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ESHG: Neoantigen Vaccine Helps Prevent Cancer in Lynch Syndrome Patients


BERLIN – A neoantigen vaccine was able to prevent cancer in a subset of Lynch syndrome patients who mounted a T-cell response to one of the neoantigens, increasing their chance of remaining disease-free over 10 years, according to results from a small clinical trial in the Netherlands.

The work, presented here at the European Human Genetics Conference on Monday by Nicoline Hoogerbrugge, a professor of hereditary cancer at Radboud University Medical Center in the Netherlands, is the result of 15 years of research. "It is the first step to a new model to prevent cancer in those at high risk of hereditary cancer," she said.

Lynch syndrome patients have an increased inherited risk of colorectal and other types of cancer. They harbor mutations in DNA mismatch repair genes, including MLH1, PMS2, MSH2, and MSH6, which lead to increased genomic mutations and microsatellite instability (MSI). MSI-high tumors are known to produce neoantigens, resulting from frameshift mutations, that do not occur in normal cells.

The idea for the vaccine was to load dendritic cells with predicted neoantigen peptides that could stimulate the formation of specific T cells that would fight any precancerous or cancer cells that carry the neoantigens.

For their Phase I/II clinical trial, which ran from 2012 to 2016, the researchers vaccinated 23 Lynch syndrome patients, including 20 that were still healthy and three that had recently received treatment for colorectal cancer. The vaccine consisted of dendritic cells loaded with predicted neoantigens from TGF-beta receptor II, caspase-5, and carcinoembryonic antigen (CEA), and each participant received up to three vaccination cycles. According to Hoogerbrugge, this was the first preventive vaccine study for non-virus-induced cancers.

She said her team was relieved to find that one year after vaccination, none of the patients had developed signs of autoimmunity or any serious side effects. In addition, T cells against the neoantigens could be found in skin biopsies of almost 90 percent of patients. Moreover, T cells specific to the TGF-beta receptor II neoantigen were cytotoxic against tumor cells in vitro.

A survival analysis conducted earlier this year showed that the nine patients who had developed TGF-beta receptor II-specific T cells were still disease-free after almost 10 years whereas the group of 14 patients without such T cells was not.

It is still unclear why some patients mounted a T-cell response against TGF-beta receptor II while others didn't. Hoogerbrugge suggested this could be because the researchers did not know how to dose the vaccine for this initial trial.

She is currently seeking funding to expand the study, with the goal of administering the vaccine early in life, including more predicted neoantigens and using them at higher loads, and increasing the number of vaccine cycles. However, she cautioned, this could potentially lead to autoimmunity issues.