Abstract
Accumulating evidence suggests that the tumor microenvironment (TME) is involved in disease progression and drug resistance in B cell malignancies, by supporting tumor growth and facilitating the ability of malignant cells to avoid immune recognition. Immunomodulatory drugs (IMiDs) such as lenalidomide have some direct anti-tumor activity, but critically also target various cellular compartments of the TME including T cells, NK cells, and stromal cells, which interfere with pro-tumor signaling while activating anti-tumor immune responses. Lenalidomide has delivered favorable clinical outcomes as a single-agent, and in combination therapy leads to durable responses in chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphomas (NHLs) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Recently, avadomide, a next generation cereblon E3 ligase modulator (CELMoD), has shown potent anti-tumor and TME immunomodulatory effects, as well as promising clinical efficacy in DLBCL. This review describes how the pleiotropic effects of IMiDs and CELMoDs could make them excellent candidates for combination therapy in the immuno-oncology era—a concept supported by preclinical data, as well as the recent approval of lenalidomide in combination with rituximab for the treatment of relapsed/refractory (R/R) FL.
Highlights
Despite recent advances in diagnosis and treatment, B cell malignancies still account for significant morbidity and mortality worldwide
Preclinical and clinical data suggests that avadomide exerts its anti-lymphoma effects in both germinal center B cell (GCB)- and ABCDLBCL subset types, unlike lenalidomide [23,66]
Due to the potent anti-tumor effects exhibited by avadomide against non-Hodgkin lymphomas (NHLs) cells, further investigation of this cereblon E3 ligase modulator (CELMoD) in larger studies in combination with novel anti-CD20 antibodies and novel immunotherapies for R/R patients has been proposed
Summary
Despite recent advances in diagnosis and treatment, B cell malignancies still account for significant morbidity and mortality worldwide. Venetoclax is a BCL2 antagonist that has shown high response rates with deep remissions in front-line and R/R CLL settings in combination with anti-CD20 antibodies [6,7] Despite these advances, there are still challenges associated with treatment with small molecule inhibitors, which include toxicity and the risk of developing drug resistance [8]. Immunomodulatory drugs (IMiDS) such as lenalidomide (Revlimid) and pomalidomide are thalidomide derivatives, with pleiotropic effects in human malignancies These agents exhibit a plethora of anti-cancer properties including anti-angiogenic, anti-proliferative and immunomodulatory effects that have demonstrated significant clinical activity for the treatment of both untreated and R/R B cell hematological malignancies as a single-agent and in combination with other agents including rituximab [10,11,12,13,14,15]. We discuss the potential future clinical development of these agents as combination partners
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