Safety and immunologic effects of IL-15 administration in nonhuman primates

Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Blood (Impact Factor: 10.45). 08/2009; 114(12):2417-26. DOI: 10.1182/blood-2008-12-189266
Source: PubMed


The administration of cytokines that modulate endogenous or transferred T-cell immunity could improve current approaches to clinical immunotherapy. Interleukin-2 (IL-2) is used most commonly for this purpose, but causes systemic toxicity and preferentially drives the expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells, which can inhibit antitumor immunity. IL-15 belongs to the gamma(c) cytokine family and possesses similar properties to IL-2, including the ability to induce T-cell proliferation. Whereas IL-2 promotes apoptosis and limits the survival of CD8(+) memory T cells, IL-15 is required for the establishment and maintenance of CD8(+) T-cell memory. However, limited data are available to guide the clinical use of IL-15. Here, we demonstrate in nonhuman primates that IL-15 administration expands memory CD8(+) and CD4(+) T cells, and natural killer (NK) cells in the peripheral blood, with minimal increases in CD4(+)CD25(+)Foxp3(+) regulatory T cells. Daily administration of IL-15 resulted in persistently elevated plasma IL-15 levels and transient toxicity. Intermittent administration of IL-15 allowed clearance of IL-15 between doses and was safe for more than 3 weeks. These findings demonstrate that IL-15 has profound immunomodulatory properties distinct from those described for IL-2, and suggest that intermittent administration of IL-15 should be considered in clinical studies.

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    • "After 5 months of ENU injection leukaemia was confirmed by peripheral blood smear observation. The two cytokines, rmG-CSF at the dose rate of 10µg/kg body weight[22]and rmIL-15 at the dose of 5µg/kg body weight[23]were injected (i.p.) in animals of one control and one ENU treated group after confirmation of leukemic induction for consecutive five days. "
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    • "Based on effects of both T and NK cells, rhIL-15 (in the absence of the IL-15Rα) is under clinical investigation in solid tumors (melanoma, renal cell carcinoma: NCT01021059, NCT01369888; advanced cancers NCT01572493, NCT01727076) and to support NK cells after adoptive transfer in leukemia patients (NCT01385423). Studies performed in nonhuman primates at the NIH administering subcutaneous rhIL-15 intermittently every 3 days demonstrated low toxicity with expansion of NK cells (in addition to CD8 memory and CD4+ T cells) in the absence of Treg expansion in vivo [95]. Interestingly, daily administration for 14 days resulted in reversible toxicities in two macaques consisting of neutropenia with a hypocellular bone marrow and anemia with a lymphoid infiltrate in the bone marrow, coinciding with a marked peripheral lymphocytosis. "
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    • "IL15 regulates T-and natural killer cell activation and proliferation, having central roles in cellmediated immunity against microbes (Yoshikai and Nishimura, 2000). Administration of exogenous IL15 in animal models causes severe but reversible neutropenia due to redistribution of neutrophils out of the circulation (Berger et al, 2009; Waldmann et al, 2011). This SNP resides in the 3 0 UTR region of the gene, which exerts a negative regulatory effect on the expression of IL15; polymorphism at the 3 0 UTR may reduce this negative regulation, resulting in an enhanced expression. "
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