IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages

Abstract

<p id="d3774804e335">Previously we demonstrated that IL-15 by continuous infusion at 2 μg/kg/d for 10 days induced a 38-fold increase in circulating natural killer (NK) cells and a 358-fold increase in CD56 ^bright NK cells. In the present study we demonstrated that IL-15 enhanced antibody-dependent cellular cytotoxicity (ADCC) of tumor-directed monoclonal antibodies in two systems. Both NK cells and macrophages were required for optimal therapeutic responses. These studies support clinical trials of IL-15 combined with tumor-directed monoclonal antibodies. In translation of this study, a phase I trial of IL-15 combined with alemtuzumab has been opened for patients with adult T cell leukemia (ATL) NCT02689453. </p><p class="first" id="d3774804e341">The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies. </p>