Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques

Thomas A. Waldmann, Enrico Lugli, Mario Roederer, Liyanage P. Perera, Jeremy V. Smedley, Rhonda P. Macallister, Carolyn K. Goldman, Bonita R. Bryant, Jean M. Decker, Thomas A. Fleisher, H. Clifford Lane, Michael C. Sneller, Roger J. Kurlander, David E. Kleiner, John M. Pletcher, William D. Figg, Jason L. Yovandich, Stephen P. Creekmore

Research output: Contribution to journalArticle

98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4787-4795
Number of pages9
JournalBlood
Volume117
Issue number18
DOIs
StatePublished - May 5 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Waldmann, T. A., Lugli, E., Roederer, M., Perera, L. P., Smedley, J. V., Macallister, R. P., Goldman, C. K., Bryant, B. R., Decker, J. M., Fleisher, T. A., Lane, H. C., Sneller, M. C., Kurlander, R. J., Kleiner, D. E., Pletcher, J. M., Figg, W. D., Yovandich, J. L., & Creekmore, S. P. (2011). Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques. Blood, 117(18), 4787-4795. https://doi.org/10.1182/blood-2010-10-311456