Immunomodulatory drug costimulates T cells via the B7-CD28 pathway

LeBlanc, Richard; Hideshima, Teru; Catley, Laurence; Shringarpure, Reshma; Burger, Renate; Mitsiades, Nicholas; Mitsiades, Constantine S.; Cheema, Puneet S.; Chauhan, Dharminder; Richardson, Paul G.; Anderson, Kenneth C.; Munshi, Nikhil C.

doi:10.1182/blood-2003-02-0361

Cited by 272 publications

(216 citation statements)

References 26 publications

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“…Multiple mechanisms have been proposed for the anti-MM activity of thalidomide and its analogs as follows: modulation of cytokines essential for MM growth and survival, antiangiogenesis, 9,10 immunomodulation, 11 and blockade of intracellular signaling pathways mediating MM cell growth and survival. 8 CPS11 and CPS49 are two compounds that have been derived from a thalidomide metabolite with antiangiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

et al. 2005

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“…Lenalidomide costimulates CD28 on T cells, leading to transcriptional activation and increased expression of IL-2 and interferon-g genes [16][17][18][19][20][21][22] stimulating T-cell proliferation and natural killer (NK) cell activity and augmenting T cell and NK cell-mediated lysis of myeloma cells. [19][20][21][22][23][24][25] It is a more potent stimulator of T-cell proliferation than thalidomide, and is 50-100 times more potent than thalidomide in augmenting IL-2 and interferon-g production.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Treatment of plasma cell dyscrasias with lenalidomide

Dimopoulos

Rajkumar

2008

Leukemia

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Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, with pleiotropic activity including antiangiogenic and antineoplastic properties. It is the product of advances in our understanding of the biology of myeloma cells, their interactions with the microenvironment and of the underlying molecular pathways. In preclinical and clinical studies, lenalidomide was more potent and less toxic than thalidomide. Subsequent phase II and III studies confirmed the activity of lenalidomide either as a single agent or in combination with dexamethasone in relapsed or refractory myeloma patients, whereas combinations with chemotherapy induce high response rates and durable remissions. Lenalidomide has been used successfully as an upfront treatment either with high or low dose dexamethasone or with melphalan and prednisone, resulting in high overall response and complete response rates and excellent 1-year survival. Lenalidomide causes less neuropathy than thalidomide; however, the risk of thromboembolism is high, especially in patients treated with lenalidomide and steroids. In this review, we summarize the mechanisms of action, toxicity and clinical activity, and the current role of lenalidomide in patients with multiple myeloma or other related plasma cell disorders.

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“…Lenalidomide can activate T cells, NK cells, or both and in some situations can lead to an expansion of immune effector cells in vivo. [9][10][11] Lenalidomide has been found to enhance immunological synapse formation, which could increase the anti-tumor effect of immune effector cells. 12 Upregulation of co-stimulatory molecules and/or surface antigens on CLL cells, which could render the leukemic cells more immunogenic, has been described.…”

Section: Introductionmentioning

confidence: 99%

Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia

Aue¹,

Njuguna²,

Tian³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundIn chronic lymphocytic leukemia lenalidomide causes striking immune activation, possibly leading to clearance of tumor cells. We conducted this study to investigate the mechanism of action of lenalidomide and the basis for its unique toxicities in chronic lymphocytic leukemia. Design and MethodsPatients with relapsed chronic lymphocytic leukemia were treated with lenalidomide 20 mg (n=10) or 10 mg (n=8) daily for 3 weeks on a 6-week cycle. Correlative studies assessed expression of co-stimulatory molecules on tumor cells, T-cell activation, cytokine levels, and changes in lymphocyte subsets. ResultsLenalidomide upregulated the co-stimulatory molecule CD80 on chronic lymphocytic leukemia and mantle cell lymphoma cells but not on normal peripheral blood B cells in vitro. T-cell activation was apparent in chronic lymphocytic leukemia, weak in mantle cell lymphoma, but absent in normal peripheral blood mononuclear cells and correlated with the upregulation of CD80 on B cells. Strong CD80 upregulation and T-cell activation predicted more severe side effects, manifesting in 83% of patients as a cytokine release syndrome within 8-72 h after the first dose of lenalidomide. Serum levels of various cytokines, including tumor necrosis factor-α, increased during treatment. CD80 upregulation on tumor cells correlated with rapid clearance of leukemic cells from the peripheral blood. In contrast, neither the severity of the cytokine release syndrome nor the degree of T-cell activation in vitro correlated with clinical response. ConclusionsUpregulation of CD80 on tumor cells and T-cell activation correlate with unique toxicities of lenalidomide in chronic lymphocytic leukemia. However, T-cell activation appears to be dispensable for the drug's anti-tumor effects. This provides a rationale for combinations of lenalidomide with fludarabine or alemtuzumab.

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Immunomodulatory drug costimulates T cells via the B7-CD28 pathway

Cited by 272 publications

References 26 publications

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

Treatment of plasma cell dyscrasias with lenalidomide

Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia

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