Abstract
Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin's lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro. An in vitro ADCC system was used to assess the ability of lenalidomide to enhance human NK cell and monocyte function in response to rituximab. Lenalidomide directly enhanced IFN-gamma production via Fc-gamma receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-gamma receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.
Highlights
Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin’s lymphoma (NHL)
antibody-dependent cellular cytotoxicity (ADCC) is suggested as one of the in vivo mechanisms of action of rituximab, the exact pathways involved are not fully understood [16]. We found that both lenalidomide and thalidomide enhanced in vitro natural killer (NK) cell production of IFN-g induced by interaction of IgG with the Fc-g receptor but only in the presence of IL-2 or IL-12
We investigated the ability of lenalidomide and thalidomide to enhance the ADCC of rituximab
Summary
Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin’s lymphoma (NHL). This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro. Results: Lenalidomide directly enhanced IFN-g production via Fc-g receptor-mediated signaling in response to IgG It was a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Conclusions: These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer. The action of lenalidomide in these studies was attributed to direct antiproliferative and apoptotic effects as well as to increased sensitivity of multiple myeloma cells to ADCC by functional cytotoxic NK effector cells
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