Zoledronic acid negatively affects the expansion of in vitro activated human NK cells and their cytolytic interactions with Ewing sarcoma cells.

Mueller SK, Altvater B, Chen C, Kailayangiri S, Ahlmann M, Dirksen U, Juergens H, Rossig C

Abstract

Disseminated Ewing sarcoma remains a fatal disease despite advanced multimodal treatment regimens. Immunotherapies as well as novel drugs and biologicals are currently being explored to eliminate minimal residual disease after conventional therapy thereby rescuing patients at a high risk for relapse. Insights into the interactions between novel therapies provide the basis for the development of effective combination strategies. We investigated the effects of the aminobisphosphonate zoledronic acid (ZA) on the in vitro expansion of human natural killer (NK) cells and their cytolytic activity against Ewing sarcoma cells. ZA significantly impaired the in vitro expansion of activated NK cells from both healthy donors and Ewing sarcoma patients in a dose-dependent manner. Expression of differentiation markers and activating receptors was unaffected by the drug. Activated NK cells from both healthy donors and patients had potent degranulation responses to Ewing sarcoma cells. In the presence of ZA at concentrations reflecting pharmaceutical serum levels, the in vitro antitumor activity of NK cells from Ewing sarcoma patients was significantly impaired. We conclude that ZA can impede in vitro NK cell expansion and cytolytic NK cell responses to Ewing sarcoma. These observations raise caution against the combination of adoptive NK cell transfer with ZA maintenance therapy in Ewing sarcoma. Future studies aim to identify potentiating interactions of novel drugs with cellular therapies.