Combined IL-15/IL-15Rα immunotherapy maximizes IL-15 activity in vivo

IL-15 has substantial potential as an immunotherapeutic agent for augmenting immune responses. However, the activity of IL-15 is mediated by a unique mechanism in which the cytokine is transpresented by cell-bound high-affinity IL-15R alpha to target cells expressing the IL-15R beta; and the common gamma-chain. Thus, the efficacy of administered IL-15 alone may be limited by the availability of free IL-15R alpha. We now show that administration of soluble IL-15/IL-15R alpha complexes greatly enhanced IL-15 half-life and bioavailability in vivo. Treatment of mice with this complex, but not with IL-15 alone, resulted in robust proliferation of memory CD8 T cells, NK cells, and NK T cells. The activity of the complex required IL-15R beta, but not IL-15R alpha, expression by the responding cells and was IL-7-independent. Interestingly, IL-15/IL-15R alpha immunotherapy also caused naive CD8 T cell activation and development into effector cells and long-term memory T cells. Lastly, complexed IL-15, as compared with IL-15 alone, dramatically reduced tumor burden in a model of B16 melanoma. These findings hold significant importance for the use of IL-15 as a potential adjuvant/therapeutic and inducer of homeostatic proliferation, without the necessity for prior immunodepletion.