Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial
Summary
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 pept
Content
# Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial
*Published: 2026 Mar*
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 ).
DOI: 10.1038/s41591-025-04182-9