Researchers have found a promising preventative cancer vaccine for Lynch syndrome patients, a disease that significantly increases the risk for several different types of cancer.
During the American Association for Cancer Research (AACR) Annual Meeting 2019 in Atlanta on April 1, researchers presented new data from a preclinical study that show that Lynch syndrome-associated neoantigens could stimulate a robust immune response that has crucial antitumor activity.
Lynch syndrome is an inherited condition that affects about one in every 280 people in the U.S. Lynch syndrome patients have a 70 to 80 percent lifetime risk of colorectal cancer, as well as an increased risk of several other cancer types, such as small intestine, stomach, endometrial, bladder and ovarian cancers.
“Currently, frequent screening to detect pre-cancers and early-stage cancer is the main approach used to prevent cancer in people with Lynch syndrome, although some people have risk-reducing surgeries and some take aspirin for colorectal cancer prevention,” Steven Lipkin, MD, PhD, the Gladys and Roland Harriman Professor of Medicine, professor of medicine in the Division of Gastroenterology and Hepatology, and vice chair for research in the Weill Department of Medicine at Weill Cornell Medicine in New York, said in a statement.
“We are extremely encouraged by our preclinical data, which suggest that rationally designed cancer vaccines may prevent some cancers associated with Lynch syndrome,” he added. “We are in the process of designing a clinical trial to test this hypothesis.”
Lynch syndrome prevents the proper repair of damaged DNA mutations that accumulate in certain parts of the genome called coding microsatellites. The coding microsatellite mutations produce novel or modified neoantigen proteins, which can be recognized by the immune system but do not usually yield a sufficiently robust immune response to prevent cancer development.
The researchers first looked at whether vaccinating mice with Lynch syndrome-associated neoantigens could stimulate a robust immune response by analyzing intestinal tumors for mutations in the coding microsatellites. The researchers found that 13 coding microsatellites had at least one mutation in 15 percent or more of the tumors.
Next, they identified which mutations could generate neoantigens and what the peptide sequences of the neoantigens were. They then took the 10 most promising neoantigens and tested how effective they would be. The researchers found that four of the neoantigens generated from coding microsatellite mutations did in fact induce a robust neoantigen-specific immune response and significantly reduced intestinal tumor burden and improved survival compared to non-vaccinated Lynch syndrome mice.
In the non-vaccinated mice, the median intestinal tumor burden was 61 mg, with a survival rate of 241 days. For the vaccinated mice, the median intestinal tumor burden was 31 mg and the survival rate was 380 days.
By combining vaccinations with the administration of the non-steroidal anti-inflammatory drug nanporxen, the researchers significantly improved the overall survival of the Lynch syndrome mice, extending it to 541 days.
“Our preclinical data are very exciting because they provide strong support for continuing the investigation and development of immunoprevention strategies for patients with Lynch syndrome,” Lipkin said.
