Can a vaccine help prevent Lynch syndrome-related cancers?

An estimated one in every 288 people has Lynch syndrome. “It’s about 1 million people in the United States,” says Eduardo Vilar-Sanchez, M.D., Ph.D.

This hereditary condition increases the likelihood of developing several cancers. “Although widely recognized for its link to colorectal and endometrial cancers, Lynch syndrome can generate other tumors as well,” says Vilar-Sanchez. He notes that ovarian, stomach, small bowel, brain, adrenal and urothelial cancers are linked to the diagnosis.

Vilar-Sanchez specializes in understanding hereditary cancer syndromes and caring for patients with the associated cancer risks. He is hopeful that a new clinical trial investigating a vaccine will offer an effective, safe and easy method of preventing Lynch syndrome-related cancers.

Lynch syndrome diagnosis is often by chance

Most people with Lynch syndrome aren’t aware they have it, Vilar-Sanchez says.

“It is usually recognized when somebody in the family gets diagnosed with cancer and undergoes genetic testing,” Vilar-Sanchez says.

But more people are becoming aware, thanks to cascade screening, an approach to genetic testing that includes notifying at-risk family members of concerning genetic findings. This includes sharing results with siblings and with children within the family.

Genetic driver of Lynch syndrome determines cancer screening frequency

There are four genes responsible for Lynch syndrome: MLH1, MSH2, MSH6 and PMS2. The cancer risks for each mutation aren’t the same, so risk management approaches may vary.

“In general, patients carrying the MLH1 or MSH2 mutations have higher risks of developing cancer than people carrying the MSH6 or PMS2 mutations,” Vilar-Sanchez says.

Techniques for identifying the mutations have improved. So have screening approaches for patients. Carriers of the MLH1 or MSH2 mutation need a colonoscopy and an upper endoscopy every one to two years to check for cancer in the stomach or small bowel. Patients are also monitored for urothelial tumors through a urine analysis.

Patients who have a uterus will also receive an endometrial ultrasound and endometrial biopsies every year or every other year.

Patients who carry the MSH6 or PMS2 mutations may space out screenings to every two or three years. But Vilar-Sanchez recognizes that this still can be a challenge for patients.

“It’s much more frequent than general population,” Vilar-Sanchez says. “The burden on these patients is significant.”

Aspirin or naproxen may serve as chemoprevention

In addition to routine screenings, there are also therapeutic approaches to reducing cancer risks in patients with Lynch syndrome.

A large clinical trial, CAPP-2, demonstrated the benefit of aspirin as chemoprevention for this patient population. However, adoption has been slow. “The clinical trial investigated a high dose of aspirin, so providers have been reluctant to offer this approach because of the concern of side effects,” Vilar-Sanchez says.

A Phase I clinical trial led by Vilar-Sanchez showed the over-the-counter anti-inflammatory drug naproxen can also be an effective chemoprevention method for Lynch syndrome patients.

But the challenge with chemoprevention, as well as with routine screening, is compliance. “These are often people who haven’t had cancer yet, so it’s easy for them to fall off course,” Vilar-Sanchez says.

Clinical trial to study vaccine designed to prevent Lynch syndrome-related cancers

But what if we could lower the risk of Lynch syndrome-related cancers with a vaccine and reduce the preventive demands on patients? Vilar-Sanchez has a vision – and a soon-to-open clinical trial – for the concept. He spoke about leading the multi-site study at the 2022 American Association of Cancer Researchers Annual Meeting.

The gene defect that causes Lynch syndrome involves an important system that repairs DNA errors. As a patient with Lynch syndrome develops a pre-malignant or early-stage cancer, the cancer cells accumulate mutated proteins because of the flaw. The clinical trial will investigate a preventive vaccine designed to recognize multiple mutated proteins frequently found in patients with Lynch syndrome.

“We want to immunize patients who are cancer-free with those shared foreign mutated proteins so that the immune system will be prepared if a patient develops a tumor to reject it,” Vilar-Sanchez says.

The vaccine is already being investigated as a therapeutic in combination with the checkpoint inhibitor pembrolizumab in microsatellite unstable solid tumors in a multi-site clinical trial. Michael Overman, M.D., is leading the clinical trial at MD Anderson. “Since the vaccine is already being used as a therapeutic, it has allowed us to move forward in development quickly. Now we’re applying it to prevention, which is the real vocation for the vaccine,” Vilar-Sanchez says.

The preventive clinical trial’s goal is to offer patients with Lynch syndrome an easier approach to managing cancer risks. “We hope this vaccine can serve as interception, and, if the results show it works, patients will be able to space out their surveillance more and more,” Vilar-Sanchez says.

By reducing the burden for patients, he hopes for an uptick in compliance. “There’s the potential to impact how a lot of people manage their cancer risks,” Vilar-Sanchez says.

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