Nous-209 Off-the-Shelf Neoantigen vaccination induces strong and broad neoantigen T cell response towards cancer interception in Lynch Syndrome carriers
Cancer interception aims to reduce cancer incidence by targeting pre-cancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndromes affecting ~ 1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair (MMR) genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy based on a heterologous prime boost using Great Ape Adenovirus and Modified Vaccinia virus Ankara encoding 209 FSPs shared across MSI neoplasms. We present the results from a Phase Ib/II single-arm trial of Nous-209 for cancer interception in LS carriers (N=45, cohort 1). Safety and immunogenicity were co-primary endpoints. Vaccination was safe and well tolerated with no intervention-related serious adverse events and no unexpected reactogenicity. The most common AEs were injection site reaction (any grade in 91% of participants post-prime and 76% post-boost with no grade 3) and fatigue (any grade in 80% post-prime and 53% post-boost with 4% grade 3 post-prime or post-boost). Neoantigen specific immune responses were observed post-vaccination in 100% of evaluable participants (N=37) with induction of potent T cell immunity (mean response at peak of ~ 1100 IFN-? spot forming cells (SFC) per million peripheral blood mononuclear cells). The immune response was durable and detectable at 1 year in 85% of participants. Both CD8+ and CD4+ T cell were induced recognizing multiple FSPs. Peptide-HLA predictions allowed the identification of >100 immunogenic FSPs and the demonstration of cytotoxic activity in vitro. Immunogenic FSPs were found in independent datasets of LS MSI colorectal pre-cancers and cancers. These results highlight the ability of Nous-209 to efficiently stimulate immunity against recurrent neoantigens in LS, supporting its development for cancer interception.