11/14/21, 1:47 PM A Potential Cancer Prevention Vaccine for Lynch Syndrome - National Cancer Institute

Could a Vaccine Prevent Colorectal Cancer in People with

Lynch Syndrome?
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April 19, 2019,
by NCI Staff

Researchers have taken the first steps toward developing a

vaccine to prevent cancer in people with Lynch syndrome,
an inherited condition that elevates a person’s risk of
colorectal, endometrial, and other types of cancer.

The scientists, led by Steven Lipkin, M.D., Ph.D., of Weill

Cornell Medicine, reported results from NCI-funded tests of
a cancer prevention vaccine at a recent meeting. The
An immune cell (pink and red)
vaccine prevented the growth of colorectal tumors in a
attacks a tumor cell (blue) that
mouse model of Lynch syndrome and prolonged the mice’s
makes neoantigens (blue and
survival compared with unvaccinated mice.
orange). A vaccine could help train
“The simplicity of this approach means that it is promising immune cells to recognize
to take forward” to a human vaccine, Dr. Lipkin said during neoantigens.
a press briefing April 1 at the American Association for Credit: J Immunol Res 2017. doi:

Cancer Research annual meeting in Atlanta. 10.1155/2017/5210459. CC BY 4.0.

As the cost of genetic testing decreases and more people

get tested for hereditary cancer syndromes, researchers are
learning that Lynch syndrome is more common than once thought. It is currently estimated that 1 in every
280 Americans has the disorder, which translates to about 1.1 million people.

Current methods for preventing cancer in people with Lynch syndrome include frequent cancer screenings
to detect precancer or early-stage cancer, low-dose aspirin for colorectal cancer prevention, and risk-
reducing surgery.

A vaccine could offer another, potentially more efficient, way to hinder cancer development.

“The holy grail is a [cancer] cure. A holier grail is [cancer] prevention,” said cancer immunology expert Louis
M. Weiner, M.D., director of Georgetown Lombardi Comprehensive Cancer Center, at the press briefing.

Shared Mutations in Lynch Syndrome Cancers

Lynch syndrome is caused by inherited gene mutations that prevent the repair of DNA errors that arise as
cells divide, a defect called mismatch repair deficiency.

“It’s like not having a DNA spell-checker,” said Asad Umar, D.V.M., Ph.D., of NCI’s Division of Cancer
Prevention (DCP). Without this defense, DNA errors accumulate in cells and may eventually lead to a variety
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11/14/21, 1:47 PM A Potential Cancer Prevention Vaccine for Lynch Syndrome - National Cancer Institute

of cancers.

Short repeated segments of DNA called microsatellites are especially prone to DNA mismatch errors. Tumors
that are mismatch repair-deficient end up accumulating alterations in these microsatellites, a
condition known as microsatellite instability.

A silver lining to microsatellite instability is that it has the potential to create novel proteins, known as
neoantigens, that are unnatural to the body. Neoantigens can trigger the immune system to launch an
attack on the cells that make these proteins.

What’s more, tumors that form in people with Lynch syndrome often have the same microsatellite
mutations. For example, a specific microsatellite mutation in the TGFBR2 gene occurs in 60% to 80% of people
with mismatch repair-deficient colorectal cancer.

Recent data suggests that some people with microsatellite instability-high cancer have evidence of an
immune reaction against several of these shared neoantigens.

The presence of shared tumor neoantigens among people with Lynch syndrome “raises the possibility of
being able to create a single type of vaccine that might work for millions of people,” said Dr. Weiner.

In past attempts to develop cancer vaccines, scientists used proteins that are found at higher than normal
levels in cancer cells. But, because these proteins are also made by normal cells, there were concerns about
unintentional side effects, Dr. Weiner pointed out.

A neoantigen-based vaccine wouldn’t have that issue, he said.

Developing and Optimizing a Cancer Vaccine

In 2011, researchers from DKFZ—the German Cancer Research Center in Heidelberg, Germany—began
clinical testing of a neoantigen vaccine in people who had advanced colorectal cancer that was microsatellite
instability-high.

DCP’s PREVENT Cancer Preclinical Drug Development Program, which focuses on unmet needs in cancer
prevention that are not adequately addressed by the private sector, recognized the potential of this vaccine
to prevent cancer in individuals with Lynch syndrome.

Dr. Lipkin, together with researchers from DKFZ, were awarded funding from the PREVENT Program to
develop a cancer prevention vaccine in mice and investigate treatments that might boost its efficacy.

First, the scientists scoured DNA from 32 colorectal tumors that developed in the mouse model of Lynch
syndrome and identified 13 shared mutations.

The researchers then used an algorithm to predict which of the shared mutations would create neoantigens,
narrowing the number of candidates down to 10. When they injected these 10 neoantigens into mice, four
triggered a strong immune response.

These four neoantigens were combined to create the mouse vaccine. Administering the vaccine plus an
adjuvant in the mouse model of Lynch syndrome reduced the development of colorectal tumors and
prolonged survival, they found.
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11/14/21, 1:47 PM A Potential Cancer Prevention Vaccine for Lynch Syndrome - National Cancer Institute

“This is one of the first cancer immunoprevention vaccines that uses anticipated neoantigens that might be
formed from DNA mismatch repair defects,” Dr. Umar said.

Next, the researchers determined whether combining the vaccine with other treatments could boost its
efficacy.

In addition to aspirin, studies have demonstrated that naproxen (Naprosyn), a commonly used pain reliever
and anti-inflammatory medication, can prevent cancer in mice. Naproxen’s potential to prevent cancer in
people with Lynch syndrome is being evaluated in an ongoing NCI-funded clinical trial.

Dr. Lipkin’s team demonstrated that naproxen was better than aspirin or a control treatment at decreasing
the development of colorectal tumors in the mouse model.

Naproxen also appeared to enhance the efficacy of the vaccine. Mice treated with the vaccine plus naproxen
lived longer than mice that received the vaccine alone or the vaccine plus aspirin. And those in the vaccine
plus naproxen group had more immune cells that recognized the vaccine neoantigens than did mice in the
vaccine alone or vaccine plus aspirin groups.

Diagnosing Lynch Syndrome

People with Lynch syndrome would be candidates for a human cancer prevention vaccine, if one is
developed. But less than 5% of the estimated 1.1 million people with Lynch syndrome know that they have it.

Current guidelines recommend that people with colorectal and endometrial cancer be tested for
microsatellite instability. If a patient’s tumor tests positive for microsatellite instability, then it is
recommended that they be tested for Lynch syndrome.

Other professional groups recommend Lynch syndrome testing for all patients diagnosed with colorectal
and endometrial cancer. If Lynch syndrome is diagnosed, it is recommended that the patient’s first-degree
relatives be tested for the condition as well.

Genetic testing for Lynch syndrome is often covered by insurers, including Medicare, noted Dr. Lipkin. If
insurance does not cover the cost, out-of-pocket costs are about $249 or less for major genetic testing
companies, he added.

However, experts agree that more needs to be done to expand genetic testing for Lynch syndrome.

Moving Toward A Human Vaccine

To develop a neoantigen vaccine for humans, Dr. Lipkin and his colleagues plan to identify shared
neoantigens that occur in the early-stage colorectal tumors of people with Lynch syndrome. This project was
awarded NCI funding via the Cancer MoonshotSMImmuno-Oncology Translational Network.

If human trials of a cancer prevention vaccine do move forward, Dr. Lipkin noted, it will take several years to
determine whether it works.

In the meantime, his team is using the mouse model to better understand exactly how the vaccine works and
ways that growing cancer cells can become resistant to its effects.

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