An investigational immunotherapy vaccine for people with Lynch syndrome has shown early promise in a Phase Ib/II study at provoking an immune response that intercepts the development of cancer. The findings, published in Nature Medicine, showed that NOUS-209, an off-the-shelf cancer vaccine designed to train the immune system to recognize and eliminate precancerous and cancerous cells before invasive disease develops, showed that it safely induced immune responses in 100% of patients treated involving both CD8+ and CD4+ T cells.
“Current management strategies for Lynch Syndrome patients—frequent screenings or elective preventive surgery—are life-changing interventions that help prevent cancer development but can significantly affect quality of life,” said principal investigator Eduardo Vilar-Sanchez, MD, PhD, a professor of clinical cancer prevention at MD Anderson. “By teaching the immune system to recognize and attack abnormal cells, this therapy offers a promising new approach to this patient population, who face a significantly higher risk of colorectal, endometrial, urothelial and other cancers.”
Lynch syndrome affects about one in 300 people and is caused by inherited mutations in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, PMS2 and EPCAM, genes that normally correct DNA replication errors. When these genes are damaged or defective, the errors accumulate, leading to microsatellite instability and somatic mutations that drive cancer development. People with Lynch syndrome have an 80% higher risk of developing cancer and often develop cancers at younger ages. Preventative measures employed today for people with Lynch syndrome include more frequent screenings such as frequent colonoscopy and chemoprevention with high doses of aspirin. In some cases, due to the high risk of endometrial and urothelial cancers, some with Lunch syndrome often undergo prophylactic preventative surgeries to remove the uterus and ovaries.
Currently, preventative measures for people with Lynch syndrome include high-dose aspirin and frequent colonoscopies. Some with Lynch syndrome also undergo prophylactic surgeries to remove the uterus or ovaries.
The use of high-dose aspirin is based on evidence showing that long-term aspirin can reduce cancer incidence in genetically high-risk individuals. “The high-dose clinical trial explored 600 milligrams daily of aspirin in Lynn Syndrome career population for a period over 2 years,” said Vilar-Sanchez, who noted that a more recent follow-up study has explored whether lower doses can achieve similar benefit. Based on early results, “it appears to be a non-inferior equivalent effect with lower doses of aspirin, with 100 mg and 300 mg doses showing comparable chemopreventive effects to 600 mg daily,” he added.
While there are some safety concerns about regular aspirin dosing surrounding gastrointestinal bleeding and other bleeds, Vilar-Sancez said these risks are not outweighed by the potential benefits. “Any preventive intervention [for Lynch syndrome carriers] will be out of context without proper risk evaluation. You’re talking lifetime risk for colon cancer of 80%, while bleeding risks are substantially lower,” he said.
Despite the relative chemopreventive effects of aspirin, other methods are needed. The clinical trial at MD Anderson focused on NOUS-209 as a potential preventative strategy to target precancerous lesions and early-stage tumors via the immune systems. This approach could be particularly effective in Lynch syndrome because MMR deficiency leads to the formation of shared mutations across people.
The vaccine targets what are known as frameshift peptides (FSPs), abnormal proteins that are generated when mutations occur in microsatellite regions of coding DNA. These newly generated peptides are foreign to the immune system and are present in a range of Lynch syndrome-associated precancers and cancers. Nous-209 is a neoantigen-directed immunotherapy based on a heterologous prime boost strategy, which uses two distinct viral vectors sequentially. In this case, the vaccine uses a great ape adenovirus for the initial prime and modified vaccinia virus Ankara (MVA) vectors for boosting immune response. It encodes 209 FSPs shared across MSI neoplasms, allowing it to “train” the immune system on the 209 shared targets to induce broad T-cell responses capable of recognizing heterogeneous and evolving lesions. The initial regimen consisted of a prime vaccination followed by a boost eight weeks later, a strategy designed to maximize both the magnitude and durability of the immune response.
This broad targeting differs from earlier vaccines developed for Lynch syndrome, which focused on a small number of recurrent neoantigens or developed personalized vaccines based on sequencing of each patient’s tumor. But such an approach to personalize vaccines are expensive and can only be applied after cancer diagnosis. The production of a broad vaccine that includes 209 FSP targets allows for the vaccine to be given before cancer has taken root, and allows for a single, off-the-shelf approach to cancer interception.
The NOUS-209 Phase Ib/II study was an open-label, single-arm trial that enrolled 45 healthy people with Lynch syndrome. Safety and immunogenicity were the coprimary endpoints. All 45 participants were included in the safety analysis, and 37 were evaluable for immune response. The vaccination was shown to be safe in all 45 patients, with no serious adverse events. Mild side effects included injection site reactions and fatigue, which are consistent with viral-vector vaccines.
The vaccine also elicited immune responses in 37 evaluable patients. “Neoantigen-specific immune responses were observed after… with induction of potent T cell immunity,” the researchers wrote. Both CD8+ and CD4+ T cells recognized multiple FSPs and immune responses remained detectable at one year in 85% of participants. Immune monitoring showed only a modest decline in response over time, suggesting sustained immunogenicity.
“We also built an additional cohort inside of the clinical trial, which is not reported in the manuscript, where we revaccinated these Lynch syndrome participants one year later to boost the immune response, and we have seen very positive outcomes with the revaccination,” Vilar-Sanchez said. “The boosting strategy shows that it’s capable of sustaining a level of immunogenicity that is adequate over time.”
Importantly, one year after vaccination, the researchers found fewer precancerous lesions and no new advanced adenomas during a surveillance colonoscopy. This observed reduction in the frequency of advanced adenomas represents a potentially encouraging early signal of efficacy, the researchers noted.
“When we were looking at the results of the exit colonoscopies of the carriers a year after the vaccination, we saw that basically none of the carriers were presenting with advanced lesions,” Vilar-Sanchez said. “That, to me, is early evidence of potential clinical activity, although it’s something we need to be cautious about and verify in a larger study.”
Based on these results the vaccine will now undergo broader study with a larger, high-risk, more diverse population of people with Lynch syndrome. The research will look to refine dosing schedules while also determining how long the immune response elicited by the vaccine lasts. Future studies are also expected to formally evaluate the optimal timing and frequency of booster vaccinations. The team also noted that it could investigator potential combination approaches to include elements of the current high-dose aspirin regimen prescribed for some patients.
If validated in larger trials, the research envision a future of immune-based interception for people living with Lynch syndrome by adding a preventive option that works alongside, or potentially reduces reliance on, frequent screening and preventive surgery.
