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

TY - JOUR

T1 - Safety and immunologic effects of IL-15 administration in nonhuman primates

AU - Berger, Carolina

AU - Berger, Michael

AU - Hackman, Robert C

AU - Gough, Michael

AU - Elliott, Carole

AU - Jensen, Michael C

AU - Riddell, Stanley R

PY - 2009/9/17

Y1 - 2009/9/17

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - CD8-Positive T-Lymphocytes/immunology

KW - Enzyme-Linked Immunosorbent Assay

KW - Flow Cytometry

KW - Genes, T-Cell Receptor

KW - Glycosylation

KW - Immunologic Memory/immunology

KW - Interleukin-15/administration & dosage

KW - Interleukin-2/metabolism

KW - Killer Cells, Natural/immunology

KW - Macaca nemestrina

KW - T-Lymphocyte Subsets/immunology

KW - T-Lymphocytes, Regulatory/immunology

U2 - 10.1182/blood-2008-12-189266

DO - 10.1182/blood-2008-12-189266

M3 - SCORING: Journal article

C2 - 19605850

VL - 114

SP - 2417

EP - 2426

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 12

ER -