Experimental Ovarian Cancer Vaccine Shows Promise in Mice
, by NCI Staff
In mouse studies, an experimental vaccine strategy has shown promise for preventing ovarian cancer.
The vaccine targets a protein that is present at elevated levels in approximately 90% of human ovarian epithelial cancers, the most common type of ovarian cancer.
Study investigators showed that the vaccine inhibited the growth of ovarian cancers in mouse models of the disease.
If ultimately shown to be safe and effective in humans, "this type of vaccine may be particularly useful for women who are BRCA1 and BRCA2 gene mutation carriers, who are at substantially increased risk of breast and ovarian cancer," said Robert Shoemaker, Ph.D., of NCI's Division of Cancer Prevention, who coauthored an editorial on the new study.
Women who carry these mutations "can be identified through genetic testing or by family history, and don't have much in the way of options" for preventing ovarian cancer other than prophylactic surgery to remove the ovaries and fallopian tubes, Dr. Shoemaker added.
The researchers, from the Lerner Research Institute at the Cleveland Clinic, reported their findings November 1 in Cancer Prevention Research.
Cancer Vaccines: Targeting "Retired" Proteins
The vaccine used in the study targets the protein AMHR2-ED. This protein is an example of what one of the study’s lead authors, Vincent Tuohy, Ph.D., calls a "retired" protein—a protein that is no longer expressed, or made, in normal body tissues as people age. AMHR2-ED is part of a larger protein, AMHR2, that regulates the growth and development of egg-containing follicles in the ovary.
Dr. Tuohy and his colleagues showed that in both mice and humans AMHR2-ED was expressed only in the ovaries. AMHR2-ED expression was markedly lower in the ovaries of postmenopausal women and comparably aged mice than in those of younger women and mice, respectively.
Notably, AMHR2-ED was expressed at high levels in all 20 human ovarian tumor samples that Dr. Tuohy's team tested.
"For reasons that are not fully understood, the AMHR2-ED gene frequently gets turned back on in ovarian cancer cells," Dr. Shoemaker explained.
The targeting of retired proteins like AMHR2-ED as a vaccination (or immunoprevention) strategy could be useful in preventing cancers that arise only in adults, like breast, ovarian, and prostate cancers, Dr. Tuohy said.
"The hypothesis is that these retired protein targets are reactivated at some early stage in carcinogenesis," the process by which normal cells are transformed into cancer cells, Dr. Shoemaker explained. "If you have a vaccine that alerts the immune system to be on the lookout for these proteins if they crop up in cancer cells, then that could have an immunoprotective effect."
Boosting Cancer Immunoprevention Research
Although immunoprevention against cancer is a fairly new field, it is a high priority for NCI, Dr. Shoemaker said.
As a result of recommendations made by the Cancer Moonshot™ Blue Ribbon Panel, in fact, NCI recently released a new funding announcement that is designed to spur research related to cancer immunoprevention.
The announcement will fund immunoprevention research projects with a focus on conditions known to increase cancer risk in adults, such as Lynch Syndrome, Barrett esophagus, and mutations in the BRCA1 and BRCA2 genes. The research projects will aim to identify the earliest changes in the carcinogenic process and develop immune-based interventions that target these changes.
The research projects will be jointly funded by NCI and three other NIH institutes, Dr. Shoemaker said.
Immunoprevention of Ovarian Cancer
The experimental vaccine—designed to induce an immune response against AMHR2-ED—consists of an engineered version of the mouse AMHR2-ED protein plus a substance to help activate the immune system, known as a vaccine adjuvant.
Dr. Tuohy's team tested the vaccine in mice that were genetically engineered to spontaneously develop tumors in both ovaries. Vaccinating the mice when they were 6–7 weeks old delayed the appearance and markedly inhibited the growth of ovarian tumors compared with mice vaccinated with the immune-boosting adjuvant alone. Mice that received the vaccine also lived substantially longer than the mice that only received the adjuvant.
And the vaccine was effective in delaying the appearance, and inhibiting the growth, of new tumors derived from mouse ovarian cancer cells that were transplanted into healthy mice.
AMHR2-ED vaccination also slowed tumor growth in mice with established ovarian tumors, suggesting that it could be used for treatment as well as prevention, the study authors wrote.
Additional experiments showed that the vaccine induced an immune response that leads to tumor-cell death via a process known as apoptosis.
The AMR2-ED vaccine appeared to be safe in mice, the researchers reported. It did not cause detectable inflammation in the ovaries of older female mice, and in younger female mice it caused only mild and transient ovarian inflammation and did not impair their fertility.
Moving the Vaccine Ahead to Clinical Trials
"Vaccination against AMHR2-ED, even if necessarily done after childbearing years, could provide a valuable option" for women who are BRCA1/2 mutation carriers, wrote Dr. Shoemaker and editorial coauthor Thomas Forsthuber, M.D., Ph.D., of the University of Texas at San Antonio.
However, completing all phases of clinical trials needed to test the safety and effectiveness of a human version of the AMHR2-ED vaccine will take at least 10 years, and there are still hurdles to overcome, Dr. Tuohy said.
"We want to start clinical trials targeting women with BRCA1/2 mutations, who are at highest risk of ovarian cancer," he continued. "But, ultimately, I envision expanding the trials to postmenopausal women, who account for 75% of the disease."
Even with the compelling early findings in mice, Drs. Shoemaker and Forsthuber cautioned that "additional research is needed to understand the underlying immune phenomena and optimize the vaccine strategy."
For instance, Dr. Shoemaker said, "there's no way to know what fraction of cancers you might prevent with this type of vaccine and which might escape this prevention strategy."
On the basis of similar, earlier studies in mice, Dr. Tuohy and his colleagues are preparing to launch a clinical trial of an experimental breast cancer vaccine that targets a different retired protein, alpha-lactalbumin, which is required for producing breast milk and is found at high levels in many human breast cancers.
The vaccine strategy could possibly be expanded, Dr. Shoemaker said. A single vaccine that targets two retired proteins, alpha-lactalbumin and AMHR2-ED, might protect against both breast and ovarian cancer in women who carry BRCA1/2 mutations.