21 februari 2026: Bron: Nature en MS Andersen Cancer Centre

Uit een fase I/II veiligheidstudie blijkt dat Nous-209 een zogenoemd immuungericht vaccin, zich nieuw vormende kanker veroorzaakt door het Lynch Syndroom, kan ontdekken en vernietigen. Bij alle deelnemende patiënten (N = 45) werden duurzame immuunreacties, tumorgerichte activiteit en vroege aanwijzingen voor het voorkomen van kanker gezien.
Het Lynch Syndroom wordt veroorzaakt door erfelijke mutaties in mismatch repair (MMR)-genen, die normaal gesproken helpen bij het herstellen van DNA-fouten. Patiënten met het Lynch Syndroom hebben een genetische aanleg voor het ontwikkelen van vormen van kanker met microsatellietinstabiliteit en ontwikkelen vaak kanker op jongere leeftijd dan de algemene bevolking.

"De huidige behandelstrategieën voor patiënten met het Lynch Syndroom – frequente screenings of curatieve preventieve chirurgie – zijn levensveranderende interventies die helpen de ontwikkeling van kanker te voorkomen, maar kunnen de kwaliteit van leven aanzienlijk beïnvloeden", aldus hoofdonderzoeker Eduardo Vilar-Sanchez, M.D., Ph.D.. "Door het immuunsysteem te leren abnormale cellen te herkennen en aan te vallen, biedt deze therapie een veelbelovende nieuwe aanpak voor deze patiëntengroep, die een aanzienlijk hoger risico loopt op darmkanker, baarmoederkanker, blaaskanker en andere vormen van kanker."

Het volledige studieverslag is gratis in te zien of te downloaden met gedetailleerde beschrijvingen en grafieken. Klik op de titel van het abstract dat 16 januari 2026 werd gepubliceerd in Nature:

Article
Open access
Published: 16 January 2026

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

Nature Medicine (2026)Cite this article

Abstract

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).

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

Deidentified individual participant clinical and genomic data that underlie the results reported in this article are available for transfer, with responses provided within 30 days of request. Interested investigators can obtain and certify the data transfer agreement and submit requests to the principal investigator (E.V.), which will coordinate with the NCI. Investigators and institutions who consent to the terms of the data transfer agreement form, including but not limited to the use of these data for the purpose of a specific project and only for research purposes, and to protect the confidentiality of the data and limit the possibility of identification of participants in any way whatsoever for the duration of the agreement will be granted access. E.V. will then facilitate the transfer of the requested deidentified data. This process is expected to be through a secure file transfer service but the study leadership reserves the right to change the specific transfer method at any time, provided appropriate levels of access authorization and control can be maintained. WES data generated in this study were deposited to the Sequence Read Archive under BioProject PRJNA1370313. Source data are provided with this paper.

References

Win, A. K. et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 26, 404–412 (2017).

Article CAS PubMed Google Scholar
Bonadona, V. et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305, 2304–2310 (2011).

Article CAS PubMed Google Scholar
Lynch, H. T., Snyder, C. L., Shaw, T. G., Heinen, C. D. & Hitchins, M. P. Milestones of Lynch syndrome: 1895-2015. Nat. Rev. Cancer 15, 181–194 (2015).

Article CAS PubMed Google Scholar
Burn, J. et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet 395, 1855–1863 (2020).

Article CAS PubMed PubMed Central Google Scholar
Baretti, M. & Le, D. T. DNA mismatch repair in cancer. Pharmacol. Ther. 189, 45–62 (2018).

Article CAS PubMed Google Scholar
Kloor, M. & von Knebel Doeberitz, M. The immune biology of microsatellite-unstable cancer. Trends Cancer 2, 121–133 (2016).

Article PubMed Google Scholar
Bolivar, A. M. et al. Genomic landscape of Lynch syndrome colorectal neoplasia identifies shared mutated neoantigens for immunoprevention. Gastroenterology 166, 787–8011 (2024).

Article CAS PubMed PubMed Central Google Scholar
Bowen, C. M., Sinha, K. M. & Vilar, E. Immunoprevention strategies for colorectal cancer in Lynch syndrome carriers. Cancer J. 30, 352–356 (2024).

Article CAS PubMed PubMed Central Google Scholar
Xie, N. et al. Neoantigens: promising targets for cancer therapy. Signal Transduct. Target. Ther. 8, 9 (2023).

Article CAS PubMed PubMed Central Google Scholar
Kloor, M. et al. A frameshift peptide neoantigen-based vaccine for mismatch repair-deficient cancers: a phase I/IIa clinical trial. Clin. Cancer Res. 26, 4503–4510 (2020).

Article CAS PubMed Google Scholar
Jolanda, I. 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 at Research Square https://doi.org/10.21203/rs.3.rs-6718232/v1 (2025).
Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).

Article CAS PubMed Google Scholar
D’Alise, A. M. et al. Phase I trial of viral vector-based personalized vaccination elicits robust neoantigen-specific antitumor T-cell responses. Clin. Cancer Res. 30, 2412–2423 (2024).

Article PubMed PubMed Central Google Scholar
Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).

Article CAS PubMed PubMed Central Google Scholar
Yarchoan, M. et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat. Med. 30, 1044–1053 (2024).

Article CAS PubMed PubMed Central Google Scholar
Sasso, E. et al. New viral vectors for infectious diseases and cancer. Semin. Immunol. 50, 101430 (2020).

Article CAS PubMed Google Scholar
Secli, L. et al. Personalized cancer vaccines go viral: viral vectors in the era of personalized immunotherapy of cancer. Int. J. Mol. Sci. 24, 16591 (2023).

Article CAS PubMed PubMed Central Google Scholar
D'Alise, A. M. et al. Adenoviral-based vaccine promotes neoantigen-specific CD8+ T cell stemness and tumor rejection. Sci. Transl. Med 14, eabo7604 (2022).

Article CAS PubMed PubMed Central Google Scholar
Pant, S. et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat. Med. 30, 531–542 (2024).

Article CAS PubMed PubMed Central Google Scholar
Sheehy, S. H. et al. ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans. Mol. Ther. 20, 2355–2368 (2012).

Article CAS PubMed PubMed Central Google Scholar
Swadling, L. et al. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci. Transl. Med. 6, 261ra153 (2014).

Article PubMed PubMed Central Google Scholar
D’Alise, A. M. et al. Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade. Nat. Commun. 10, 2688 (2019).

Article PubMed PubMed Central Google Scholar
Garzia, I. et al. Tumor burden dictates the neoantigen features required to generate an effective cancer vaccine. Cancer Immunol. Res. 12, 440–452 (2024).

Article CAS PubMed PubMed Central Google Scholar
Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

Article CAS PubMed Google Scholar
Ahrends, T. et al. CD4+ T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness. Immunity 47, 848–861 (2017).

Article CAS PubMed Google Scholar
De Paolis, E. et al. Characterization of shared neoantigens landscape in mismatch repair deficient endometrial cancer. NPJ Precis. Oncol. 8, 283 (2024).

Article PubMed PubMed Central Google Scholar
Leoni, G. et al. A genetic vaccine encoding shared cancer neoantigens to treat tumors with microsatellite instability. Cancer Res. 80, 3972–3982 (2020).

Article CAS PubMed Google Scholar
De Marco, L. et al. Abstract PR-05: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients. Cancer Immunol. Res. 12, PR-05 (2024).

Article Google Scholar
Del Carmen, G. et al. Colorectal surveillance outcomes from an institutional longitudinal cohort of lynch syndrome carriers. Front. Oncol. 13, 1146825 (2023).

Article PubMed PubMed Central Google Scholar
Castillo-Iturra, J., Sanchez, A. & Balaguer, F. Colonoscopic surveillance in Lynch syndrome: guidelines in perspective. Fam. Cancer 23, 459–468 (2024).

Article PubMed PubMed Central Google Scholar
Sanchez, A. et al. Gene-specific detection rate of adenomas and advanced adenomas in Lynch syndrome. Gastroenterology 169, 663–675 (2025).

Article CAS PubMed Google Scholar
Dabir, P. D. et al. Microsatellite instability screening in colorectal adenomas to detect Lynch syndrome patients? A systematic review and meta-analysis. Eur. J. Hum. Genet. 28, 277–286 (2020).

Article CAS PubMed Google Scholar
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).

Article CAS PubMed PubMed Central Google Scholar
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

Article CAS PubMed PubMed Central Google Scholar
Danecek, P. et al. Twelve years of SAMtools and BCFtools. Gigascience 10, giab008 (2021).

Article PubMed PubMed Central Google Scholar
McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

Article CAS PubMed PubMed Central Google Scholar
Niu, B. et al. MSIsensor: microsatellite instability detection using paired tumor–normal sequence data. Bioinformatics 30, 1015–1016 (2014).

Article CAS PubMed Google Scholar
Roudko, V. et al. Shared immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors. Cell 183, 1634–1649 (2020).

Article CAS PubMed PubMed Central Google Scholar

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Acknowledgements

Nouscom provided the vaccine to the NCI under a Clinical Trials Agreement and contributed to the study design, data analysis and the decision to publish the results. Employees of Nouscom received salaries for their contributions to the study. We thank the participants and their families for their involvement in this clinical trial. This work was supported by grants UG1 CA242609 and R01 CA257375 (US National Institutes of Health (NIH)/NCI) to E.V. and the generous philanthropic contributions to MD Anderson Cancer Center SPORE in Gastrointestinal Cancer P50 CA221707 (US NIH/NCI) and P30 CA016672 (US NIH/NCI) to the University of Texas MD Anderson Cancer Center Core Support Grant. J.W. was supported by the Paul Calabresi Clinical Oncology Program Award K12 (CA088084–20). F.D. was supported by the Cancer Prevention Research Training Program (CPRTP) postdoctoral fellowship in cancer prevention program RP170259 (Cancer Prevention and Research Institute of Texas).

Author information

These authors contributed equally: Anna Morena D’Alise, Jason Willis.

Authors and Affiliations

Nouscom SRL, Rome, Italy

Anna Morena D’Alise, Guido Leoni, Irene Garzia, Laura Antonucci, Lorenzo De Marco, Elisa Micarelli, Laura Seclì & Elisa Scarselli
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Jason Willis
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Fahriye Duzagac, Nan Deng, Charles M. Bowen, Lana A. Vornik, Araceli Garcia-Gonzalez, Laura Reyes-Uribe, Powel H. Brown, Krishna M. Sinha & Eduardo Vilar
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA

Michael J. Hall
University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA

Marcia Cruz-Correa & Veroushka Ballester
City of Hope Comprehensive Cancer Center, Duarte, CA, USA

Gregory E. Idos
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Selvi Thirumurthi
Nouscom AG, Basel, Switzerland

Sven Gogov
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Wenli Dong & J. Jack Lee
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA

Ellen Richmond, Asad Umar & Luz Maria Rodriguez
Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA

Luz Maria Rodriguez

Contributions

E.V. and E.S. designed the study. E.V., J.W., M.J.H., M.C.C., G.E.I., S.T., V.B., L.A.V., A.G., E.R., A.U., P.H.B. and L.M.R. contributed to clinical oversight and participant recruitment, enrollment and treatment. A.M.D. oversaw the immunomonitoring work and analysis. L.A. and I.G., performed the immunological assays. L.D.M., E.M., G.L. and N.D. performed the computational analyses. C.M.B., K.M.S., F.D. and L.R. contributed to execution and data analysis. S.G. and L.S. contributed to data analysis. W.D. and J.J.L. contributed to the statistical analysis. A.M.D., E.V., E.S. and J.W. wrote, reviewed and edited the manuscript. All authors reviewed the manuscript, provided edits and approved the final version. E.S. and E.V. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Elisa Scarselli or Eduardo Vilar.

Ethics declarations

Competing interests

E.V. has had a consulting or advisory role with Janssen Research and Development, Recursion Pharma, Nouscom, Abbvie, Moderna, Permanence Bio and Parabilis, has received research support from Janssen Research and Development and has equity in Permanence Bio. J.W. has had a consulting role with Healios H.K. and TME Therapeutics and has received research support from Amal Therapeutics. E.S. is Nouscom cofounder and employee and reports stock ownership. A.M.D. and S.G. are employees of Nouscom and report stock ownership. I.G., L.A., L.D.M., E.M. and L.S. are employees of Nouscom. M.C.C. has research contracts with BMS, Jannsen, MERCK, AstraZeneca, Abbvie, Huyabio, BeiGene, Natera, Exact Sciences, INCYTE, Astellas, Genentech, GenMab, Revolution Medicine and Pfizer. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Asaf Maoz, Else Marit Inderberg and Zsofia Stadler for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.