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.
Hsu
Andy K
AK
Hematology Immunology Translational Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Quach
Hang
H
Tai
Tsin
T
Prince
H Miles
HM
Harrison
Simon J
SJ
Trapani
Joseph A
JA
Smyth
Mark J
MJ
Neeson
Paul
P
Ritchie
David S
DS
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