7.1.3 Interleukin-15
IL-15 is mainly produced by activated myeloid cells as a membrane-bound heterodimer associated with IL-15Rα in such a way that it is trans-presented to NK cells and T cells expressing IL2/IL-15Rβ and the common γ chain receptor.Importantly, IL15 is critically needed for the ontogeny of NK cells and CD8+ T cells, and also induces the proliferation, cytotoxic action and the release of other cytokines such as IFN-γ from these cells, highlighting its role in potentiating the immune response.Preclinical observations strongly support the potential antitumor activity of IL-15 mediated by NK cells and T lymphocytes.Unlike IL-2, IL-15 does not stimulate Treg cells, a subset that might reduce the anti-tumor activity of NK and T cells.This is due to the fact that IL-15 does not bind to the IL-2Rα chain (also known as CD25).
In vitro and in vivo preclinical studies indicate that IL-15 is more bioactive when trans-presented adsorbed onto the IL-15Rα receptor subunit.Recombinant IL-15 is quickly eliminated from the blood due to its small molecular size (it has an in vivo half-life of 2.5 h), and several approaches have therefore focused on designing more stable protein constructs encompassing IL-15 and IL-15Rα that display a longer half-life and better biodistribution parameters.The different therapeutic form of IL-15 and its signal receptor are described in Figure 7.2.
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Figure 7.2 Engineered interleukin-15 (IL-15) va riants.IL-15 is mainly produced as a
membrane-bound heterodimer associated with IL-15Rα.The interaction of the IL-15-IL15-Rα complex with IL-2/IL-15Rβ and the common γc receptor triggers the phosphorylation of Janus kinase-1 (JAK1)and JAK3 and the recruitment and subsequent phosphorylation of signal transducer and activator of transcription-3 (STAT3) and STAT5.Clinical trials have tested the safety and efficacy of recombinant aglycosylated IL-15 and engineered variants to mimic the trans-presentation process and to enhance the half-life in circulation.These variants included the superagonist RLI protein (comprising the binding domain of IL-15Rα fused to IL-15), ALT-803 (comprising mutated IL-15 fused to the binding domain of IL-15Rα and an IgG1 Fc domain) and Sushi-IL15-Apo (a fusion protein encompassing the binding domain of IL-15Rα, IL-15 and apolipoprotein A-I).(Please scan the QR code on the Preface to get original color figures.)
Source: Berraondo P, Sanmamed M F, Ochoa M C, Etxeberria I, Aznar M A, Pérez-Gracia J L, Rodríguez-Ruiz M E, Ponz-Sarvise M, Castañón E, Melero I.“Cytokines in Clinical Cancer Immunotherapy”.BritishJournalofCancer, 2019, 120(1):6-15.
IL-15 is mainly produced as a membrane-bound heterodimer associated with IL15Rα.The interaction of the IL-15-IL15-Rα complex with IL-2/IL-15Rβ and the common γc receptor triggers the phosphorylation of Janus kinase-1 (JAK1) and JAK3 and the recruitment and subsequent phosphorylation of signal transducer and activator of transcription-3 (STAT3) and STAT5.Clinical trials have tested the safety and efficacy of recombinant aglycosylated IL-15 and engineered variants to mimic the trans-presentation process and to enhance the half-life in circulation.These variants included the super agonist RLI protein (comprising the binding domain of IL-15Rα fused to IL-15),ALT-803 (comprising mutated IL-15 fused to the binding domain of IL-15Rα and an IgG1 Fc domain) and Sushi-IL15-Apo (a fusion protein encompassing the binding domain of IL-15Rα, IL-15 and apolipoprotein A-I).
Other clinical studies involving IL-15 proteins as experimental agents are ongoing.Most also include administering IL-15 in combination with other agents.Some trials are testing IL-15 as an adjuvant in T cell or NK cell adoptive cell therapies (NCT01875601, NCT02465957 and NCT01385423).