Work

1055 Preclinical characterization of local and systemic pharmacodynamic biomarkers of AT-108, a first-in-class in situ tumor-to-dendritic cell reprogramming agent

Year: 2026

Type: conference-abstract

Abstract: Background Defective antigen presentation and scarcity of conventional type 1 dendritic cells (cDC1s) contribute to cancer progression and resistance to immune checkpoint blockade (ICB). 1–6 We have developed AT-108, a replication-deficient adenoviral vector encoding transcription factors PU.1, IRF8, and BATF3 (PIB) that reprograms tumor cells into professional antigen-presenting cDC1-like cells. In preclinical models, intratumoral delivery of AT-108 resulted in monotherapy efficacy and synergy with ICB, resulting in complete tumor regression and abscopal antitumor responses.7 As AT-108 advances towards first-in-human studies, translational pharmacodynamic biomarkers are needed to demonstrate delivery, transgene expression, tumor microenvironment (TME) remodeling, and systemic immune activation. Here, we identified translational tumor- and blood-based biomarkers associated with AT-108 activity.Methods AT-108 was evaluated as monotherapy in the syngeneic ICB-resistant T-cell LOW B16 and T-cellMEDIUM YUMM1.7 models, compared with a non-coding adenoviral vector and PBS controls. Tumor and blood samples were analyzed using RT-ddPCR, RNA sequencing, flow cytometry, plasma proteomics, and immunofluorescence.Results AT-108 delivery and transgene expression were confirmed by immunofluorescence in tumor sections, and by RT-ddPCR and RNA sequencing in dissociated tumors. PIB transcript levels inversely correlated with tumor burden, linking transgene expression to therapeutic activity. Transcriptomic profiling revealed TME remodeling, characterized by induction of type I (OASL2, IRF7) and type II (IFNGR1, STAT4, TBX21) interferon signaling, cytotoxic lymphocyte programs (GZMB, CCR7, CD40LG), and humoral immune responses (LTB, IGHG2C), compared to treatment with control adenoviral vector. Immunofluorescence also showed co-localization of AT-108-tranduced cells with BCL6 + lymphoid aggregates, consistent with immunogenic tertiary lymphoid-like structure formation. TME remodeling was confirmed by flow cytometry, which showed increased intratumoral T-bet+PD-1- effector, Gzmb+ cytotoxic CD8+ T cells, and CXCR5+ PD-1+ germinal center follicular helper T cells (Tfh), DCs and reduced immunosuppressive Arg-1+/PD-L1+ myeloid populations. These pharmacodynamic changes were mimicked systemically, with expansion of effector, cytotoxic, CD44+ CD62L+ memory, and Ki67+ proliferating T cells, CXCR5+ ICOS+ PD-1+ Tfh cells, and DCs measured in peripheral blood by flow cytometry. Integrated blood transcriptomics and plasma proteomics identified induction of mitochondrial, type I interferon, and humoral immune programs together with increased circulating immunoglobulins, consistent with systemic immune activation and B-cell engagement. Finally, AT-108-induced tumor transcriptional signatures were associated with improved overall survival in human melanoma and head and neck cancer datasets, supporting the translational relevance of immune programs activated by AT-108.Conclusions Together, these findings establish a translational biomarker framework for in situ cDC1reprogramming and demonstrate that AT-108 expression, tumor remodeling and systemic immune activation can be monitored through tumor- and blood-based biomarkers.References Sharma P, et al. Immune checkpoint therapy—current perspectives and future directions. Cell. 2023;186:1652–1669. Broz M. L, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014;26:638–52. Salmon H, et al. Expansion and Activation of CD103+ Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity. 2016;44:924–938.Saito S, et al. Targeting Dendritic Cell Dysfunction to Circumvent Anti-PD1 Resistance in Head and Neck Cancer. Clinical Cancer Research. 2024;30:1934.Ho WW, et al. Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy. Proc. Natl. Acad. Sci. U. S. A. 2021;118:e2105323118.Heras-Murillo I, et al. Immunotherapy with conventional type-1 dendritic cells induces immune memory and limits tumor relapse. Nature Communications. 2025;16(1):16–3369.Ascic E, et al. In vivo dendritic cell reprogramming for cancer immunotherapy. Science. 2024.Ethics Approval Animal experiments were approved by the Swedish Malmö–Lund Animal Research Ethics Committee (Dnr 5.8.18-19343/2017, approved February 28, 2018; Dnr 5.8.18-06921/2025, approved May 21, 2025).

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1055