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

Abstract

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...

Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial

“…Others have demonstrated a small increase in the absolute numbers of NK cells in an elderly population treated with a dose of 15 mg lenalidomide combined with dexamethasone, but we could not confirm this. 14 Besides GVHD, the most common AEs were blood and bone marrow toxicities, mainly consisting of neutropenia and thrombocytopenia, infections, and other metabolic/laboratory AEs. A total of 17% of patients stopped treatment because of AEs.…”

IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect

“…21 Recent studies demonstrate that dexamethasone also profoundly impairs the immunomodulatory profile of lenalidomide. 22,23 These findings have fostered interest in developing steroid-limiting or steroidsparing treatments to maximize the immunomodulating properties of lenalidomide. 24 Our data provide a preclinical justification for a phase 2 trial of IPH2101 in combination with lenalidomide as the first "dual immunotherapy" for patients with MM.…”

Molecular mechanisms of natural killer cell activation in response to cellular stress

“…Interestingly, although CD8 T cells were the main effectors responsible for the therapeutic effects of chemotherapy in these settings, the efficient priming of these cells required the presence of upstream innate immunity, such as gd T cells. 143 As the phenotype and function of NK cells are modulated in humans during chemotherapy 144,145 and many cellular stress pathways activated by chemotherapy can increase tumor cell sensitivity to NK cell-mediated cytotoxicity and recognition (as discussed in the previous sections), it will be important to determine whether NK cells can also contribute to the efficacy of chemotherapy.…”