Experimental ovarian cancer vaccine gets promising results in mice

Paul Basilio, MDLinx | November 29, 2017

An experimental vaccine strategy has shown promise for preventing ovarian cancer in mouse studies, according to findings published in Cancer Prevention Research by a team at the Lerner Research Institute at the Cleveland Clinic, Cleveland, OH.

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The targeting of retired proteins as a vaccination strategy could be useful in preventing cancers like breast, ovarian, and prostate cancers that arise only in adults.

The vaccine targets a protein present at elevated levels in approximately 90% of human ovarian epithelial cancers, which is the most common type of ovarian cancer. Investigators showed that the vaccine inhibited the growth of ovarian cancers in mouse models of the disease.

“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, PhD, of the National Cancer Institute'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, Dr. Shoemaker added. These patients do not have many options for preventing ovarian cancer other than prophylactic removal of the ovaries and fallopian tubes.

Targeting "Retired" Proteins

The vaccine used in the study targets the AMHR2-ED protein. Vincent Tuohy, PhD, one of the study’s lead authors, refers to this protein as “retired”, because it is no longer expressed in normal body tissues as people age. AMHR2-ED is part of a larger protein, AMHR2, which regulates the growth and development of egg-containing follicles in the ovary.

Dr. Tuohy and his colleagues showed that AMHR2-ED was expressed only in the ovaries in both mice and humans. 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 tested by Dr. Tuohy's team.

"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 like breast, ovarian, and prostate cancers that arise only in adults, Dr. Tuohy said.

According to Dr. Shoemaker, the hypothesis behind this research is that the retired protein targets are reactivated at an early stage in carcinogenesis, the process by which normal cells are transformed into cancer cells.

"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," he added.

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 vaccine adjuvant to help activate the immune system.

Dr. Tuohy's team tested the vaccine in mice 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 when compared with mice vaccinated with the immune-boosting adjuvant alone. Mice that received the vaccine also lived substantially longer than mice that received only the adjuvant.

The vaccine was also 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 AMHR2-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, MD, PhD, 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."

To read more about this study, click here

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