Lenalidomide: a novel anticancer drug with multiple modalities

Galustian, Christine; Dalgleish, Angus

doi:10.1517/14656560802627903

Cited by 69 publications

(38 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[8][9][10][11][12] Studies in lymphoma and multiple myeloma (MM) models have demonstrated that lenalidomide exerts higher antitumor activity than thalidomide, has a unique capacity to stimulate the innate immune system, enhances the antitumor activity of rituximab, and inhibits angiogenesis. 13,14 The effects of lenalidomide appear to be related to the ability of immunomodulatory drug compounds to inhibit tumor necrosis factor-a, vascular endothelial growth factor, and nuclear factor kappa B (NF-KB) activity in tumor cells.…”

mentioning

confidence: 99%

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

Hernandez‐Ilizaliturri

Deeb

Zinzani

et al. 2011

Cancer

283

180

View full text Add to dashboard Cite

BACKGROUND: There is a need to develop novel therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response. Lenalidomide was previously shown to induce an overall response rate (ORR) of 28% in patients with relapsed/refractory DLBCL. It is currently unknown if response rates differ between patients with different DLBCL subtypes. METHODS: The authors retrospectively evaluated clinical outcomes of patients with germinal center B-cell-like versus nongerminal center B-cell-like DLBCL treated with salvage lenalidomide at 4 academic institutions. RESULTS: Forty patients with relapsed/refractory DLBCL were included (24 men; 16 women; median age, 66 years; median of 4 prior treatments, including rituximab chemotherapy). Patients were classified as germinal center B-cell-like (n ¼ 23) or nongerminal center B-cell-like (n ¼ 17) DLBCL according to the Hans algorithm. The subgroups were similar in terms of stage, international prognostic index score, prior number of treatments, and rituximab resistance. A significant difference in clinical response to lenalidomide was observed in nongerminal center B-cell-like versus germinal center B-cell-like patients. ORR was 52.9% versus 8.7% (P ¼ .006); complete response rate was 23.5% versus 4.3%. Median progression-free survival was 6.2 versus 1.7 months (P ¼ .004), although no difference in OS was observed between nongerminal center B-cell-like and germinal center B-cell-like DLBCL patients. CONCLUSIONS: The data suggest that the 2 major subgroups of patients with DLBCL (germinal center B cell and nongerminal center B cell) have different antitumor responsiveness to lenalidomide in the relapsed/refractory setting. A large international trial (NCT01197560) has been opened to enrollment in an attempt to prospectively validate these retrospective observations. Cancer 2011;117:5058-

show abstract

mentioning

confidence: 99%

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

Hernandez‐Ilizaliturri

Deeb

Zinzani

et al. 2011

Cancer

283

180

View full text Add to dashboard Cite

show abstract

“…11,12 The anti-MM effect of immunomodulatory drugs is thought to be mediated by the combined effects of tumor necrosis factor ␣ inhibition, direct inhibition of plasma cell proliferation, suppression of angiogenesis, and promotion of T-cell costimulation, [13][14][15][16] and disruption of adhesion between malignant plasma cells and BM stroma. [17][18][19] Lenalidomide also shows substantial capacity to activate natural killer (NK) cell cytotoxicity and NK cell-driven antibodydependent cell-mediated cytotoxicity (ADCC). 20,21 In vitro studies have shown that peripheral blood mononuclear cells (PBMCs) are required for lenalidomide-induced NK cell function, and this is achieved indirectly through activation of nuclear factor of activated T cell 2 (NFAT2) in T cells.…”

mentioning

confidence: 99%

The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy

Hsu¹,

Quach

Tai³

et al. 2011

Blood

139

126

View full text Add to dashboard Cite

Lenalidomide combined with dexamethasone is an effective treatment for refractory/ relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses.We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of lenalidomide and dexamethasone. NK cell numbers increased from a mean of 2.20 ؎ 0.05 ؋ 10 5 /mL (baseline) to a mean of 3.90 ؎ 0.03 ؋ 10 5 /mL (cycle 6; P ‫؍‬ .05); however, in vitro NKcell-mediated cytotoxicity decreased from 48.9% ؎ 6.8% to 27.6% ؎ 5.1% (P ‫؍‬ .0028) and could not be rescued by lenalidomide retreatment. Lenalidomide increased normal donor NK-cell cytotoxicity in vitro from 38.5% to 53.3%, but this was completely abrogated by dexamethasone. Dexamethasone suppression of NK cellmediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomideinduced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell-mediated cytotoxicity was mediated by CD4 ؉ T-cell production of interleukin 2 and that dexamethasone acted by suppressing interleukin-2 production. Similarly, the reduced ability of NK cells from patients with MM to respond to lenalidomide was also due to impaired CD4 T-cell function. IntroductionMultiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells in the bone marrow (BM) and accumulation of monoclonal paraprotein in the serum of the majority of affected patients. 1 There is evidence that MM, at least in its early stages, is under the control of innate and adaptive immune responses, 2-9 which are ultimately subverted by the production of plasma cell and BMderived immunosuppressive cytokines including interleukin 6 (IL-6), transforming growth factor ␤ (TGF-␤), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), and tumor necrosis factor ␣ (TNF-␣). 10 The disease-associated immunoparesis of MM is further compounded by the immunosuppressive effects of anti-MM therapy. 10 Conventional MM therapy has used alkylator or anthracyclinebased chemotherapy in combination with the corticosteroids dexamethasone or prednisolone. Increasingly, nonchemotherapy agents such as the immunomodulatory (IMiD) drugs thalidomide and lenalidomide or the proteasome inhibitor Bortezomib have been incorporated into induction regimens commonly to replace chemotherapy agents, but are still used in combination with high-dose corticosteroids such as dexamethasone. 11,12 The anti-MM effect of immunomodulatory drugs is thought to be mediated by the combined effects of tumor necrosis factor ␣ inhibition, direct inhibition of plasma cell proliferation, suppression of angiogenesis, and promotion of T-cell costimulation, [13][14][15][16] and disruption of adhesion between malignant plasma cells and BM stroma. [17][18][19] Lenalidomide also shows substantial capacity to activate natural killer (NK) cell cytotoxicity and NK cell-driven antibodydependent cell-mediat...

show abstract

“…Incubation of cancer cells with DHA alone was found to be less effective than in combination with holotransferrin, indicating that intracellular iron plays a role in the cytotoxic effects of DHA . In addition to conventional chemotherapies, ART was also combined with the immune modulatory drug LEN (Galustian & Dalgleish, 2009). These in vitro studies demonstrated the effects of ART on the cell cycle, and the studies showed restoration of cytotoxicity in an ART-resistant cell by adopting a pulsed-schedule of combination treatment.…”

Section: Combination Strategies To Enhance Efficacy Of Arts As Anticamentioning

confidence: 97%

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

Li¹,

Hickman²,

Weina³

2011

Vasculogenesis and Angiogenesis - From Embryonic Development to Regenerative Medicine

View full text Add to dashboard Cite

Lenalidomide: a novel anticancer drug with multiple modalities

Cited by 69 publications

References 71 publications

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

Contact Info

Product

Resources

About