Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial.

Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome 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 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 cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45). Safety and immunogenicity were coprimary endpoints. Safety was assessed in 45 participants. Vaccination was safe with no intervention-related serious adverse events (AEs). The most common AEs were injection-site reactions (any grade in 91% of participants after prime and 76% after boost with no grade 3) and fatigue (any grade in 80% after prime and 53% after boost with 4% grade 3 after prime or after boost). Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity (mean response at peak of ~1,100 interferon-γ spot-forming cells 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 cells were induced, recognizing multiple FSPs. Peptide-human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro. Immunogenic FSPs were found in independent datasets of LS MSI colorectal precancers and cancers. These results highlight Nous-209 ability to efficiently stimulate immunity against neoantigens in LS, supporting its development for cancer interception (ClinicalTrials.gov identifier: NCT05078866 ).