The Ovarian Cancer Research Fund has awarded a $900,000 research grant to Kunle Odunsi, MD, Department of Gynecologic Oncology, and his colleagues at Roswell Park Cancer Institute (RPCI) to collaborate on developing a promising vaccine to unleash the power of the immune system against cancer.
The prestigious award will help Dr. Odunsi and the RPCI research team* combine four different approaches, all designed to enhance the immune system's response to ovarian cancer.
Ovarian cancers are usually fatal within five years, despite extensive surgery and chemotherapy used to treat them. Dr. Odunsi's team previously tested an experimental anti-tumor vaccine in 18 women who had surgery to remove their ovarian tumors and who were receiving chemotherapy. The vaccine did not cure the cancer, but it did get the immune system to make antibodies and specialized cells with the capacity to kill ovarian cancer targets. The vaccine also appeared to lengthen the time until tumors reappeared.
Dr. Odunsi, who is a gynecologic cancer surgeon as well as a cancer researcher, feels that “one of the most challenging malignancies in women is cancer of the ovaries, because about 70% of patients present initially with advanced-stage disease.” Explaining that a vaccine might help, he said, “I look at all of us as cancer survivors. Cancer cells are constantly being formed, but the immune system keeps them in check.”
The new grant will allow Dr. Odunsi and his collaborators to combine their efforts to make the vaccine work better. For the vaccine to work, cancer cells must have a foreign protein on their surface so they stand out from normal cells. The collaborative effort will explore ways to keep cancer cells from hiding from the immune system and to heighten the immune system's ability to respond to the vaccine. Positive results may allow the researchers to move ahead to large-scale clinical trials.
Roswell Park Cancer Institute (RPCI), founded in 1898, is the nation's first cancer research, treatment and education center and is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation's leading cancer centers. RPCI has affiliate sites and collaborative programs in New York, Pennsylvania, and China. For more information, visit RPCI's website at http://www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or e-mail [email protected].
Experimental Vaccine May Fight Ovarian Cancer
The body's immune system provides constant surveillance for invaders. It detects and attacks tumor cells that may arise, but it restrains itself from attacking the cells of the body itself. When cells turn cancerous, their surfaces often display small changes that make the immune system suspicious that they are foreign. According to Dr. Kunle Odunsi, a clinical researcher and cancer surgeon at Roswell Park Cancer Institute, ovarian cancer cells sometimes display a new protein on their surface called NY-ESO-1. Researchers hypothesize that most of the time, the immune system pounces on cells that display NY-ESO-1 and kills them. If the immune system fails to notice the small change, the cells with NY-ESO-1 can grow into life-threatening ovarian tumors.
Some ovarian cancer cells might escape the immune system, because fewer than half the tumors display NY-ESO-1, and even in tumors that have it, the cells may not display it on their surfaces all the time, according to Dr. Odunsi. Another problem is that the immune system doesn't always recognize NY-ESO-1 as an important change, so it may not attack cells with the NY-ESO-1 protein on their surface.
Dr. Odunsi and his colleagues have made a therapeutic vaccine that trains the immune system to recognize and attack NY-ESO-1. The vaccine also puts the immune system on alert so it recognizes the small changes that signal that a cell may be cancerous. In order to make ovarian cancer cells as conspicuous as possible so the immune system will eliminate them, patients in the clinical trial will also receive a drug called decitabine. In preliminary studies by one of Dr. Odunsi's collaborators, decitabine encourages ovarian cancer to display NY-ESO-1.
RPCI Scientists Want to Unchain
the Immune System to Kill Tumor Cells
Protul Shrikant, PhD, Department of Immunology, Roswell Park Cancer Institute, is studying how the immune system eliminates invasive cells and organisms without harming normal cells. The immune system accomplishes this by deploying two types of white blood cells. White blood cells of the first type (CD8 lymphocytes) are poised to attack whenever an antigen (foreign protein) is presented to them. But our bodies are full of proteins, so to prevent our own proteins from coming under immune attack, the second type of white blood cells (CD4 T regulatory lymphocytes) remember which proteins are our own and prevent the CD8 lymphocytes from attacking and destroying healthy cells.
To a lymphocyte, ovarian cancer cells do not look very different from normal cells. The CD4 lymphocytes can get confused and shield the tumor cells from being attacked. Dr. Shrikant is looking for ways to keep the CD4 lymphocytes from being fooled and restrict their ability to chain and render the killer CD8 lymphocytes ineffective.
Dr. Shrikant has developed a novel animal model in which the model dies from ovarian cancer and also has high numbers of T regulatory CD4 lymphocytes that dampen CD8 T cell mediated effective immune responses. His research team will test a chemically altered version of a common amino acid, tryptophan, to poison the subset of “bad” CD4 lymphocytes and thereby unleash tumor-specific CD8 cells to respond and kill ovarian tumor cells. He also plans studies to determine whether the host tumor immunity persists so that ovarian cancer can be eradicated.
DNA Changes May Make Tumor Cells Stand Out
Dr. Kunle Odunsi is testing a therapeutic vaccine to suppress the growth of ovarian cancer. This vaccine boosts the body's ability to seek out and kill ovarian cancer cells that display a “foreign” protein, NY-ESO-1. This foreign protein (antigen) is not found on non-cancer cells, but some ovarian cancer cells do not display it either. One of Dr. Odunsi's colleagues at Roswell Park Cancer Institute, Adam Karpf, PhD, Department of Pharmacology & Therapeutics, is looking for ways to encourage all the cancer cells to display the antigen. The idea is to make them as conspicuous as possible so the immune system will eliminate them.
Dr. Karpf will conduct his experiments using ovarian cancer cells in culture as well as ovarian cancer cells growing as tumors in animal models. The drug he will use to encourage the cells to display NY-ESO-1 is decitabine, which is currently used to treat other disorders where cell growth is out of control. Decitabine changes the DNA, turning on the genes that code for the cancer antigen NY-ESO-1. Once the cells are making the antigen, Dr. Karpf will treat them with the kind of chemotherapy that is used for treating ovarian cancer. This is important to make sure that the chemotherapy still works, even though the DNA is altered.
Dr. Karpf's study will show whether a combination of anti-cancer vaccine, decitabine, and chemotherapy might work in patients who have ovarian cancer. This is a complicated series of steps, and Dr. Karpf knows that these drugs may have to be given in a certain order with a set time between doses. His experiments are the first step in trying to work out a better treatment for ovarian cancer.
Certain Genes May Increase the Risk of Ovarian Cancer
Patients with ovarian cancer have high levels of regulatory T cells, the rare type of cells that keep the immune system from mounting a strong attack. Kirsten Moysich, PhD, Department of Cancer Control and Prevention, at Roswell Park Cancer Institute, believes that regulatory T cells may prevent people from developing tumor immunity. She acknowledges that regulatory T cells play an important role in keeping the immune system from attacking its own body. Unfortunately, they may also keep the body from attacking cancer cells, which differ only slightly from normal cells.
Why do some women have more regulatory T cells than others? According to Dr. Moysich and her colleagues, the answer may lie in their genes. Dr. Moysich can rattle off a half dozen genes that she believes may increase or decrease the number of regulatory T cells. The new grant from the Ovarian Cancer Research Fund will allow her to test whether any of these genes are more common in patients with ovarian cancer than in other people. She will also evaluate 250 women with ovarian cancer to see whether they are less likely to survive if they have these genes.
Dr. Moysich hopes that her research will reveal which women are at high risk so they can be screened for cancer, hopefully catching ovarian cancer while it can still be cured.