Abstract LB455: Preclinical efficacy and biomarker characterization of AT-108, a first-in-class in situ tumor-to-dendritic cell reprogramming agent

Abstract Defective antigen presentation and limited infiltration of professional antigen-presenting cells drive resistance to cancer immunotherapy. Type 1 conventional dendritic cells (cDC1s) are key orchestrators of antitumor immunity and their presence in tumors is associated with favorable clinical outcomes. We previously demonstrated that intratumoral delivery of an adenoviral vector encoding PU. 1, IRF8, and BATF3 (Ad5-PIB) reprograms tumor cells into cDC1-like antigen-presenting cells and synergizes with immune checkpoint blockade (ICB) to elicit antitumor immunity. Here, we characterized systemic immunity induced by Ad5-PIB, selected AT-108 as lead candidate, defined treatment requirements for durable efficacy and profiled biomarkers of response. Primary cancer cells, human xenografts, and syngeneic models were used to characterize Ad5-PIB and AT-108. In vivo efficacy was evaluated following intratumoral administration in ICB-resistant models MHCLOW T-cellLOW B16, T-cellLOW PANC02 and T-cellMEDIUM YUMM1. 7, or intraperitoneal administration in ID8 ascites model, as monotherapy or combined with ICBs (anti-PD-1, anti-CTLA-4). Transduction, reprogramming, and immune profiling were assessed by flow cytometry, and transgene expression confirmed by RT-ddPCR. Ascites burden was monitored by luciferase imaging. Ad5-PIB combined with ICB induced abscopal effects and long-term tumor-free survival in B16, associated with increased T cells and NK cells, and reduced regulatory T cells in injected and non-injected tumors. Screening of 25 PIB-encoding expression cassette variants incorporating distinct promoters and post-transcriptional regulatory elements identified AT-108, an optimized vector enabling superior cDC1 reprogramming, T-cell activation, and in vivo efficacy. AT-108 monotherapy induced 20% complete responses (CRs) in YUMM1. 7 and doubled median survival in B16. In combination with ICB, AT-108 achieved 50% CRs in B16 and extended survival in PANC02. Transduction peaked 1-2 days post-injection and persisted for 9-15 days, supporting re-dosing every two days to sustain transduction. A three-injection lead cycle was required for CRs, with maintenance dosing improving durability. The optimized regimen enabled dose-dependent efficacy in B16 and induced regression of ID8 ascites as monotherapy. Monotherapy efficacy was associated with detectable transgene expression in B16 tumors and increased effector/cytotoxic T cells, follicular helper T cells and dendritic cells in tumors and blood, identifying candidate pharmacodynamic markers for AT-108. Combination with ICB further amplified lymphocyte infiltration. These findings show that AT-108 induces systemic, dose-dependent efficacy with broad activity across distinct tumor microenvironments and highlights key biomarker parameters to explore in a future clinical trial. Citation Format: Fritiof Åkerström, Xavier Catena, Marta Santiago, Ana Perego, Ruixian Liu, Arun Sundaramurthy, Lihan Xie, Emilie Renaud, Andreea-Medeea Matei, Xiaoli Huang, Emma Leire, Ozcan Met, Inge-Marie Svane, Shane Olwill, Cristiana Pires, Filipe Pereira, Fabio Rosa. Preclinical efficacy and biomarker characterization of AT-108, a first-in-class in situ tumor-to-dendritic cell reprogramming agent abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB455.