Updates in Vaccine Chemoprevention in Lynch Syndrome

Blake Jones, MD - CGA-IGC Communications Committee Member

In the April issue of Familial Cancer, Romy N. Kuipers and colleagues provide an excellent, up-to-date review of the current state of vaccine-based chemoprevention strategies in Lynch Syndrome (LS).[1]

Those who care for LS patients are probably familiar with these efforts, as are many of our patients. This review provides an excellent resource for catching up on the current state of LS vaccine research in preparation for the inevitable next time one of our patients asks for an update.

The authors succinctly lay out the clinical and molecular characteristics of LS-related cancers that make them optimal targets for vaccine therapies. Specifically, the characteristic mismatch-repair defects result in abnormal protein expression and neoantigens that are preserved across LS patients, representing an attractive target for broadly applicable vaccines. Additionally, these neoantigens are highly immunogenic and tumor-specific, allowing for robust and targeted vaccine-induced immune activation. Finally, LS patients are prone to a high rate of neoplastic and pre-neoplastic lesions, ideal for inducing a durable vaccine-mediated immune response. The authors emphasize the promise of LS vaccines as a preventive strategy, acting on pre-neoplasia or early neoplasia before the immune evasion strategies of more advanced tumors are established.

The remainder of the article delves into a detailed account of specific vaccine antigen and delivery strategies while highlighting existing studies examining vaccine effectiveness in the prevention of or therapy for LS-associated cancers. Those interested in the molecular and biochemical approach to LS vaccination will find this section interesting, though it will be less relevant to our patients. Below I will highlight the studies and existing data provided in the article.

The authors first focus on tumor-associated antigens (TAAs), in which particular self-derived antigens are overexpressed in tumor cells. The weakness of TAAs is the risk of autoimmunity and weak immunogenicity, as these antigens are not unique to tumor cells. With that said, there is one phase IIb study of unaffected LS patients utilizing the TAAs CEA, MICU, and TBXT in an adenovirus vector vaccine (NCT05419011). The study is active but no longer recruiting, with no published data as of yet.

The authors again highlight that neoantigens present a more promising target for LS vaccines given their tumor specificity and stronger immunogenicity compared to TAAs. As such, the bulk of existing clinical trials assessing vaccine effectiveness in LS are centered on this approach. Table 3 within the article provides a concise but thorough assessment of published or ongoing clinical trials of vaccine prevention or therapeutic efforts in LS or dMMR tumors.

The authors themselves conducted a phase I/II trial of a dendritic cell-based delivery vaccine utilizing both neoantigens and CEA as a TAA in 23 LS patients (3 with recently resected CRC and 20 disease-free patients).[2] The vaccine demonstrated safety. Thirty-nine percent of patients developed a mutant neoantigen-specific T-cell response, and all were free of CRC or advanced adenomas at 11 years.

Two parallel phase I/II trials are underway using the NOUS-209 adenovirus-encoded frameshift neoantigen vaccine in both affected (along with pembrolizumab) and unaffected LS patients — (NCT04041310) and (NCT05078866), respectively. While results for the first trial have not been published, in the second, researchers observed that all evaluated patients demonstrated a neoantigen-specific immune response, which was durable at 1 year in 85% of those assessed.[3] No serious adverse events were reported. Tumor-related clinical outcomes were not reported; however, there was a reduction in pre-cancerous lesions and no advanced adenomas detected in the cohort at 1-year post-vaccination.

All of the studies listed in this article are no more advanced than phase II, and there are currently no phase III trials listed on ClinicalTrials.gov. This highlights the challenges that remain in developing LS chemoprevention and therapeutic vaccines, and as of now there is a shortage of clinical outcome data. With that said, it was recently announced that NOUS-209 received fast-track designation from the FDA, which lends hope that these efforts will accelerate in the near future.[4]

1. Kuipers RN, et al. Vaccine strategies for cancer prevention in Lynch syndrome: the potential of dendritic cell-based therapy. Fam Cancer. 2026;25(2):41. doi:10.1007/s10689-026-00559-y

2. de Vries IJM, et al. Preventive dendritic cell vaccination induced TGF-βRII frameshift neoantigen-specific T-cells are linked to long-term disease-free survival in Lynch Syndrome patients [Preprint]. Posted July 2025. doi:10.21203/rs.3.rs-6718232/v1

3. D’Alise AM, et al. NOUS-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial. Nat Med. 2026;32(3):1002-1011. doi:10.1038/s41591-025-04182-9

4. Nouscom. Nouscom receives U.S. FDA fast track designation for NOUS-209, a novel immunotherapy for the prevention of Lynch syndrome-associated cancers. BioSpace. Published June 2026. Accessed June 3, 2026. https://www.biospace.com/press-releases/nouscom-receives-u-s-fda-fast-track-designation-for-nous-209-a-novel-immunotherapy-for-the-prevention-of-lynch-syndrome-associated-cancers