Lenalidomide (Revlimid; CC-5013) and pomalidomide (CC-4047) are IMiDs proprietary drugs having immunomodulatory properties that have both shown activity in cancer clinical trials; lenalidomide is approved in the United States for a subset of MDS patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone. These drugs exhibit a range of interesting clinical properties, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities although exact cellular target(s) remain unclear. Also, anti-inflammatory effects on LPS-stimulated monocytes (TNF-alpha is decreased) and costimulatory effects on anti-CD3 stimulated T cells, (enhanced T cell proliferation and proinflammatory cytokine production) are observed. These drugs also cause augmentation of NK-cell cytotoxic activity against tumour-cell targets. Having shown that pomalidomide confers T cell-dependent adjuvant-like protection in a preclinical whole tumour-cell vaccine-model, we now show that lenalidomide and pomalidomide strongly inhibit T-regulatory cell proliferation and suppressor-function. Both drugs inhibit IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by upto 50%. Furthermore, suppressor function of pre-treated T regulatory cells against autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph-node T regulatory cells after pomalidomide treatment. Inhibition of T regulatory cell function was not due to changes in TGF-beta or IL-10 production but was associated with decreased T regulatory cell FOXP3 expression. In conclusion, our data provide one explanation for adjuvant properties of lenalidomide and pomalidomide and suggest that they may help overcome an important barrier to tumour-specific immunity in cancer patients.

T-regulatory cells suppress anti-tumour immunity in cancer patients and in murine tumour models. Furthermore, their activity is likely to have an effect on the effectiveness of immunotherapeutic treatments for cancer. Here we describe the current status of developing clinical strategies for modulating Treg activity in cancer patients.

SummaryThe IMiDs â immunomodulatory compounds lenalidomide and pomalidomide are agents with anti-inflammatory, immunomodulatory and anticancer activity. An excellent success rate has been shown for multiple myeloma in phase I/II clinical trials leading to Food and Drug Administration approval of lenalidomide. One mechanism by which these drugs could enhance anti-tumour immunity may be through enhanced dendritic cell (DC) function. Thalidomide, a compound structurally related to lenalidomide and pomalidomide, is known to enhance DC function, and we have investigated whether its analogues, pomalidomide and lenalidomide, also have functional effects on DCs. We used mouse bone marrow-derived DCs treated with 5 or 10 lM pomalidomide, or lenalidomide from day 1 of culture. Treatment with IMiD â immunomodulatory compounds increased expression of Class I (H2-Kb), CD86, and pomalidomide also increased Class II (I-Ab) expression in bone marrow-derived DCs, as measured by flow cytometry. Fluorescent bead uptake was increased by up to 45% when DCs were treated with 5 or 10 lM pomalidomide or lenalidomide compared with non-treated DCs. Antigen presentation assays using DCs primed with ovalbumin, and syngeneic T cells from transgenic OTI and OTII mice (containing MHC restricted, ovalbumin-specific, T cells) showed that both pomalidomide and lenalidomide effectively increased CD8 + T-cell cross-priming (by up to 47%) and that pomalidomide alone was effective in increasing CD4 + T-cell priming (by 30%). Our observations suggest that pomalidomide and lenalidomide enhance tumour antigen uptake by DCs with an increased efficacy of antigen presentation, indicating a possible use of these drugs in DC vaccine therapies.

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BACKGROUND: Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma and, along with pomalidomide, are being investigated in various other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about their primary mode of therapeutic action in patients with cancer. METHODS: As part of a continuing research effort, we have investigated the effects of these agents on the metastatic capacity of murine colorectal cancer cell lines both in vivo and in vitro. Allied to these, we have studied their effects on the molecular pathways associated with metastasis. RESULTS: Results indicate that thalidomide, lenalidomide and pomalidomide significantly inhibit the metastatic capability of colorectal carcinoma cells. Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence. In addition, an in vivo experimental metastasis model also showed that treatment with the drugs resulted in a significantly lower number of metastatic pulmonary nodules relative to control mice. Allied to these cellular and phenotypic changes were alterations in molecular markers of metastasis and in intracellular signalling competency. CONCLUSIONS: These results provide evidence that in addition to their immunomodulatory effects, thalidomide, lenalidomide and pomalidomide can impair the metastatic capacity of tumours, and that this mechanism may involve alterations to cell signalling functionality.

Lenalidomide may be a promising candidate for combination with docetaxel in the treatment of CRPC.

PurposeBisphosphonates are established as a supportive therapy for a number of malignancies which metastasise to bone. Previous reports also suggest potent antitumour and antiangiogenic properties. We investigated the in vitro activity of two aminobisphosphonates, pamidronate (PAM) and zoledronic acid (ZOL) on the growth and survival of three renal cell carcinoma cell lines (Caki-2, 769-P and D69581). Experimental design

BackgroundFor blood, most 24/7 standard (immuno)chemistry parameters are either measured in serum or in lithium heparin plasma. Standard serum and plasma gel tubes have their shortcomings when timely analysis of high quality results is required. Serum requires clotting time and interference of gel globules in the plasma and adsorption of hydrophobic analytes into the gel layer potentially compromises high quality results from lithium heparin gel tubes. We sought to evaluate the impact of BD Vacutainer® Barricor™ Tube (Barricor™) on laboratory efficiency by measuring its effect on TAT and sample quality, as well as evaluate potential cost opportunities resulting from improved sample quality.MethodsTAT data and remediation activities were extracted and captured during two 6 months phases. Serum was used as the predominant matrix in the first phase and Barricor™ plasma was used in the second phase.ResultsBarricor™ significantly reduced the median TAT, especially for routine-priority samples during peak-hours. The TAT key-performance-indicator (percentage of results available within 90 ​min) improved to >90% for STAT as well as routine priority samples. Converting from serum gel, Barricor™ reduced fibrin-related remediation activities from 2.3% to 0.4%. This resulted in remediation-related cost reduction of €6.010,47 over the study period.ConclusionsBy implementing Barricor™, we saw a significant reduction in TAT and a reduction in fibrin-related remediation time and costs, when compared to a predominant serum workflow. The improved TAT opens up the possibility of consolidating to one single priority level, eliminating the need for the use of the STAT priority level.