Nanoparticulate Immunoactive Complex for Local Chemoimmunotherapy: From Murine Models to Pilot Canine Study.

UNLABELLED: Chemoimmunotherapy leverages the immune system to control tumor growth and develop durable antitumor immunity. With this goal, we previously developed a nanoparticulate immunoactive complex (IMAX), composed of polyethyleneimine-lithocholic acid conjugate, paclitaxel, and a cyclic dinucleotide, which showed robust antitumor activity in multiple mouse models following intratumoral administration. In this study, we evaluated the biodistribution of locally delivered IMAX and determined a safe and effective dose in mice to inform pilot safety and efficacy evaluations in dogs. In mice, IMAX remained localized at the injection site with minimal systemic exposure, induced rapid immune cell infiltration, evidenced by gross skin reactions and histologic changes, and achieved complete tumor regression even at one-fifth of the initial dose. Laboratory dogs tolerated IMAX well, with only transient, manageable adverse events. In a pilot study in companion dogs with naturally occurring cancer, IMAX administered at conservative doses induced histologic changes indicating immune cell infiltration and necrosis, accompanied by transcriptomic signatures of early innate immune pathway activation, resulting in measurable antitumor effects in the dogs with mammary carcinoma. These findings support the feasibility and safety of local IMAX therapy in tumor-bearing dogs and warrant further investigation with optimized dosing and combination strategies.

SIGNIFICANCE: Locally administered nanoparticulate IMAX induces complete tumor regression in mice and triggers rapid immune cell infiltration, while producing measurable antitumor responses in companion dogs with mammary carcinoma, supporting the translational potential.