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

Abstract

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 (N�) cells and their cytonatural killer (N�) cells and their cyto-N�) cells and their cytolytic activity against Ewing sarcoma cells. ZA significantly impaired the in vitro expansion of activated N� cells from both healthy donors and Ewing sarcoma patients in a dosedependent manner. Expression of differentiation markers and activating receptors was unaffected by the drug. Activated N� 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 N� cells from Ewing sarcoma patients was significantly impaired. We conclude that ZA can impede in vitro N� cell expansion and cytolytic N� cell responses to Ewing sarcoma. These observations raise caution against the combination of adoptive N� cell transfer with ZA maintenance therapy in Ewing sarcoma. Future studies aim to identify potentiating interactions of novel drugs with cellular therapies.

Stromal expression of Fer suppresses tumor progression in renal cell carcinoma and is a predictor of survival

“…CD57 is frequently used to detect NK cells in human tissue, which have been recognized to have anti-tumoral properties, including increased survival time, in various malignancies (37)(38)(39). This is consistent with the hypothesis that increased stromal Fer expression is associated with decreased malignant potential and improved prognosis in RCC.…”

Oestrogen and zoledronic acid driven changes to the bone and immune environments: Potential mechanisms underlying the differential anti-tumour effects of zoledronic acid in pre- and post-menopausal conditions

“…In contrast, one study investigating the in vitro effects of ZOL on NK cells from healthy donors and Ewing sarcoma patients found that ZOL significantly impaired expansion of NK cells. In this study, ZOL impaired the degranulation response of NK cells to Ewing sarcoma stimulus suggesting a decrease in functional activity in which ZOL may help increase the survival of tumour cells in this context [93] .…”

Bisphosphonates in common pediatric and adult bone sarcomas

“…With a peak of incidence at the age of 45 years, chondrosarcoma is a cartilaginous tumor characterized by malignant chondrocytes trapped in a poorly-vascularized hyaline-like extracellular matrix [95]. Depending on the histological subtype, chondrosarcomas are associated with somatic mutations in IDH-1 or IDH-2, EXT, p53, Rb, or COL2A1.…”