20: Heterodimeric IL-15 regulates the balance of effector and regulatory cells, favoring anti-tumor responses

The common γ -chain cytokine interleukin-15 (IL-15) regulates immune homeostasis and the fate of many lymphocyte subsets, and holds potential in fighting infections and cancer. We have previously showed that co-expression of IL-15 and IL-15 Receptor alpha (IL-15R α ) in the same cell allows for efficient production and secretion of bioactive IL-15/IL-15R α heterodimer, whereas single-chain IL-15 is unstable. This led to the hypothesis that the physiologically relevant molecule in vivo is the heterodimer. Consistent with this hypothesis, we determined that the IL-15 found in the plasma of mice and humans is the heterodimer. We have developed stable, clonal HEK293-derived human cell lines producing naturally processed and glycosylated IL-15/IL-15R α heterodimers. Repeated subcutaneous administration of purified IL-15 heterodimers in macaques resulted in sustained plasma IL-15 levels and in dose-dependent expansion of NK and T cells in blood and tissues, demonstrating pharmacokinetics and in vivo bioactivity superior to monomer IL-15. Even at the dose of 50 μg/kg, the cytokine was well tolerated with no major side effects. Interestingly, IL-15 heterodimer promotes the preferential expansion of CD8+NK and CD8+ and CD4+ effector T (Teffs) cells, without preferentially affecting Tregs. As result, sustained IL-15 levels are associated with lower relative frequency of Tregs and an increased ratio of Teffs/Tregs. Use of IL-15 heterodimers in the colon carcinoma mouse cancer model resulted in a significant delay in tumor growth, as a consequence of the infiltration of cytotoxic CD8+ T cells and the increase in the ratio Teff/Treg in the tumor environment. In conclusion, the favorable pharmacokinetic/pharmacodynamic profile of IL-15 heterodimer allows for lower dose, simple s.c. delivery, and lowers the possibility of toxicity due to cytokine spike. Preclinical cancer studies suggested that IL-15 heterodimer-based immunotherapy favors the development of anti-tumor responses by favoring cytotoxic over regulatory cells.