Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques
- 5 May 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 117 (18), 4787-4795
- https://doi.org/10.1182/blood-2010-10-311456
Abstract
IL-15 uses the heterotrimeric receptor IL-2/IL-15Rβ and the γ chain shared with IL-2 and the cytokine-specific IL-15Rα. 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 μg/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.Keywords
This publication has 43 references indexed in Scilit:
- Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primatesBlood, 2010
- The colony-stimulating factors and cancerNature Reviews Cancer, 2010
- Safety and immunologic effects of IL-15 administration in nonhuman primatesBlood, 2009
- Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancerProceedings of the National Academy of Sciences of the United States of America, 2009
- IL-15 as a mediator of CD4 + help for CD8 + T cell longevity and avoidance of TRAIL-mediated apoptosisProceedings of the National Academy of Sciences of the United States of America, 2008
- The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cellsProceedings of the National Academy of Sciences of the United States of America, 2007
- The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine designNature Reviews Immunology, 2006
- IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primatesJCI Insight, 2006
- Differential Effects of IL-2 and IL-15 on Expression of IL-2 Receptor αBiochemical and Biophysical Research Communications, 2001
- Control of Homeostasis of CD8 + Memory T Cells by Opposing CytokinesScience, 2000