.

"EGCG may have health benefits through an epigenetic mechanism, meaning we aren't changing the underlying DNA codes, but just influencing what gets expressed, what cells get turned on," Ho said. "And we may be able to do this with a simple, whole-food approach."

Laboratory studies done with mice, Ho said, showed that treatment with EGCG significantly increased the numbers and frequencies of regulatory T cells found in spleen and lymph notes, and in the process helped to control the immune response.

"Epigenetic regulation can be potentially exploited in generating suppressive regulatory T cells for therapeutic purposes, and is of significant clinical importance for the suppression of autoimmune diseases," the researchers said in their study.

The research was done by scientists from OSU, the University of Connecticut, and Changwon National University in South Korea. The work was supported by the National Institute of Environmental Health Sciences and the Oregon Agricultural Experiment Station.

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New clinical trial to test novel approach to treat triple-negative breast cancer

ScienceDaily (June 2, 2011) — A multicenter clinical trial led by a researcher at the University of Maryland Marlene and Stewart Greenebaum Cancer Center will evaluate a new approach to treat triple-negative breast cancer, an often-aggressive type of cancer that is more common among African-Americans and young women. The study will help researchers determine if an experimental drug, entinostat, can reprogram tumor cells to express a protein called an estrogen receptor to make them sensitive to hormone therapy.

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Saranya Chumsri, M.D., an oncologist at the Greenebaum Cancer Center and assistant professor of medicine at the University of Maryland School of Medicine, is the principal investigator of the newly opened National Cancer Institute-funded study. The trial is based on laboratory studies by Angela H. Brodie, Ph.D., an internationally recognized University of Maryland breast cancer researcher, and her colleagues. Their research, recently published in the journal Cancer Research, found that entinostat can cause triple-negative breast cancer cells to become sensitive to a hormone therapy such as an aromatase inhibitor. Dr. Brodie pioneered the development of aromatase inhibitors, a class of breast cancer drugs that reduces the level of estrogen produced by the body, thereby cutting off the fuel to cancer cells.

In this Phase II trial, doctors will treat newly diagnosed postmenopausal patients with entinostat and an aromatase inhibitor called anastrozole (Arimidex) before they have surgery to remove their cancer. Researchers will analyze tissue from the tumor and blood samples to evaluate whether the treatment is effective. After surgery, patients will receive standard treatment, such as chemotherapy and radiation.

"We hope that entinostat will make the tumor cells more sensitive to the drug anastrozole, causing the tumor to shrink or, at the very least, stop growing," Dr. Chumsri says. "For patients with triple-negative breast cancer, chemotherapy is currently the only drug treatment option, and it has a lot of side effects compared to hormone therapies like anastrozole."

Triple-negative breast cancer is unique in that it lacks three common receptors in the cell -- estrogen, progesterone or human epidermal growth factor 2 (HER2), which are the targets of drugs widely used today to treat breast cancer. As a result, this cancer can be very difficult to treat; it doesn't respond to therapies that target estrogen and progesterone receptors, such as tamoxifen (Nolvadex), fulvestrant (Faslodex) and aromatase inhibitors (Femara, Arimidex and Aromasin), or to HER2-targeted therapies such as trastuzumab (Herceptin) and lapatinib (Tykerb).

About 15 to 20 percent of breast cancers are triple-negative. For unknown reasons, there is a higher prevalence of this type of breast cancer among African-Americans, young women and women with the BRCA1 gene mutation. African-American women are twice as likely as white women to have this type of cancer, which can be very aggressive and spread to other parts of the body, such as the lungs, liver and brain.

The clinical trial is based on laboratory studies by Dr. Brodie, a professor of pharmacology and experimental therapeutics, and Gauri J. Sabnis, Ph.D., an assistant professor of pharmacology and experimental therapeutics, at the University of Maryland School of Medicine, in collaboration with Saraswati Sukumar, M.S., Ph.D., a professor of oncology and pathology at the Johns Hopkins University School of Medicine. Their research showed that entinostat can sensitize triple-negative breast cancer cells to treatment with an aromatase inhibitor, and when combined with an aromatase inhibitor, also reduce the growth and spread of tumors in animal models.

"Adding to her long list of remarkable achievements, Dr. Brodie has continued her research into aromatase inhibitors, searching for ways to overcome tumors' resistance to treatment," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine. "This multicenter clinical trial led by Dr. Saranya Chumsri is an excellent example of how our scientists turn discoveries made in the lab into new treatments that may benefit patients."

Entinostat is an oral, selective histone deacetylase (HDAC) inhibitor. This anti-cancer agent is being developed by Syndax Pharmaceuticals, Inc., and is being investigated in other clinical studies for the treatment of advanced estrogen receptor-positive breast cancer, advanced non-small-cell lung cancer, advanced colorectal cancer and Hodgkin's lymphoma.

Triple-negative breast cancer patients in this clinical trial will take entinostat weekly and anastrozole once daily for two to four weeks while they are waiting to have surgery. Researchers will use blood tests and tissue analysis of tumors to evaluate the effectiveness of the combination therapy.

Researchers hope to enroll a total of 41 patients at 20 sites, including the University of Maryland Greenebaum Cancer Center. The centers involved in the study are affiliated with the University of Chicago Phase II study research consortium and the California Cancer Consortium.

Dr. Chumsri says that if the results of this trial are positive, researchers plan to launch a larger study to test the combination therapy on women whose cancer has metastasized to other parts of the body. "These women have limited treatment options. Hopefully, this treatment would give them a longer period in which their cancer is not progressing, with only minimal side effects compared to chemotherapy," she says.

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Study reveals need for personalized approach in treatment of acute myeloid leukemia

ScienceDaily (May 16, 2011) — A new discovery in mice by researchers at Wake Forest Baptist Medical Center may one day allow doctors to spare some patients with acute myeloid leukemia (AML) from toxic treatments, while also opening the door for new therapeutic research.

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AML, the most common form of acute leukemia seen in adults, is an aggressive form of cancer that primarily affects the elderly. Despite years of research, outcomes for most patients remain poor, particularly for one subset of patients with a specific mutation of the FLT3 receptor.

At a microscopic level, each cell's surface is covered in proteins that allow for signals on the outside of a cell to "turn on" various activities inside that cell. FLT3 is one of those receptor proteins. Mutations of the FLT3 receptor are among the most common mutations seen in the disease -- affecting about 20 to 30 percent of AML patients -- and have been associated with worse prognosis.

A new study, published recently in the journal Experimental Hematology, reveals that one particular mutation of the FLT3 receptor, called internal tandem duplication (ITD), alters the patient's responsiveness to standard therapy.

"This research uses a mouse model to define the changes in chemotherapy response that the presence of the FLT3-ITD causes," said Timothy S. Pardee, M.D., Ph.D., an assistant professor of hematology and oncology and lead author of the study. "While its affect on prognosis has been well documented, its affect on therapy response has been poorly understood."

Pardee and colleagues used mice that had leukemia, either with or without the FLT3-ITD, to examine the effects of the mutation on responsiveness to two drugs used in combination as standard chemotherapy treatment for AML patients: cytarabine and doxorubicin. Both drugs work by altering the DNA of cells in different ways, causing them to essentially commit suicide.

The researchers found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin, but makes them extra sensitive to cytarabine, when the drugs are administered separately. More importantly, the mutation causes the cells to be resistant overall to the combination of the two drugs, the most common clinical application.

When the mutation occurs, it is a cancer-initiating event. The receptor is no longer able to turn itself off, so it continuously signals the cells to grow and repair damage, such as the damage intentionally caused by doxorubicin.

"The mice who had this mutation seemed to be able to repair certain kinds of DNA damage, specifically, the double strand DNA breaks that the doxorubicin creates," Pardee said. "The FLT3-ITD mutation is telling the cell to repair itself at a pace that keeps up with the amount of damage the drug is designed to cause. If you have a cancer cell that you're trying to kill by doing a certain type of damage and that cell is better at repairing that kind of damage, you have to do more damage to get the cell to die. The mice that were treated with just doxorubicin died at the same rate as those that received no treatment at all."

And, while the FLT3-ITD mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

"It's almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell," Pardee said. "When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it."

Doxorubicin falls into a class of extremely toxic drugs known as anthracyclines. As with other chemotherapy agents, they are known to cause hair loss. However, they are also known to suppress normal cells in the bone marrow and to cause cardiac toxicity. Treatment with drugs of this class can directly injure the heart muscle and sometimes even cause heart failure, Pardee explained.

"Virtually every AML patient in America and Europe who can handle this combination of drugs will receive this standard treatment under current practice guidelines," Pardee said. "More studies are needed to determine the applicability of these findings in humans, but this study shows, in an animal model, that those with the FLT3-ITD mutation are deriving no benefit from the addition of doxorubicin.

"We're hopeful that in the future, these findings will lead to more personalized patient care," he said. "The 'one-size-fits-all' approach to treating AML needs to be re-examined."

In addition to investigating ways to personalize approaches in treatment, Pardee said that future research may focus on developing drugs that can be combined with cytarabine in patients with this mutation and be effective, perhaps by inhibiting the FLT3 receptor or working in ways other than creating double strand DNA breaks.

This research was funded by several sources including the Leukemia and Lymphoma Society, National Cancer Institute, and Wake Forest University Comprehensive Cancer Center. Johannes Zuber, M.D., and Scott W. Lowe, Ph.D., of the Cold Spring Harbor Laboratory, in New York, appear as co-authors on the paper. Lowe is also affiliated with Howard Hughes Medical Institute, in New York.

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