The idea is to deliver into the body bits of proteins, or antigens, from cancer cells to stimulate the immune system to attack any incipient tumors. The concept isn’t new, and it has faced skepticism. A decade ago, a Nature editorial dismissed a prominent breast cancer advocacy group’s goal of developing a preventive vaccine by 2020 as “misguided,” in part because of the genetic complexity of tumors. The editorial called the goal an “objective that science cannot yet deliver.” But now, a few teams—including one funded by the same advocacy group, the National Breast Cancer Coalition (NBCC)—are poised to test preventive vaccines, in some cases in healthy people at high genetic risk for breast and other cancers. Their efforts have been propelled by new insights into the genetic changes in early cancers, along with the recognition that because even nascent tumors can suppress the immune system, the vaccines should work best in healthy people who have never had cancer.
Researchers are trying out several vaccine strategies. Some use so-called tumor antigens, molecular markers that are scarce on healthy cells but plentiful on cancer cells. The Lynch vaccine instead targets “neoantigens,” a potent type of antigen only found on tumor cells. Some deploy just a single antigen whereas others use a large number, in a bid to broadly shield against cancer. The best approach is unclear, and developers also face the difficult challenge of measuring success without waiting decades for healthy people to develop cancers.
Early trials are yielding glimmers of promise. If the idea works to prevent one or a few cancers, it could be extended to meet an ambitious goal suggested by President Joe Biden: developing a vaccine that could prevent many types of cancer, modeled on the messenger RNA (mRNA) vaccines that have helped fight the COVID-19 pandemic. “We are a long way from a general vaccine” to prevent cancer, says medical oncologist Shizuko Sei of the National Cancer Institute’s Division of Cancer Prevention. “But it could be in the distant future. It’s a stepwise approach.”
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As some teams are trying to broaden the immune response triggered by cancer vaccines, others want to make it safer and more precise by targeting neoantigens, only found on cancer cells. Those efforts have accelerated over the past decade thanks to a surge in tumor genome sequencing, which has revealed a flood of neoantigens. Some drive cancer growth, whereas others have no apparent function. Most are unique to an individual cancer—an obstacle for developing preventive vaccines, which have to target markers that can be predicted in advance.
Some neoantigens reliably appear on many people’s tumors, however. For instance, pancreatic cancer is almost always triggered by mutations in a growth protein called KRAS, which give rise to a predictable set of neoantigens. This spring, Johns Hopkins University immunologist Elizabeth Jaffee and colleague Neeha Zaidi will begin to safety test a vaccine containing mutated KRAS peptides in 25 men and women who haven’t had cancer but are at high risk because of an inherited mutation or family history. KRAS is like pancreatic cancer’s Achilles’ heel, Jaffee says: It’s the first of several genes to get mutated. As a result, the team hopes early tumor cells won’t be able to evade the vaccine by ditching KRAS and finding another way to grow.
Lynch syndrome cancers also sport a predictable set of neoantigens. That’s because patients’ DNA repair problem leads to “frameshift” mutations, which shift how a cell’s proteinmaking machinery reads a gene, scrambling the resulting protein in a consistent way. A peptide vaccine containing a few of these neoantigens, which was developed by a German team, caused no serious side effects when tested in people with cancer. A similar vaccine designed for mice with Lynch syndrome reduced tumor growth, researchers reported in July 2021 in Gastroenterology.
The vaccine Vilar-Sanchez’s team will test is more ambitious: It consists of viruses modified to carry DNA for a whopping 209 frameshift neoantigens found in Lynch tumors. People’s immune systems vary in how they respond to specific neoantigens, and different individuals’ tumors won’t all make the same set. “Therefore, the best [approach] is to have many,” says Elisa Scarselli, chief scientific officer of Nouscom, an Italian company developing the vaccine.
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