Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Abstract

Lenalidomide is an orally active immunomodulatory drug that has direct antineoplastic activity and indirect effects mediated through multiple types of immune cells found in the tumor microenvironment, including B, T, natural killer (NK), and dendritic cells. Recently, the E3 ubiquitin ligase cereblon was identified as a molecular target that may underlie the effects of lenalidomide on tumor cells, as well as on cells in the tumor microenvironment. Decreases in cereblon attenuate these effects and also confer resistance to lenalidomide. Tumoricidal effects of lenalidomide are associated with reduced interferon regulatory factor 4, a downstream target of cereblon. Lenalidomide stimulates proliferation and activation of NK cells, thereby enhancing NK cell–mediated cytotoxicity and antibody-dependent cellular cytotoxicity. These effects appear to be secondary to cytokine production from T cells. Lenalidomide has been shown to produce synergistic effects in experimental models when evaluated in combination with rituximab, dexamethasone, bortezomib, and B-cell receptor signaling inhibitors, consistent with mechanisms complementary to these agents. These experimental findings have translated to the clinic, where single-agent use displays durable responses in relapsed/refractory non-Hodgkin lymphoma, and combination with rituximab and other agents leads to improved responses at first line and in relapsed/refractory disease. The activity of lenalidomide is evident across multiple lymphoma subtypes, including indolent and aggressive forms. The interaction among cell types in the immune microenvironment is increasingly recognized as important to tumor cell recognition and destruction, as well as to protection of normal immune cells, as reflected by lenalidomide studies across multiple types of B-cell lymphomas.

Upregulation of TET Activity with Ascorbic Acid Induces Epigenetic Modulation of Lymphoma Cells

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Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

“…16,17 Lenalidomide is an immunomodulatory agent with pleotropic effects that may include immune modulation and disruption of tumor-microenvironment interactions. 18,19 Ibrutinib covalently binds Bruton tyrosine kinase (BTK), thereby irreversibly inactivating the kinase. 20 BTK is essential for B-cell receptor (BCR) signaling, and loss-of-function mutations lead to the virtual absence of mature B cells.…”

Frontline strategy for follicular lymphoma: are we ready to abandon chemotherapy?

“…In experimental B-cell models, lenalidomide appears synergistic with multiple agents, including rituximab, dexamethasone, and BCR pathway inhibitors. 34 Based on the premise that augmentation of NK cell activity could enhance rituximab-mediated ADCC, investigators at MD Anderson Cancer Center launched a study in 2008 to explore lenalidomide and rituximab (a regimen referred to as "R squared") in previously untreated indolent lymphoma. The study enrolled 110 patients who received up to 12 months of oral lenalidomide with monthly rituximab.…”