ID: 238: IL-15 markedly augmented the number of circulating NK cells and enhanced ADCC mediated by tumor-directed monoclonal antibodies

Abstract

Interleukin-15, that activates antitumor T and natural killer cells, has potential applications in cancer immunotherapy. IL-15 administered at 20 μg/kg/day by continuous intravenous (CIV) infusion for 10 days to nonhuman primates yielded an 80–100-fold expansion of circulating CD8+ effector memory T-cells, a 15-fold increase in the number of monocytes and an 8-fold increase in NK cells. Based on these observations we performed a first-in-human phase 1 clinical trial of rhIL-15 administered by bolus infusions and a trial of IL-15 by CIV in patients with metastatic malignancy. When administered by CIV at 2 μg/kg per day IL-15 led to a 30-fold increase in the number of NK cells and over a 200-fold increase in the number of CD56+ CD16− NK cells. It was clear from these clinical trials that to be effective IL-15 would have to be administered in combination with agents with specificity directed toward the tumor. Given the capacity of IL-15 to increase NK cells an attractive strategy was to use it in conjunction with an antitumor antibody to augment ADCC. When IL-15 was administered with rituximab it markedly increased the ADCC effectiveness of this antibody in a syngeneic mouse model of human B-cell lymphoma involving EL4 leukemia cells transfected with human CD20. Activity of this combination was lost in Fc alpha-R-1- mice. Furthermore IL-15 augmented the ADCC of alemtuzumab in a xenograft model of human adult T-cell leukemia (ATL). These studies support our clinical trial involving IL-15 with alemtuzumab in patients with acute ATL.