The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy.
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 NK-cell-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 cell-mediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomide-induced 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. Our findings indicate that lenalidomide immunostimulatory effects on patient NK cells are severely blunted by concurrent dexamethasone administration.
Hematology Immunology Translational Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Andy K
AK
Hsu
Hang
H
Quach
Tsin
T
Tai
H Miles
HM
Prince
Simon J
SJ
Harrison
Joseph A
JA
Trapani
Mark J
MJ
Smyth
Paul
P
Neeson
David S
DS
Ritchie
D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D003602:Cytotoxicity, Immunologic; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D000077269:Lenalidomide; D008213:Lymphocyte Activation / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000098862:T Lineage-Specific Activation Antigen 1
D000893:Anti-Inflammatory Agents; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D000098862:T Lineage-Specific Activation Antigen 1; D007376:Interleukin-2; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide