Lynch syndrome, named for American physician Dr. Henry T. Lynch, is a hereditary condition that causes a predisposition to several types of cancer, most commonly colorectal but to other types as well, including ovarian, endometrial and stomach cancer. The root of this disorder lies in a genetic defect known as DNA mismatch repair deficiency (or dMMR), which affects the process by which mistakes are repaired when our DNA is copied during cell division. People with Lynch syndrome can have up to an 80% increased lifetime risk of developing colorectal cancer, and are more susceptible to developing colorectal and other types of cancers at an earlier age. Accounting for 3-5% of all colon cancers, Lynch syndrome is an excellent target for preventative treatment, like a vaccine. Research exploring a Lynch syndrome vaccine seeks to harness the body’s innate immune response to target tumor cells and has yielded promising results.
In Lynch syndrome, dMMR leads to something called microsatellite instability (MSI), which leaves DNA especially vulnerable to mutations. Mutations that impact cancer-related genes, such as those that suppress tumorigenesis, in turn can lead to the appearance and growth of tumors. These tumors produce a unique type of peptide known as a neoantigen. The presence of high numbers of neoantigens makes tumors that arise as a result of MSI particularly responsive to immunotherapy. Recently, research has focused on using neoantigen-based vaccines to boost a patient’s immune response, encouraging the immune system to recognize these neoantigens and react accordingly. The added benefit to a treatment of this design is that it strives to specifically target malignant growths, while sparing normal tissues.
Studies conducted in both Lynch syndrome mouse models and in humans with advanced-stage disease have shown that neoantigen-based vaccines have the potential to be highly effective in suppressing tumor growth and prolonging survival. One study published in Gastroenterology explored the cancer-preventative effect of a vaccine comprising four types of neoantigens in mice, and found that the number of intestinal tumors seen was significantly reduced and overall survival rates improved. Researchers observed that there was a strong immune response in those mice that had received the vaccine over those that hadn’t, suggesting that vaccination may be a powerful defense against cancer growth. A phase I/IIa clinical trial in humans with advanced-stage Lynch syndrome also found that vaccination with neoantigens was tolerated well and induced a strong immune response in participants. Additionally, Nouscom, a Switzerland-based clinical stage immune-oncology company, is undertaking a study that will evaluate the safety and immunogenicity of a vaccine comprising 209 neoantigens. In using a wide spectrum of neoantigens, researchers hope to induce an equally broad immune response.
Questions remain over which combination of neoantigens is most effective in generating an immune response, how many are needed, and how they may differ between individuals. Vaccines may be used in conjunction with other therapies, including immune checkpoint inhibitors and non-steroidal anti-inflammatory drugs, to bolster effect. As with other cancer immunotherapies, vaccination carries with it the risk of immune evasion, wherein the tumor develops strategies to suppress or avoid a patient’s immune response. However, if used preventatively rather than therapeutically, a vaccine may be able to target cancer cells in the early stages when they are most vulnerable, thereby boosting its efficacy. Additional challenges to the use of neoantigen vaccines include prohibitive cost and an especially long development cycle, which may keep patients with poor prognoses waiting too long for treatment.
It is estimated that 1 in 279 people have Lynch syndrome1, but 95% of those people don’t know they have it2. While screening methods have advanced, prevention and treatment have been elusive. Vaccines have garnered lots of well-deserved attention in the field of immunotherapy and are a promising weapon in the long-fought battle against cancer. If proven effective, neoantigen-based vaccines could represent a major step forward in treating Lynch syndrome, and could potentially be applied across other cancer syndromes where MSI-H plays a role.
Learn more about Lynch syndrome.
References:
1Win, A.K. et al. (2017) Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidimiol. Prev. 26, 404-412.
2Cancer.gov. Cancer MoonshotSM Blue Ribbon Panel.
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