Lenalidomide Enhances Natural Killer Cell and Monocyte-Mediated Antibody-Dependent Cellular Cytotoxicity of Rituximab-Treated CD20+ Tumor Cells

Abstract

Purpose: 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. Experimental Design: 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. Results: Lenalidomide directly enhanced IFN-g production via Fc-g 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-g receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. 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.

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study

“…[14][15][16] There are three plausible approaches of introducing lenalidomide to upfront therapy: (i) lenalidomide maintenance following initial chemoimmunotherapy, (ii) addition of concomitant lenalidomide treatment to chemoimmunotherapy or (iii) both. Based on the in vitro synergy of lenalidomide with rituximab and cytotoxic therapy, 18,19 as well as the potential impact on microenvironment mediated drug resistance, 20,21 we elected to first test the combination approach. The addition of concurrent lenalidomide to R-CHOP is challenging because of the potential for overlapping hematological toxicity that may result in a negative impact on the dose intensity of R-CHOP, a potentially curative regimen in this setting.…”

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

“…The clinical value of thalidomide against solid tumours may lie in its immunomodulatory, anti-angiogenic and anti-metastatic properties. The immunomodulatory feature is believed to be a crucial determinant of clinical success and as such, analogues of thalidomide and those related to it have shown greatly increased potency for costimulation of T-cell and NK cells (Corral et al, 1999;Haslett et al, 2003;Aragon-Ching et al, 2007;Wu et al, 2008). These drugs have impressive activity in both haematological cancers (Galustian et al, 2004); however, it is not known whether the activity of solid tumours will be as strong.…”

“…It is important to understand that the induction of tumour cytotoxicity can also be a result of an enhanced immunological responses caused by IMiDs. The increased proliferation of a number of immune cell groups, including CD4-positive and CD8-positive cells in addition to the initiation of dendritic cell function, can lead to the activation of natural killer cells that drive cytophagy and cytolysis (Davies et al, 2001;Hayashi et al, 2005;Wu et al, 2008).…”

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

“…Methyl-b-cyclodextrin (MbCD), cytochalasin B, genistein, and herbimycin were obtained from Sigma-Aldrich (St. Louis, MO), and Syk inhibitor II was from Calbiochem (Gibbstown, NJ). Perifosine, edelfosine, and PP2 were from Cayman Chemical (Ann Arbor, MI), and rituximab was from Genentech (16). RPMI 1640 medium, FCS, Dulbecco's PBS, L-glutamine, penicillin-streptomycin, and gentamicin were purchased from Biological Industries (Beit Haemek, Israel).…”