Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by <i>Ex Vivo</i> –Expanded Autologous NK Cells

Abstract

<b>Purpose:</b> Daratumumab and its use in combination with other agents is becoming a new standard of care for the treatment of multiple myeloma. We mechanistically studied how daratumumab acts on natural killer (NK) cells.<b>Experimental Design:</b> Quantities of NK cells in peripheral blood and/or bone marrow of patients with multiple myeloma or healthy donors were examined by flow cytometry. NK-cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded <i>in vitro</i> using feeder cells. Combination treatment of daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model.<b>Results:</b> CD38^-/low NK cells survived, whereas CD38⁺ NK cells were almost completely eliminated, in peripheral blood and bone marrow of daratumumab-treated multiple myeloma patients. NK-cell depletion occurred due to daratumumab-induced NK-cell fratricide via antibody-dependent cellular cytotoxicity. Consequently, CD38^-/low NK cells were more effective for eradicating multiple myeloma cells than were CD38⁺ NK cells in the presence of daratumumab. Blockade of CD38 with the F(ab)₂ fragments of daratumumab inhibited the antibody-mediated NK-cell fratricide. CD38^-/low NK cells displayed a significantly better potential for expansion than CD38⁺ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against multiple myeloma cells. Therefore, infusion of <i>ex vivo</i>-expanded autologous NK cells from daratumumab-treated patients may improve the antibody therapy.<b>Conclusions:</b> We unravel a fratricide mechanism for daratumumab-mediated NK-cell depletion and provide a potential therapeutic strategy to overcome this side effect in daratumumab-treated patients with multiple myeloma. <i>Clin Cancer Res; 24(16); 4006-17. ©2018 AACR</i>.