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Lenalidomide (CC-5013; Revlimid®) represents one compound in a category of new medications known as immunomodulatory drugs (IMiD's® ). These compounds are thalidomide derivatives that lack many of the toxicities associated with thalidomide, while possessing an enhanced potency and pharmacologic profile for the regulation of cellular immunity and cytokine response [1]. The structural modification of thalidomide to produce lenalidomide is relatively minor (Figure 1) [2]. The exact mechanism of action has yet to be determined, but these medications exert their effects by altering ligand-induced cellular responses and thereby modify a broad spectrum of responses such as, antigen-initiated immune regulation and cytokine-induced antiangiogenesis. Not only has the potency of the medication improved when compared with the parent compound, thalidomide, but the side-effect profile has changed considerably. Also the neurologic toxicity and pro-thrombotic effects of thalidomide are reduced in the structural analog. This report will review the preclinical and clinical results of the investigations with this exciting new therapeutic, its toxicities and future prospects.
Preclinical evaluation
The pharmacologic effects of lenalidomide derive from modulation of the cytokine response by altering the balance of effector cell responses to biologic triggers, which may result in either inhibitory or stimulatory effects on cytokine production, depending upon target-cell lineage and ligand stimulus. Experiments evaluating inhibition of tumor necrosis factor (TNF)-α elaboration by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs) demonstrated a 100-50,000 higher potency of IMiD's compared with thalidomide, as inhibitors of cytokine generation [3,4]. However, in the setting of T-cell activation, lenalidomide appears to enhance TNF-α production which was observed in vitro and in a Phase I solid tumor study consisting primarily of patients with metastatic melanoma [5,6].
The generation of interleukin (IL)-12 is also influenced by the presence of lenalidomide. This cytokine is important for promoting the expansion and activity of T-cells and natural killer (NK) cells as the body augments innate and adaptive immunity [7]. Similar to TNF-α, lenalidomide inhibits IL-12 production by LPS-stimulated PBMCs; however, when T-cells are stimulated, levels of IL-12 are increased in vivo and in vitro [6,8]. This finding supports the investigation of lenalidomide as a tumor vaccine adjunct, as enhanced NK cell activity and supplemental IL-12 have been shown to augment antitumor response and inhibit metastasis formation [9-11].
Thalidomide has known...