NOUS-209 Off-the-shelf Immunotherapy Has the Potential to Hit Primary and Metachronous Colorectal and Urothelial Cancers in Lynch Syndrome

Lynch syndrome (LS) is characterized by the development of microsatellite instable (MSI) cancers that share neoantigens, offering an opportunity for targeted immunotherapy. NOUS-209 is a heterologous prime-boost cancer vaccine in clinical development, employing viral vectors encoding 209 shared neoantigen peptides derived from frameshift mutations (FSMs) commonly found in MSI tumors. In this study, we investigated the presence and dynamics of NOUS-209 targeted FSMs in both primary and metachronous LS-associated cancers. Whole-exome sequencing was performed for 73 tumors, including 58 colorectal cancers (CRC) and 15 urothelial cancers (UC), from 58 individuals with confirmed LS. A median of 57 FSMs per CRC and 24 FSMs per UC was observed, with similar FSM burdens in both primary and metachronous tumors. Analysis of nine matched primary-metachronous tumor pairs revealed evidence of immune editing: FSMs predicted to encode highly immunogenic neoepitopes were selectively lost in metachronous tumors, while those with lower predicted immunogenicity were retained. Importantly, all subsequent primary cancers acquired novel FSMs encoding neoantigens with strong predicted HLA-binding affinity, supporting the rationale for NOUS-209-mediated immune interception. These findings demonstrated that NOUS-209 FSMs are present in both CRCs and UCs in LS, expanding the therapeutic potential of NOUS-209 beyond CRC. Moreover, the emergence of novel targetable FSMs in metachronous tumors suggests that NOUS-209 immunotherapy may be effective in the prevention of both primary and metachronous LS-associated cancers.