Recent clinical studies of the immunomodulatory drug (IMiD®) lenalidomide

Bartlett, J. Blake; Tozer, A.W.; Stirling, David I.; Zeldis, Jerome B.

doi:10.1038/sj.bjc.6602774

Cited by 59 publications

(42 citation statements)

References 37 publications

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“…1,2 Perhaps the best example of such an agent is lenalidomide (LEN), [3][4][5] a structural analog of thalidomide with similar but more potent immunomodulatory activities. [6][7][8] Since its approval by the FDA, lenalidomide has demonstrated impressive results in patients with newly-diagnosed and relapsed multiple myeloma 9,10 and also improved graft versus multiple myeloma effects after allogeneic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab

et al. 2010

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The online version of this article has a supplementary Appendix. BackgroundIn our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. Design and MethodsTo explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. ResultsDaratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cellmediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. ConclusionsOur results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma. daratumumab. Haematologica 2011;96(2):284-290. doi:10.3324/haematol.2010 This is an open-access paper.

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Section: Introductionmentioning

confidence: 99%

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab

et al. 2010

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“…There is growing evidence supporting a role for thalidomidederived immunomodulatory drugs known as IMiDs in cancer therapy (Galustian et al, 2004;Bartlett et al, 2005;Shalapour et al, 2006;Melchert et al, 2007;Verhelle et al, 2007). This proprietary class of therapeutic analogues, as exemplified by lenalidomide (Revlimid, Celgene, Summit, NJ, USA, CC-5013) was developed on the basis of structural activity relationship studies focussing on molecular alterations to the central ring framework of the thalidomide molecule as an approach to enhancing the immunomodulatory characteristics of the agents (Stirling, 2001;Bartlett et al, 2004).…”

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confidence: 99%

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

et al. 2009

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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.

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“…Lenalidomide has also been approved for 5q myelodysplastic syndrome. Both agents are under evaluation for the treatment of several solid tumors, including thyroid cancer [65][66][67] and for a range of autoimmune diseases [68].…”

Section: Thalidomide and Lenalidomidementioning

confidence: 99%