Mutations Targeted by Nous-209 Immunotherapy Occur Early in Lynch Syndrome Carriers’ Precancer Lesions with Microsatellite Instability

This study provides a molecular characterization of precancerous colorectal lesions in Lynch syndrome (LS) carriers to assess the preventive potential of Nous-209 immunotherapy against colorectal cancer development. A total of 50 adenomas and 12 advanced adenomas (AA) were collected from 26 LS carriers with pathogenic variants in either MLH1 or MSH2. Molecular analyses included assessment of mismatch repair (MMR) status, microsatellite instability (MSI), and detection of mutations targeted by Nous-209. We found that 83% of AAs and 58% of adenomas were MMR-deficient (dMMR). Notably, although all dMMR AA were MSI-high (MSI-H), only 66% of dMMR adenomas showed MSI-H. The presence of Nous-209 mutations correlated strongly with MSI status, with mutation counts ranging from 15 to 57 in dMMR/MSI-H lesions. dMMR adenomas classified as MSI-low carried a limited number of mutations (6-19), whereas microsatellite-stable lesions harbored very few (0-2) Nous-209 mutations, regardless of MMR proficiency. These findings confirm the molecular heterogeneity of precancerous lesions and support the potential of Nous-209 immunotherapy to prevent MSI colorectal cancer in LS by targeting the adenoma-carcinoma sequence at the time of MSI acquisition. PREVENTION RELEVANCE: Our study shows that MSI and neoantigen accumulation emerge during the evolution of precancerous lesions in LS. These findings support the clinical evaluation of Nous-209, a shared neoantigen vaccine, as an immunoprevention strategy for MSI-driven colorectal carcinogenesis, with important implications for cancer prevention research.