Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial.
Level 4 - case-series / case-control
Phase 1b/2 single-arm clinical trial without a control group.
PubMed 41545594 · doi:10.1038/s41591-025-04182-9
What was done
Cohort 1 of a phase 1b/2 single-arm trial evaluated the safety and immunogenicity (co-primary endpoints) of Nous-209 in 45 individuals carrying Lynch syndrome mutations (ClinicalTrials.gov: NCT05078866). Nous-209 is an off-the-shelf neoantigen vaccine using a heterologous prime-boost regimen (great ape adenovirus prime, modified vaccinia virus Ankara boost) encoding 209 shared frameshift peptides resulting from microsatellite instability. Safety was assessed in 45 participants, and immunogenicity was evaluated in 37 participants using interferon-γ ELISpot assays, CD4+/CD8+ phenotyping, and in vitro cytotoxicity assays.
What was found
No intervention-related serious adverse events were reported (n = 45). Common adverse events included injection-site reactions (any grade: 91% post-prime, 76% post-boost; 0% grade 3) and fatigue (any grade: 80% post-prime, 53% post-boost; 4% grade 3). Neoantigen-specific immune responses developed in 100% of evaluable participants (n = 37), generating a mean peak response of ~1,100 interferon-γ spot-forming cells per million peripheral blood mononuclear cells. Responses remained detectable at 1 year in 85% of participants. The vaccine induced both CD4+ and CD8+ T cells across more than 100 immunogenic frameshift peptides with demonstrated in vitro cytotoxicity.
Why it matters
Demonstrates that a shared-neoantigen vaccine can reliably elicit broad, durable T-cell immunity in Lynch syndrome carriers, providing clinical proof of concept for neoantigen-targeted cancer interception before tumor development.
Limits
Single-arm, non-randomized design without an untreated control group. Sample size was small (n = 45 overall, n = 37 evaluable for immunogenicity). The study measured surrogate immunogenicity and safety endpoints rather than long-term clinical reduction in cancer incidence or adenoma recurrence.
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