Lenalidomide Alone and in Combination with Rituximab Enhances NK Cell Immune Synapse Formation in Chronic Lymphocytic Leukemia (CLL) Cells in Vitro through Activation of Rho and Rac1 GTPases.
Abstract:3441
Poster Board III-329
Background
CLL is characterized by the progressive accumulation of monoclonal B lymphocytes. One theory to explain how CLL cells avoid elimination through immune surveillance mechanisms is through a defect in the ability of T-cells to form immunological synapses with antigen-presenting tumor B-cells (Ramsay et al JCI 2008). Lenalidomide is an immunomodulatory agent with clinical activity in the treatment of B-cell mali… Show more
“…• Increased NK cell cytotoxicity through the enhancement of NK cell immune synapse formation [400,408]. • Decreased SOCS1 expression [398].…”
Section: Nk Cellsmentioning
confidence: 99%
“…[152,360,376,[396][397][398][399][400][401][402][403][404][405][406][407][408]. The most important conclusion from CLL research is that IMiDs' anticancer effects are very complex, which is unsurprising considering the complex effects of these drugs on intracellular regulation and extracellular crosstalk between a wide range of cells.…”
Analysis of the monocyte subsets (i.e. classical, intermediate, non-classical) in peripheral blood samples requires a careful standardization of peripheral blood sampling and pre-analytic handling of the samples with respect to the anticoagulant used, filling of sample tubes, and cryopreservation of cells prior to analysis.
“…• Increased NK cell cytotoxicity through the enhancement of NK cell immune synapse formation [400,408]. • Decreased SOCS1 expression [398].…”
Section: Nk Cellsmentioning
confidence: 99%
“…[152,360,376,[396][397][398][399][400][401][402][403][404][405][406][407][408]. The most important conclusion from CLL research is that IMiDs' anticancer effects are very complex, which is unsurprising considering the complex effects of these drugs on intracellular regulation and extracellular crosstalk between a wide range of cells.…”
Analysis of the monocyte subsets (i.e. classical, intermediate, non-classical) in peripheral blood samples requires a careful standardization of peripheral blood sampling and pre-analytic handling of the samples with respect to the anticoagulant used, filling of sample tubes, and cryopreservation of cells prior to analysis.
“…Lenalidomide is a potent immunomodulatory agent that exhibits both tumouricidal and antiproliferative activity. Lenalidomide may exert its antitumour activity by reversing the defective ability of T cells and natural killer cells to form synapses with tumour B cells, thereby enhancing immune‐mediated cytotoxicity (Ramsay et al , , ; Gaidarova et al , ,b). Lenalidomide also increases tumour suppressor gene expression and inhibits production of pro‐angiogenic factors such as vascular endothelial growth factor in NHL cells (Zhang et al , ).…”
SummaryThis phase II study evaluated the safety and efficacy of lenalidomide in combination with rituximab in patients with relapsed/refractory, indolent non-Hodgkin lymphoma (NHL). Patients were treated with daily lenalidomide in 28-d cycles and weekly rituximab for 4 weeks. Lenalidomide was continued until progression or unacceptable toxicity. Twenty-two patients were assessed for FCGR3A polymorphisms. Thirty patients were enrolled; 27 were evaluable for response. The overall response rate (ORR) was 74% including 44% complete responses (CR); median progression-free survival (PFS) was 12Á4 months. The 13 rituximab refractory patients had an ORR of 61Á5% (four CR/unconfirmed CR). The ORR was 77% in the 22 follicular lymphoma patients (nine CR/unconfirmed CR). At a median follow-up time of 43 months, the median duration of response and time to next therapy were 15Á4 and 37Á4 months, respectively. Most common grade 3/4 adverse events were lymphopenia (45%), neutropenia (55%), fatigue (23%) and hyponatraemia (9%). The ORR and PFS in patients with low-affinity FCGR3A polymorphisms (F/F and F/V) suggest that lenalidomide may improve the activity of rituximab in these patients. These data suggest that combining lenalidomide with rituximab can produce durable responses with acceptable toxicity in patients with indolent NHL.
“…The therapeutic potential of lenalidomide in CLL seems to reside in its broad immunomodulatory effects on the tumor microenvironment . Among these: enhancement of IL‐2, TNF‐α and IFN‐γ production by T cells, and of CD8 + T cells and NK cells cytotoxicity, regulatory T cells (Tregs) inhibition, downregulation of vascular endothelial growth factor production, downregulation of programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) interaction between T and CLL cells, and reduction of nurse‐like cells support to tumor cells by downregulation of CCL2, IGF1, CXCL12, and HGF1 and by promoting their differentiation toward an M1 phenotype . Lenalidomide also enhanced the immunogenicity of CLL cells by increasing the expression of co‐stimulatory molecules CD40, CD80, CD83, and CD86, as well as the expression of CD40L .…”
Lenalidomide alone or in combination with GM-CSF and low-dose CTX as immune adjuvant to the Apo-DC vaccine elicited tumor-specific T-cell responses in CLL patients. However, unexpected toxicity was observed and caution is suggested in further exploring this drug as immune adjuvant in CLL.
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