Next, we investigated the effects of cyclophosphamide treatment on the MM cell secretome and subsequent immune effector (macrophage) cell recruitment and functional responses

Next, we investigated the effects of cyclophosphamide treatment on the MM cell secretome and subsequent immune effector (macrophage) cell recruitment and functional responses. the migratory capacity of macrophages and increased CD32 and CD64 Fc receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression P2RY5 on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens. efficacy Cisatracurium besylate of antibodies and improved outcome has been seen in conjunction with high affinity polymorphisms of FcRIIa/CD32a, which are not expressed on NK cells.27 This may be particularly important in the context of treatment with daratumumab. Originally, it was thought that ADCC mediated by NK cells would constitute one of the most important mechanisms of action of daratumumab.28 However, with the benefit of careful correlative studies from clinical trials, we now know that treatment with daratumumab leads to rapid depletion of NK cells, which are strongly CD38 positive, and that this can last up to 6?months following cessation of treatment.29 Therefore, to maximize Cisatracurium besylate the clinical efficacy of daratumumab, it may be necessary to have a sufficient number of activated TAMs. 30 This has recently been demonstrated by Viola data from a clinical trial, set up to assess the addition of cyclophosphamide to a daratumumab-containing regimen (CyBorD-DARA), uncovered observations suggesting that this treatment combination increased the vulnerability of MM cells to phagocytosis by macrophages.30 Our study investigates the specific mechanism of action of cyclophosphamide in the induction of ADCP test. *