Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs

Schäfer, Peter; Gandhi, Anita K.; Loveland, Michelle A.; Chen, Roger S.; Man, Hon‐Wah; Schnetkamp, Paul P. M.; Wolbring, Gregor; Govinda, Sowmya; Corral, Laura G.; Payvandi, Faribourz; Muller, George W.; Stirling, David I.

doi:10.1124/jpet.102.048496

Cited by 162 publications

(96 citation statements)

References 38 publications

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“…There remains strong in vitro evidence that conventional T cells show a Th1 cytokine bias when cultured with thalidomide analogues, 49,50 and along with others, we report similar findings for NKT cells cultured with lenalidomide. [29][30][31] There is also evidence that lenalidomide can enhance the activation of conventional T cells in vivo, 16,22,51 but most studies, including our own, suggest lenalidomide's in vitro effects on NKT cells are co-stimulatory, and would therefore require an additional activation signalFsuch as that provided by aGalCer in in vitro assays.…”

Section: Discussionsupporting

confidence: 70%

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

et al. 2010

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Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function.

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Section: Discussionsupporting

confidence: 70%

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

et al. 2010

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“…93 The ability of the nonspecific 'angiogenesis inhibitors' such as thalidomide and lenalidomide to provide more profound responses (in the absence of improvements in angiogenesis) suggests that the clinical activity is independent of the inhibition of angiogenesis (further details as per authors 84,85,89,90 in Table 5). …”

Section: Spotlightmentioning

confidence: 99%

Choosing between stem cell therapy and drugs in myelofibrosis

Kröger

Mesa

2008

Leukemia

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“…It also increases production of the antiinflammatory cytokine IL-10 by LPS-stimulated PBMC and consequently inhibits the expression, but not the enzymatic activity, of cyclooxygenase-2 (20). Lenalidomide induces T-cell proliferation and IL-2 and interferon (IFN)-c production (19,21) and it augments cytotoxic activity of natural killer cells (22).…”

Section: Pharmaco Dynami C Pr Oper Tiesmentioning

confidence: 99%

Lenalidomide in the treatment of multiple myeloma: a review

2008

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Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined antiinflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties. In relapsed or refractory multiple myeloma (MM), lenalidomide, combined with standard dose dexamethasone, is superior to dexamethasone alone in terms of time to progression, response rate and overall survival. The most commonly reported adverse events include haematological toxicity with manageable neutropenia and thrombopenia. Lenalidomide does not trigger the limiting toxicities of thalidomide: somnolence, neuropathy and constipation. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of MM patients who have received at least one prior therapy and is administered orally at the dose of 25 mg q.d. for 21 days of 28-day cycles. The drug is being investigated for the treatment of newly diagnosed MM. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical trial data on lenalidomide.

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Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs

Abstract: CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers.

Cited by 162 publications

References 38 publications

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

Choosing between stem cell therapy and drugs in myelofibrosis

Lenalidomide in the treatment of multiple myeloma: a review

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