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Immunotherapy Maximizes IL-15 Activity In Vivo1
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030
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
to target cells expressing the IL-15R
and the common 
-chain. Thus, the efficacy of administered IL-15 alone may be limited by the availability of free IL-15R. We now show that administration of soluble IL-15/IL-15R 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, but not IL-15R, expression by the responding cells and was IL-7-independent. Interestingly, IL-15/IL-15R 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI51583 and P01 AI56172 (to L.L.) and U.S. Public Health Service Training Grant T32 AI07080 (to T.A.S.).
2 Current address: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
3 Address correspondence and reprint requests to Dr. Leo Lefrançois, Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1319. E-mail address: llefranc{at}neuron.uchc.edu
4 Abbreviations used in this paper: C, common -chain; sIL, soluble IL; VSV, vesicular stomatitis virus; hIL, human IL; rm, recombinant murine.
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