Abstract 266: Redtail: A dual-programmable virotherapy platform for systemic tumor targeting and localized gene delivery.

Abstract RedTail is a next-generation gene therapy platform combining systemic delivery with tumor selectivity. Unlike conventional oncolytic viruses, RedTail integrates programmable targeting for precise tumor specificity and genetic payload delivery for immune modulation of the tumor microenvironment (TME). It employs a tumor-specific, replicating extracellular enveloped vaccinia virus (EEV) cloaked in a second human cell-derived membrane (the “Envelope”) from engineered host cell lines; chimeric CD55 overexpression in the Envelope confers resistance to complement and neutralizing antibodies, enabling systemic administration. The Envelope can be further designed to express targeting proteins. The viral genome can be modified to deliver immune-cell activating therapeutic payloads such as IL-15 Superagonist along with bispecific T-cell engagers (BiTEs) for localized expression in the tumor microenvironment. Delivering BITEs at high concentrations to the tumor while simultaneously activating T-cells in the TME through in situ expression of an immunostimulatory payload may overcome the challenges seen to date with T-cell engagers in solid tumors. Methods: RedTail EEVs were produced using engineered host cell lines expressing chimeric antigen receptors (CARs). The RedTail EEVs were further engineered to express BITEs and T-cell activating payloads at high concentrations in situ. Tumor targeting, viral amplification, and transgene expression were assessed by viral titers, ELISA, flow cytometry, and immunohistochemistry. Results: The first programmable characteristic of RedTail is its extracellular membrane. RedTail EEVs were manufactured using host cell lines engineered to express CARs, producing particles that displayed CARs (e.g., anti-HER2, anti-Trop2) on their surface with corresponding tropism.The second programmable characteristic is the viral genome, engineered to express genetic payloads including BiTEs targeting tumor antigens along with CD3 to recruit and activate T cells. A T-cell activating payload was also included. Viral infection was enhanced for tumor cells that displayed the cognate target, and resulted in tumor cell lysis along with high levels of expression of the BITE and the immune stimulating payload.This dual programmability—membrane engineering for targeting and genome programming for payload delivery—represents a unique approach among systemic virotherapies. Conclusions: This dual programmability enables systemic tumor targeting, immune priming, and localized expression of both a T-cell engager and an immune priming payload, positioning RedTail as a next-generation systemic platform with a unique approach to T-cell targeting in solid tumors. Citation Format: Yunyi Kang, Duong H. Nguyen, Stephanie Songco, Trevor Smith, David Nguyen, Yan Pang, Lina Schulte, Hongli Zhang, Sinje Tigges, Fabian Kortum, Daniela Kleinholz, Susan Tamraz, Ivelina Minev, Evan Cassavaugh, Travis Clifton, Thomas Herrmann, Barbara Hartl, Antonio F. Santidrian. Redtail: A dual-programmable virotherapy platform for systemic tumor targeting and localized gene delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 266.