Abstract LB-C005: RedTail: A next-generation systemic platform for tumor-specific delivery of bites and immune activation

Abstract Introduction RedTail is a next-generation gene therapy platform that combines systemic delivery with with high payload expression. The platform uses a tumor specific, replicating extracellular enveloped vaccinia virus (EEV) expressing a chimeric form of CD55, providing resistance to complement and neutralizing antibodies and enabling systemic administration. The viral genome can be engineered to express immune activating payloads such as an IL-15 superagonist (IL-15 SA) and tumor-targeting bispecific T-cell engagers (BiTEs) for localized production within the tumor microenviroment (TME). Tumor selective viral amplification induces cancer cell lysis, T cell infiltration, and delivers high concentrations of immunomodulatory payloads such as IL-15 SA directly into tumors, altering the composition of the TME and potentially overcoming long-standing challenges with T-cell engagement in solid tumors. Methods RedTail EEVs were produced using selected host cell lines that provide protection against serum mediated inactivation. RedTail vectors engineered to express the IL-15 SA transgene were evaluated in vitro and in vivo to assess tumor targeted delivery of the payload and therapeutic efficacy. The vectors were further modified to produce BiTEs locally in the TME at high concentrations. Results Systemic administration of CLD-401, the first RedTail lead candidate expressing IL-15 SA, demonstrated robust tumor selectivity enabled by the CD55 expressing EEV, which protected the vector from complement mediated lysis and neutralizing antibodies in human serum ex vivo. In tumor bearing animals, CLD-401 selectively amplified within tumors, driving high intratumoral IL-15 SA expression at levels comparable to clinically validated IL-15 SA–Fc therapies, while remaining undetectable in nontumor tissues. IL-15 SA and viral expression peaked around day 6 and declined by day 17, corresponding with 80% complete tumor responses, strong immune cell infiltration, and remodeling of cytokine and immune cell profiles exclusively in tumor bearing hosts. Building on this platform, RedTail vectors were next engineered to express tumor targeted BiTE molecules alongside IL-15 SA. Infection of tumor cells resulted in efficient viral replication, tumor cell lysis, and high production of both BiTEs and IL-15 SA. Conclusions The RedTail platform enables efficient systemic delivery, selective tumor targeting, and transforms tumors into an in situ bioreactor for localized therapeutic production. It drives tumor restricted amplification, direct tumor cell killing, and robust antitumor immune activation while preserving oncolytic activity. Its modular design supports integration of diverse payloads, including IL-15 SA and BiTEs, allowing tailored interventions across cancer types. Together, these features position RedTail as a next-generation platform capable of enhancing T cell recruitment, promoting IL-15–mediated expansion, and redirecting T cells for potent, tumor selective cytotoxicity. Citation Format: Duong H. Nguyen, Yunyi Kang, Stephanie Songco, Trevor Smith, David Nguyen, Yan Pang, Robert Porter, Lina Schulte, Hongli Zhang, Sinje Tigges, Fabian Kortum, Daniela Kleinholz, Susan Tamraz, Ivelina Minev, Evan Cassavaugh, Travis Clifton, Thomas Herrmann, Barbara Hartl, Antonio Santidrian. RedTail: A next-generation systemic platform for tumor-specific delivery of bites and immune activation [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C005.