People with gene mutations known as Lynch syndrome face a more than 70% lifetime risk of developing colorectal cancer, as well as an elevated risk of bladder cancer, ovarian cancer, and other tumor types. Although the disorder can be easily detected with genetic testing, patients have few good preventative strategies other than undergoing frequent cancer-screening tests like colonoscopies or having risk-reducing surgeries.
Scientists at Weill Cornell Medicine in New York are developing a different strategy for patients with Lynch syndrome: a vaccine to prevent cancer from ever forming. At the American Association for Cancer Research (AACR) meeting in Atlanta, they presented data showing that a combination of their vaccine and the anti-inflammatory drug naproxen could extend life in mouse models of Lynch syndrome.
The vaccine the Weill Cornell researchers developed consists of four “neoantigens,” which are proteins that Lynch-mutated genes produce. The immune system normally recognizes these proteins as foreign invaders, but it doesn’t generate a strong enough response to prevent cancers from forming.
So the team screened more than 50 Lynch-related neoantigens, in search of the ones that produced the strongest immune responses, said geneticist and co-author Steven Lipkin, M.D, Ph.D., a professor of medicine at Weill Cornell, in an interview with FierceBiotechResearch. “We picked the four best,” Lipkin said. “In the mouse model of Lynch syndrome, about nine out of ten tumors have one of these four mutations.”
Lynch syndrome mice that received the vaccine developed only half the intestinal tumors as did animals that didn’t get the vaccine. And they lived 380 days, vs. 241 days for the unvaccinated mice.
Adding naproxen, the ingredient in the over-the-counter pain reliever Aleve, made the vaccine even more effective. The overall survival in mice that received the combo treatment was 541 days, vs. 380 days for animals that only got the vaccine.
The idea to add naproxen came from real-world experience with people who are diagnosed with Lynch syndrome, Lipkin said. “For Lynch patients, aspirin is used as a non-steroidal anti-inflammatory agent to reduce the colorectal cancer risk,” he said. “There’s some evidence from prior animal studies that naproxen is like a super-aspirin. We saw the same result.”
Lipkin is coordinating with European cancer vaccine startup Nouscom to determine the best delivery technology for the vaccine. The mouse trial presented at AACR used a peptide-based vaccine to deliver the four neoantigens. Nouscom is developing a T-cell viral vector that can express up to 200 neoantigens. “The next phase of research will be to take our approach, improve it, and then compare it to the Nouscom approach. We’ll see which is better, then take it forward to a clinical trial,” Lipkin said.
It will take some work to determine the best design for a trial of the vaccine in people, however. Lipkin said his team is still determining whether to include separate arms of the trial to test the vaccine by itself against the naproxen combo or other treatments. And first there will need to be a phase 1 study to prove safety and to track biomarkers, so they can determine if the vaccine is generating a strong enough immune response.
For the phase 2 and 3 portion of the research, patients will need to be followed for three years to prove the effectiveness of the vaccine, Lipkin added.
One potential benefit of a vaccine approach to preventing cancer in people who are genetically predisposed to it, Lipkin said, is that they may be able to reduce their risk with as little as 2 to 4 injections of the neoantigens. He already knows patients are open to that strategy.
“Patients are very interested,” Lipkin said. “They say, ‘Aspirin? Really? Can’t you do better than that?’ They want something more sophisticated.”