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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    • "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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    ABSTRACT: Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.
    06/2014; DOI:10.1155/2014/205796
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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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    ABSTRACT: Background: Host germline variations and their potential prognostic importance is an emerging area of interest in paediatric ALL. Methods: We investigated the associations between 20 germline variations and various clinical end points in 463 children with ALL. Results: After adjusting for known prognostic factors, variants in two genes were found to be independently associated with poorer EFS: ABCB1 T/T at either 2677 (rs2032582) or 3435 (rs1045642) position (P=0.003) and IL15 67276493G/G (rs17015014; P=0.022). These variants showed a strong additive effect affecting outcome (P<0.001), whereby patients with both risk genotypes had the worst EFS (P=0.001), even after adjusting for MRD levels at the end of remission induction. The adverse effect of ABCB1 T/T genotypes was most pronounced in patients with favourable cytogenetics (P=0.011) while the IL15 67276493G/G genotype mainly affected patients without common chromosomal abnormalities (P=0.022). In both cytogenetic subgroups, increasing number of such risk genotypes still predicted worsening outcome (P<0.001 and=0.009, respectively). Conclusion: These results point to the prognostic importance of host genetic variants, although the specific mechanisms remain unclarified. Inclusion of ABCB1 and IL15 variants may help improve risk assignment strategies in paediatric ALL.
    British Journal of Cancer 01/2014; 110(6). DOI:10.1038/bjc.2014.7 · 4.84 Impact Factor
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    • "Of concern is that the majority of preclinical studies assessing potential immunotherapeutic regimens use younger mice, which likely fail to replicate human clinical cancer treatment conditions with regard to age. Therefore, understanding the impact of age on IT responses and outcome is critical as sig­ nificant toxicities can be observed with systemic IT (McInnes et al., 1997; Suntharalingam et al., 2006; Waldmann, 2006; Berger et al., 2009; Attarwala, 2010; Di Giacomo et al., 2010; Weber et al., 2012). "
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    ABSTRACT: Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.
    Journal of Experimental Medicine 09/2013; 210(11). DOI:10.1084/jem.20131219 · 12.52 Impact Factor
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