Abstract RedTail is a next-generation gene therapy platform engineered for systemic delivery and tumor selectivity. It uses a tumor-specific replication form of extracellular enveloped vaccinia virus (EEV) with chimeric CD55 expression to resist complement and neutralizing antibodies, enabling robust systemic administration. CLD-401, the lead candidate, converts tumors into factories producing IL-15(N72D)-IL-15RαSushi (IL-15 superagonist, IL-15 SA), a clinically validated cytokine that potently activates NK and CD8+ T cells. Methods Resistance to humoral immunity was assessed via plaque assays. Tumor cytotoxicity was measured by real-time impedance analysis. CLD-401 was administered systemically in multiple syngeneic models to evaluate tumor selectivity and IL-15 SA expression. Biodistribution and pharmacokinetics were quantified by dPCR. Flow cytometry and IHC characterized immune infiltration. Results To enable effective systemic delivery, CLD-401 was manufactured using an optimized host cell line that supports high production of EEV. These CD55 expressing EEV particles e were resistant to complement-mediated lysis and neutralizing antibodies in both syngeneic models and in ex vivo experiments using human serum. This immune evasion mechanism enables CLD-401 to selectively target tumors while maintaining robust systemic activity. In tumor-bearing preclinical models, but not in non-tumor-bearing controls, systemic administration resulted in tumor-specific viral amplification, which correlated with in situ IL-15 SA expression at levels comparable to clinically validated efficacy in bladder cancer reported with the approved IL-15-SA-Fc. IL-15 SA and viral expression peaked in tumors and plasma around day 6 and declined by day 17, coinciding with 80% tumor complete responses and tumor clearance, while remaining undetectable in other organs. Data confirmed strong local IL-15 SA production after systemic virotherapy, promoting antitumor immune cell infiltration and activation. Tumor amplification of CLD-401 and IL-15 SA expression also drove changes in peripheral cytokine profiles and immune cell populations, observed significantly in tumor-bearing animals but not in disease-free models suggesting a remodeling of the tumor microenvironment. CLD-401 supported repeat dosing, achieving superior efficacy compared to single-dose regimens indicating a lack of a neutralizing response. Conclusions Systemic CLD-401 enables tumor-specific amplification and high-level IL-15 SA expression, achieving durable regression without off-target toxicity. These findings support IND-enabling studies for CLD-401 and highlight the potential of the RedTail platforms as a next-generation systemic virotherapy with targeted and efficient delivery of genetic payloads. Citation Format: Duong H. Nguyen, Yunyi Kang, 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 Härtl, Antonio F. Santidrian. CLD-401, an IL-15 superagonist gene medicine via redtail virotherapy, achieves sustained tumor eradication 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 4310.
Nguyen et al. (Fri,) studied this question.