People with gene mutations known as Lynch syndrome face a risk of developing colorectal cancer over 70%, as well as an increased risk of bladder cancer, ovarian cancer and other tumor types. Although the disorder can be easily detected by genetic testing, patients have good good preventive strategies than performing frequent cancer screening tests such as colonoscopy or risk reduction operations.
Researchers at Weill Cornell Medicine in New York develop a different strategy for patients with Lynch syndrome: a vaccine for preventing cancer from eternal formation. At the Atlanta AACR meeting, the data showed that a combination of their vaccine and the anti-inflammatory drug naproxen could extend the life of mouse models of Lynch syndrome.
The vaccine Weill Cornell researchers developed consists of four "neoantigens", which are proteins that Lynch mutated genes produce. The immune system usually recognizes these proteins as foreign invaders, but it does not generate a strong enough response to prevent cancers.
Then, the team screened more than 50 Lynch-related neoantigens, in search of those who produced the strongest immune responses, said the geneticist and co-author Steven Lipkin, MD, Ph.D., professor of medicine at Weill Cornell, in an interview with FierceBiotechResearch. "We chose the four bests," Lipkin said. "In the mouse model of Lynch syndrome, about nine out of ten tumors have one of these four mutations."
Lynch syndrome, which received the vaccine, developed only half of the intestinal tumors, as did animals not receiving the vaccine. And they lived 380 days, vs. 241 days for the unvaccinated mice.
The addition of naproxen, ingredient in over-the-counter pain relief Aleve, made the vaccine even more effective. The overall survival of mice receiving the combination therapy was 541 days versus 380 days for the vaccine-only animals.
The idea of adding naproxen came from real-world experience with people diagnosed with Lynch syndrome, Lipkin said. "For Lynch patients, aspirin is used as a non-steroidal anti-inflammatory agent to reduce the risk of colorectal cancer," he said. "There is some evidence from previous animal experiments that naproxen is like a super-aspirin. We experienced the same result."
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Lipkin coordinates with European cancer vaccine startup Nouscom to determine the best delivery technology for the vaccine. The mouse sample presented by AACR used a peptide-based vaccine to deliver the four neoantigens. Nouscom develops a T cell viral vector that can express up to 200 neoantigens. "The next phase of the study is to take our approach, improve it, and compare it to the Nouscom approach. We want to see what's better, then move it on to a clinical trial," Lipkin said.
It will, however, take some work to determine the best design for a human vaccine trial. Lipkin said his team still decides whether to insert separate arms into the trial to test the vaccine itself against naproxen combo or other treatments. And first, there must be a Phase 1 study to prove safety and track biomarkers to determine if the vaccine generates a strong enough immune response.
For Phases 2 and 3 of the study, patients should be followed for three years to prove the effectiveness of the vaccine, Lipkin added.
A potential benefit of a vaccine approach to cancer prevention in people genetically received against it, Lipkin says, may be able to reduce their risk by as little as 2 to 4 injections of neoantigens. He already knows that patients are open to this strategy.
"Patients are very interested," said Lipkin. "They say," Aspirin? Really? Can't you do better than that? "They want something more sophisticated."