Anti-Leukemic Effect of IMiDs® in AML Involves the Direct Cytotoxicity Effects in Addition to a Biased NK Activation,

Abstract 3224

Lenalidomide is an immunomodulatory drug (IMiD®) that has shown efficacy in the treatment of patients with multiple myeloma (MM) and myelodysplastic syndrome with 5q deletion. This drug has several potential antitumor mechanisms of action, shown in MM (Görgün G et al. Blood. 2010). In addition to its direct anti-MM effect, lenalidomide also stimulates T-cell proliferation, IL-2 and interferon-γ (IFNγ) production (Corral LG et al.J Immunol. 1999), and enhances cytotoxic T lymphocyte (CTL) and natural killer (NK) effector cell activity against MM cells (Davies et al. Blood. 2001).

We examined the in vitro antileukemic effects of two IMiDs® (lenalidomide and another derivative of thalidomide, pomalidomide) in AML.

We have shown that both lenalidomide and pomalidomide treatment had an effect on two major mechanisms involved in the antileukemic action: on one hand, on the function of effector cells including NK cells, on the other hand, a direct toxic effect on leukemic blasts.

First, we have shown that these drugs induced rapid phenotypic modifications of NK cells, independently of other cells or cytokines. Our data favor a transition of these cells towards more immature NK cells (CD56^bright phenotype) as indicated by the upregulation of CD56 and the downregulation of KIR and CD57 that are hallmarks of educated and differentiated NK cells. These drugs also modulated activating receptors (NKp30 and NKp46), chemokine receptors (CXCR4) and cytokine receptors (IL7R) by downregulating their expression. Lenalidomide and pomalidomide do not affect other NK cells surface molecules such as activating receptors (NKG2D, DNAM1), adhesion molecules (CD44) and homing receptors (CD62L, CXCR3 and CCR7).

Intriguingly, despite downregulation of NKp46 and moderate downregulation of NKp30, NK cells cytotoxicity against leukemia targets was conserved.

We also showed that IMiDs® had a direct effect on contact-dependent NK cells functions, independently of cytokines stimulation, inducing a specific undescribed profile CD107⁺/IFNγ⁻/TNFα⁺⁺. This new subset has never been previously identified to our knowledge.

Finally, we observed a direct toxicity of IMiDs® on AML blasts that was independent on immune effectors including NK cells. This may be partly due to oxidative stress.

Altogether, these data indicate new interesting functions of IMiDs® that are able to modify the differentiation and functional status of the NK cells and act in addition directly on AML blasts. Further studies are needed to develop pre-clinical models as well as the identification of the basis of NK differentiation of this new NK subset.