Harnessing cancer's inner enemy

Women with advanced ovarian cancer who have a natural immune response to a protein made by their tumors may live substantially longer after diagnosis than women who do not, according to a study from scientists at the University of Washington and the Hutchinson Center. The findings provide new support for the potential of immunotherapy, a form of treatment that relies on harnessing the immune system's innate ability to fight cancer.

UW research scientist Vivian Goodell and colleagues screened blood samples from 104 ovarian-cancer patients for the presence of antibodies — proteins made by the immune system — to three proteins commonly produced in excess by ovarian cancers. The researchers found that women who produced antibodies against one of the proteins, called p53, had a median survival time of 51 months after diagnosis compared to 24 months for women whose blood had undetectable levels of p53 antibodies.

Benefits of immunotherapy

The researchers and their collaborators are now testing ways to boost this innate cancer-fighting response with the hope of improving survival for all patients with the disease, said Dr. Nora Disis, an associate professor of medicine at UW and the senior author of the study.

"The real value of these findings will be in their application to new therapies for women with ovarian cancer," said Disis, also a member of the Center's Clinical Research Division. "We already have begun several clinical trials for patients that utilize this new information."

The study is published as an early release paper on the Journal of Clinical Oncology's Web site. Coauthors include Dr. Lupe Salazar, Heidi Gray and Dr. Ron Swensen of UW, Drs. Nicole Urban and Martin McIntosh of the PHS Division, and Dr. Charles Drescher, a gynecologic oncologist at Swedish Medical Center and an associate member of the PHS Division.

Prior studies led by both Urban and Disis have shown that ovarian cancer can trigger an immune response in women with the disease, which opens up the possibility of developing immune-based therapies, Urban said. Immunotherapy has the advantage of being highly specific for cancer cells, as opposed to traditional chemotherapy, which can cause painful side effects because of its non-specific attack on healthy cells.

For the current study, the researchers obtained blood serum from a subset of participants who developed ovarian cancer while in an ovarian-cancer screening trial. That study is part of the Pacific Ovarian Cancer Research Consortium, a National Cancer Institute-funded Specialized Program of Research Excellence (SPORE) in Ovarian Cancer directed by Urban.

Blood samples drawn at the time of surgery to remove the cancer were analyzed for antibodies against three proteins: p53, HER-2/neu, and topoisomerase II. The three proteins are often produced in excess amounts by ovarian-cancer cells and are also suspected to contribute to the aggressiveness of the disease. The investigators developed new, highly sensitive tests for measuring the antibodies.

Sera from women with advanced disease (stages III or IV) were more likely to have antibodies against all of the proteins than women with earlier stage (I or II) disease. However, only p53 antibodies were associated with increased survival for women who had advanced disease at the time of their diagnosis. Because ovarian cancer causes non-specific symptoms such as bloating or gastrointestinal discomfort, most ovarian-cancer patients are diagnosed at an advanced stage, when cure rates are less than 50 percent.

T-cell response

The researchers demonstrated that the increase in survival was not simply due to general immune-system competence as indicated by a woman's ability to produce antibodies against a non-cancer protein, tetanus toxin. Survival rates did not significantly differ between women who did or did not produce antibodies to the toxin.

Although this study focused on antibodies, which are proteins produced by the immune system that bind to foreign or abnormal proteins to fight disease, the researchers are primarily interested in the therapeutic potential of another type of immune response that is mediated by a type of disease-fighting cells called T cells. However, the researchers note in their paper that the production of antibodies against specific proteins like p53 is often associated with a T-cell response against the same abnormal protein.

Earlier work by other labs has found that the ability of T cells to circulate through ovarian tumors was associated with increased survival, and several labs at the Hutchinson Center are developing T-cell based therapies for cancer. A clinical trial for advanced ovarian cancer using T-cell therapy against another ovarian-cancer protein identified by Urban's lab, NY-ESO-1, is currently under way at the Seattle Cancer Care Alliance. That study is led by Dr. Cassian Yee in collaboration with Urban.

Although previous studies at other institutions have not demonstrated a link between p53 antibodies and a favorable prognosis for ovarian cancer, Disis said the current study is stronger than earlier reports for several reasons.

"First, because of Nicole's SPORE, we have access to a large number of very high-quality specimens collected at the time of cancer diagnosis, which enabled us to conduct a prospective study," Disis said. "We also developed very powerful methods both for antibody detection and for data analysis."

New clinical trials

Disis said that two clinical trials have begun that aim to boost the innate T-cell response in advanced ovarian-cancer patients. One, led by Salazar, involves use of a drug that blocks a class of immune-system cells whose job is to dampen the cancer-specific T-cell response. The goal is to enhance the ability of the cancer-fighting T-cells to gain access to the tumor.