CLD-401: A next-generation systemic gene therapy for tumor-localized expression of IL-15 superagonist.

Abstract

e14517 Background: RedTail is a next-generation gene therapy platform engineered for systemic delivery and highly selective, tumor-specific payload expression. The platform uses a tumor specific, extracellular enveloped vaccinia virus (EEV) expressing a chimeric form of CD55, providing resistance to complement and neutralizing antibodies, and enabling systemic administration, that has been engineered to only replicate in tumor cells. Our lead candidate, CLD-401, delivers an IL-15 superagonist (IL-15[N72D]-IL-15Rα), a potent cytokine that induces NK and CD8⁺ T cell responses in the tumor microenvironment (TME), driving robust antitumor immunity and efficacy. This platform represents a promising approach for safe, effective immuno-gene therapy in metastatic cancer. Methods: CLD-401 was administered systemically in syngeneic tumor-bearing mice. ELISA quantified IL-15 superagonist in serum and tumor lysates. Flow cytometry assessed immune infiltration and qPCR evaluated viral amplification in tumors versus normal tissues. Results: CLD-401 demonstrated robust production of EEV overexpressing CD55 and IL-15 superagonist, enabling selective tumor targeting without immune clearance after systemic delivery. CD55 overexpression conferred resistance to complement-mediated lysis and neutralizing antibodies. Following intravenous administration, CLD-401 efficiently homed to tumors and remodeled the TME, inducing substantial immune cell infiltration. Within tumors, CLD-401 amplified and reprogrammed tumor cells to produce high levels of IL-15 superagonist locally, while systemic exposure to IL-15 remained minimal, confirming tumor-localized payload delivery. This localized cytokine drove profound TME remodeling and resulted in complete tumor regression in murine breast and lung cancer models. Pharmacokinetic analysis of viral clearance and IL15 expression informed an optimized multidose regimen that maximized therapeutic response. In vitro, secreted IL-15 superagonist demonstrated functional activity by activating human and murine immune cells. qPCR confirmed tumor-specific viral amplification with negligible replication in normal mice or human tissues/cells, underscoring the platform’s tumor selectivity and safety. Conclusions: CLD-401 combines tumor-selective amplification with localized cytokine delivery, achieving potent antitumor immunity and durable responses while minimizing systemic toxicity. These findings support CLD-401 as a promising candidate for clinical development in targeting metastatic cancer.