Abstract 1809: Stimulation of antibody dependent cell-mediated cytotoxicity by interleukin-15 is equivalent to interleukin-2

Abstract

Abstract An important strategy for the treatment of cancer involves administration of tumor-specific antibodies that target tumor cells for destruction by the individual's leukocytes via antibody dependent cell-mediated cytotoxicity (ADCC). However, ADCC is frequently depressed in individuals with cancer. Interleukin-2 (IL-2), a pro-inflammatory cytokine, enhances ADCC and is used clinically for this purpose. Interleukin-15 (IL-15) is a cytokine that shares many functions with IL-2, including stimulation of ADCC and proliferation and activation of natural killer cells. In contrast to IL-2, IL-15 supports the survival of CD8+ memory T cells, does not produce T cell activation-induced cell death and has no marked effects on Treg cells. Since these different functions may prove beneficial when using a cytokine to stimulate ADCC in vivo in cancer immunotherapy, we compared the in vitro effect of IL-15 (generously provided by Dr. Stephen Creekmore, NCI-Frederick) versus IL-2 to enhance ADCC. Using a standard 51Cr release assay, M21 human melanoma cells were loaded with 51Cr and incubated for four hours at 37° with human peripheral blood mononuclear cells (PBMC), hu14.18K322A, (generously provided by Dr. Fariba Navid of St. Jude Children's Research Hospital) a monoclonal antibody specific for GD2 (disialoganglioside) that is overexpressed on M21 cells (5 ng/ml), and either media, IL-2 (10 ng/ml) or IL-15 (10 ng/ml). The ratio of effectors (PBMCs) to targets (M21) was 10:1 or 30:1 and % cytotoxicity was determined from which lytic units were calculated. Incubation with IL-2 augmented ADCC from 163±39 to 230±40 lytic units (n=6, mean±SEM) while incubation with IL-15 enhanced ADCC from 148±27 to 229±36 lytic units (n=6). ADCC response was comparable for IL-2 and IL-15 (p=0.4857) and similar results were obtained using higher and lower concentrations of hu14.18K322A (0.1 – 100 ng/ml) and IL-2 and IL-15 (5 – 25 ng/ml), and after pre-incubation of PBMCs with IL-2 or IL-15 (4 – 44 hours). These experiments indicate that IL-2 and IL-15 demonstrate comparable stimulation of ADCC in vitro. If IL-15 produces equivalent enhancement of ADCC compared to IL-2 in vivo, it may be a potential immunotherapeutic for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2011-1809