Eduardo Vilar-Sanchez, MD, presented the safety and immunogenicity of re-vaccination with Nous-209, a neoantigen vaccine for cancer interception in Lynch syndrome (LS) (Abstract 34380) at EMSO Congress 2026.
LS, also called hereditary nonpolyposis colorectal cancer (CRC), is a genetic pan-cancer syndrome predisposing to a variety of cancers, including colorectal, endometrial, ovarian, urothelial, gastric, small bowel, pancreas, and others. LS is the most common hereditary cancer predisposition syndrome, occurring in 1 in 279 individuals in the US, with an estimated life-time risk of CRC as high as 70%.
Mismatch repair deficiency (dMMR) is the hallmark of carcinogenesis in LS. dMMR neoplasms accumulate insertions or deletions of small DNA fragments in microsatellites, generating novel non-self frameshift peptides (FSPs) leading to mutated, highly immunogenic neoantigens. Shared and recurrent neoantigens across dMMR neoplasms are ideal targets for cancer interception.
Nous-209 is an off-the-shelf vaccine based on great ape adenovirus (GAd) for prime and boost and modified vaccinia Ankara (MVA) for boost. These vectors encode 209 FSPs shared across different dMMR in LS and sporadic neoplasms, and were validated in independent cohorts.
Initial results of the phase 1b/2 multicenter clinical trial (NCT05078866) of Nous-209 in healthy carriers of LS were reported. A cohort of 45 patients received GAd prime with MVA boost at 8 weeks. Vaccination was timed so the 52 week end-of-study evaluation would coincide with participants’ usual surveillance colonoscopies.
Primary endpoints were safety and immunogenicity. Secondary endpoints included changes in the incidence of CRC and adenomas/advanced adenomas (AA, which are pre-CRC lesions). Nous-209 is safe and well-tolerated. Adverse events were low grade and reactogenic as expected with an adenoviral vaccine. 100% of 37 participants with peripheral blood mononuclear cells (PBMC) evaluable for immunogenicity showed a robust T cell response by ex vivo ELISpot. A year after the initial dose this response was maintained in 33.
Dr. Vilar-Sanchez reported that re-vaccination at 1 year effectively boosts the immune response to levels seen after initial vaccination following either GAd/MVA (n=11) or MVA alone (n=14). Annual retreatment was not associated with any new safety signal.
The expected yearly incidence of AA is about 4%. At baseline the initial cohort had 4.7% AA. (n=2 of 43). At end-of-study year 1 there were no AA or CRC detected (n=43). No AA or CRC occurred in the subsequent colonoscopy at year 2 follow-up (n=17), admittedly a limited number of participants.
A phase 2/phase 3 multinational, registrational study is planned to randomly assign genetically confirmed high-risk LS carriers (N=1600) 1:1 to Nous-209 yearly vaccination vs placebo. The efficacy endpoint is prevention of pre-cancers, CRC, and LS-related cancers.
Discussant Zsofia Stadler, MD, said, “This is a landmark first study of a vaccine for cancer prevention in Lynch syndrome. The authors should be commended for this.”
She said she is excited the Nous-209 phase 2/3 trial is launching. “I do think we are entering a new frontier of immune-based cancer interception and prevention, but I do caution that immune response is not cancer prevention. We need that large randomized control trial.”
