Abstract 6427: Nous-209 off-the-shelf neoantigen immunotherapy induces robust neoantigen T cell response with the potential to intercept cancer in Lynch syndrome carriers

Abstract Cancer interception represents a new approach, aimed at targeting precancerous lesions and therefore preventing cancer occurrence. Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes, with an estimated prevalence of one in 300, and high-risk predisposition to several types of cancer, with up to 80% lifetime risk to develop CRC. LS is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. Loss of MMR proteins causes an accumulation of mutations in the microsatellite sequences, known as Microsatellite instability (MSI), that can lead to shared frameshift mutations (FSP). Nous-209 is a neoantigen directed immunotherapy encoding 209 FSP shared across sporadic and hereditary MSI tumors and precancer lesions in clinical development for interception and treatment of MSI tumors (Leoni et al., 2020; NCT04041310). Here, we report the full set of safety and immunogenicity results of a Phase Ib/II study of Nous-209 monotherapy in LS carriers. NCT05078866 is a Phase Ib/II single-arm, open-label, trial of Nous-209 for cancer interception in LS carriers assessing as co-primary endpoints the safety and immunogenicity against the FSP neoantigens encoded by Nous-209. Nous-209 is administered intramuscularly: one prime with a Great Ape Adenovirus (GAd20-209-FSPs) on day 1, followed by a boost with a Modified Vaccinia Ankara (MVA-209-FSPs) at week 8. Immunogenicity was measured by ex-vivo IFN-γ ELISpot assay utilizing pre- and post-vaccination peripheral blood mononuclear cells (PMBCs) samples collected at different timepoints. The trial fully enrolled 45 LS carriers, all receiving GAd20-209-FSPs and MVA-209-FSPs. Most pts (21 of 45, 46.7%) harbored MSH2 pathogenic germline variants. 19 of 45 (42.2%) pts had a prior history of cancer. Treatment was safe and well tolerated with no treatment-related serious adverse events (AEs) and no unexpected reactogenicity. The most common AEs were injection site reactions (any grade: 84% post-prime, 73% post-boost; grade 3: 0%) and fatigue (any grade: 78% post-prime, 51% post-boost; grade 3: 4%). Neoantigen specific immune responses post Nous-209 were observed in 100% of evaluable participants (37/37), with induction of robust T cell immunity reaching a mean of T cell response at peak of ∼ 1100 IFN-γ spot forming cells (SFC) per million of PBMC, polyfunctional and long lasting CD8 and CD4 T cell responses broadly recognizing multiple FSPs. The use of peptide binding HLA predictions allowed the precise identification of several immunogenic FSPs, shown to be present in independent datasets of MSI premalignant lesions and cancers in LS carriers. The complete safety and immunogenicity results from this Phase Ib/II trial support the further development of Nous-209 monotherapy, highlighting its potential to efficiently stimulate the immune system and intercept cancer in LS carriers. Citation Format: Jason Willis, Anna Morena D'Alise, Michael J. Hall, Marcia Cruz-Correa, Gregory E. Idos, Selvi Thirumurthi, Veroushka Ballester, Guido Leoni, Irene Garzia, Laura Antonucci, Lorenzo De Marco, Elisa Micarelli, Sven Gogov, Wenli Dong, J. Jack Lee, Lana A. Vornik, Araceli Garcia-Gonzalez, Laura Reyes-Uribe, Ellen Richmond, Asad Umar, Powel H. Brown, Luz Maria Rodriguez, Elisa Scarselli, Eduardo Vilar. Nous-209 off-the-shelf neoantigen immunotherapy induces robust neoantigen T cell response with the potential to intercept cancer in Lynch syndrome carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6427.