Chimeric IL-15 as a next-generation immunotherapeutic: preclinical assessment of efficacy and safety

Interleukin-15 (IL-15) is a potent immunostimulatory cytokine but is limited by rapid clearance and systemic toxicity. To overcome these limitations, our laboratory generated a chimeric IL-15 by fusing human IL-15 to the murine IgG2a Fc domain and evaluated its activity, efficacy, pharmacokinetics, and safety. The purified protein showed accurate molecular integrity determined through SDS-PAGE and Western blot. In-vitro, chimeric IL-15 induced dose-dependent activation of CD4⁺ and CD8⁺ T cells and NK cells, with increased frequencies of CD8⁺CD107a⁺ cytotoxic T cells and CD8⁺IFN-γ⁺ effector populations. In-vivo treatment resulted in time- and dose-dependent expansion of splenic cytotoxic lymphocyte subsets. Pharmacokinetic analysis demonstrated rapid distribution and a prolonged half-life of 40-53 h, while biodistribution studies confirmed widespread tissue localisation without abnormal accumulation. In syngeneic B16F10 melanoma and 4T1 breast cancer models, chimeric IL-15 significantly inhibited tumour growth and improved survival, accompanied by increased infiltration and activation of CD8⁺ T cells and NK cells in tumours and lymphoid tissues. Acute and subacute toxicity studies revealed no major haematological, biochemical, or histopathological abnormalities, with only transient, reversible elevations in liver enzymes at higher doses. Collectively, these findings demonstrate that chimeric IL-15 induces robust antitumor immunity with improved pharmacokinetics and a favourable safety profile, supporting its further preclinical development as a next-generation cancer immunotherapeutic.