HOUSTON, Texas — Dr. Stacy Norton was just 7 when colon cancer took her mother’s life, part of a painful family pattern of aggressive cancers appearing far earlier than expected. Years later, the Houston physician chose to take part in research that could help change that story for herself and her children: testing a new type of cancer vaccine designed to prevent disease before it starts.
Norton is one of roughly 1 million people in the United States living with Lynch syndrome, an inherited genetic condition that sharply raises the odds of colorectal cancer and increases the risk for several other cancers. People with the syndrome are commonly advised to undergo annual colonoscopies — much more frequently than the general population — so doctors can find and remove precancerous polyps before they become dangerous.
Researchers are now working on vaccines intended to add another layer of protection, training the immune system to recognize and attack the earliest signs of Lynch syndrome-related colon cancer before a tumor can fully develop. At least three experimental Lynch syndrome vaccines are moving forward, including two in early-stage clinical trials in the U.S. and another set to launch in Britain.
One of those vaccines, which Norton helped test, has shown enough early promise that Dr. Eduardo Vilar-Sanchez of MD Anderson Cancer Center, the study’s lead researcher, expects to begin a larger trial early next year.
“It gives me hope,” said Norton, 59, who works at Houston Methodist Willowbrook Hospital. She has already survived another cancer linked to Lynch syndrome, and both of her children, now in their 20s, inherited the same mutation. If a vaccine proves effective, she said, “perhaps they won’t have to have a colonoscopy every single year for the rest of their lives.”
Lynch syndrome is caused by an inherited genetic mutation
At the center of Lynch syndrome are genes known as mismatch-repair genes, which function like a biological spellcheck system, correcting DNA errors that happen as cells divide. When one of these genes is defective, the body becomes less able to repair those mistakes, allowing genetic changes to accumulate and potentially develop into cancer, often before age 50.
Colorectal cancer is the most common cancer associated with Lynch syndrome. While the average person faces about a 5% lifetime risk of developing it, that risk can climb as high as 80% for Lynch carriers, depending on which inherited gene mutation they have, Vilar-Sanchez said.
The condition also carries a significant risk of endometrial, or uterine, cancer. People with Lynch syndrome have elevated chances of developing pancreatic, stomach, ovarian and certain skin cancers as well, along with a type of brain tumor — the same disease that claimed Norton’s sister’s life at 25.
Norton knew some of her mother’s relatives had also experienced colon cancer, but she was in her 40s before a gene test confirmed she has Lynch syndrome. She switched from every-so-often to yearly colonoscopies. As an obstetrician/gynecologist familiar with other Lynch risks, Norton also decided to have a precautionary hysterectomy. Surgeons discovered early-stage cancer in her removed uterus.
Possible vaccines to stop gene-caused cancer
Today there are two cancer-preventing vaccines, the HPV and hepatitis B shots that block infection from those tumor-causing viruses. But developing vaccines to prevent gene-caused cancer is more challenging than alerting the body to foreign intruders like a virus.
Lynch-fueled growths “tend to accumulate hundreds of mutations that are going to generate proteins that are novel, not made by our normal cells,” Vilar-Sanchez said. “You can train the immune system to recognize those proteins.”
In a first-step study, Norton and 44 other Lynch carriers tested a vaccine made by Swiss biotech Nouscom that teaches the immune system to spot 209 of those abnormalities in Lynch-caused precancers. That revved up tumor-eliminating T cells and a year later, colonoscopies showed fewer precancerous growths and no advanced polyps, the MD Anderson team reported in Nature Medicine.
“Can we even further stimulate the immune system” to keep up with Lynch syndrome-spurred tumor formation, asked Dr. John Marshall, a Georgetown University oncologist and adviser to the Colorectal Cancer Alliance who wasn’t involved with the study. “This early paper suggests that yeah, maybe we can.”
For the first time since 2014, Norton’s own colonoscopies one and two years after vaccination were polyp-free. She’s also part of a subset of study participants given a booster shot a year later; more data on that is expected this fall.
Oxford University researchers are beginning initial testing of a similar approach to attack Lynch-spurred precancers, a vaccine made by Massachusetts-based Moderna using the mRNA technology behind its COVID-19 shot.
And scientists are awaiting results from a slightly larger study comparing California-based ImmunityBio’s Tri-Ad5 vaccine, which flags some different cancer markers, to a placebo.
Is Lynch syndrome tied to the rise in young adult colon cancer?
About 158,000 people are diagnosed with colorectal cancer in the U.S. each year, most of them over 50. Cases in younger adults are increasing, though it isn’t clear why.
Lynch syndrome affects about 1 in 279 people. While most don’t know it, more may be learning they have the inherited disorder, Vilar-Sanchez said, as genetic testing is increasingly discussed with people with Lynch-related cancer in the family or who get certain tumors at young ages. That in turn can show if close relatives might also be at risk.
For the average person, U.S. guidelines call for routine colorectal cancer screening — with a colonoscopy or other kinds of tests — to begin at age 45. But at any age, get a checkup for symptoms such as blood in stool or rectal bleeding; changes in bowel habits such as diarrhea, constipation or narrowing of stool that lasts more than a few days; unintended weight loss; and cramps or abdominal pain.
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