Journal
BLOOD
Volume 117, Issue 18, Pages 4787-4795Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-10-311456
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Funding
- National Cancer Institute (Frederick, MD)
- National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD)
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IL-15 uses the heterotrimeric receptor IL-2/IL-15R beta and the gamma chain shared with IL-2 and the cytokine-specific IL-15R alpha. Although IL-15 shares actions with IL-2 that include activation of natural killer (NK) and CD8 T cells, IL-15 is not associated with capillary leak syndrome, activation-induced cell death, or with a major effect on the number of functional regulatory T cells. To prepare for human trials to determine whether IL-15 is superior to IL-2 in cancer therapy, recombinant human IL-15 (rhIL-15) was produced under current good manufacturing practices. A safety study in rhesus macaques was performed in 4 groups of 6 animals each that received vehicle diluent control or rhIL-15 at 10, 20, or 50 mu g/kg/d IV for 12 days. The major toxicity was grade 3/4 transient neutropenia. Bone marrow examinations demonstrated increased marrow cellularity, including cells of the neutrophil series. Furthermore, neutrophils were observed in sinusoids of enlarged livers and spleens, suggesting that IL-15 mediated neutrophil redistribution from the circulation to tissues. The observation that IL-15 administration was associated with increased numbers of circulating NK and CD8 central and effector-memory T cells, in conjunction with efficacy studies in murine tumor models, supports the use of multiple daily infusions of rhIL-15 in patients with metastatic malignancies. (Blood. 2011; 117(18): 4787-4795)
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