High efficacy of lenalidomide in Multiple Myeloma (MM) patients is related to its direct anti-proliferative and anti-angiogenic properties inducing cell cycle arrest of myeloma cells, and downregulation of interleukin (IL)-6 and vascular endothelial growth factor levels in the tumor microenvironment, respectively. Furthermore, lenalidomide has been supposed to indirectly increase immunotherapy responses in MM patients, stimulating T-cell proliferation, enhancing IL-2, interferon-gamma and tumor necrosis factor-alpha secretion by T helper-1 cells, as well as downregulating regulatory T cells and upregulating cytotoxic effects of natural killer (NK) cells. To determine the effects of lenalidomide on NK cells, we evaluated the numbers of circulating NK cells in 15 MM patients (12 males and 3 females), with a median age of 75 years (range, 56-86), during treatment with continuous low-dose of lenalidomide (LDR). Seven of these 15 MM patients were newly diagnosed MM patients receiving continuous alternate-day LD-R (10 mg on alternate days) in combination with low dose steroids (15 mg/day), the remaining were MM patients receiving continuous alternate-day LD-R maintenance therapy after autologous stem cell transplantation. Flow cytometry analysis was performed using the Cytomics FC500 (Coulter, Miami, FL) to determine the expression of T-cell antigens (CD3, CD4, CD8), NK-cell antigen (CD56) and NK-cell–activation antigens (CD2, HLA DR). All antibodies were obtained from Beckman Coulter. Phenotypic analysis of all these T- and NK-cell antigens were performed before and at month +1, +3, +6, +9 and +12 during R therapy. All MM patients showed a progressive increase in the percentage of CD3+ CD56+ NK cells during the first 6 months of R therapy reaching a plateau maintained until month +12 after initiation of therapy: the median percentage of NK cells was 4% before R treatment versus 10%, 13%, 30%, 31% and 27% at +1, +3, +6, +9 and +12 months, respectively. Mean fold increase of NK cells during R therapy was 1.5, 2.5 and 6.5 at +1, +3, and +6 months, respectively. Progressive increase of NK cells was concomitantly associated with reduction in tumor-linked monoclonal immunoglobulin in all patients. Our preliminary data document that prolonged low-dose R treatment in MM patients increases circulating NK cells further supporting that this drug may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.

Prolonged low-dose lenalidomide treatment increases the number of circulating natural killer cells in multiple mieloma patients

Giudice V;SELLERI, Carmine
2013

Abstract

High efficacy of lenalidomide in Multiple Myeloma (MM) patients is related to its direct anti-proliferative and anti-angiogenic properties inducing cell cycle arrest of myeloma cells, and downregulation of interleukin (IL)-6 and vascular endothelial growth factor levels in the tumor microenvironment, respectively. Furthermore, lenalidomide has been supposed to indirectly increase immunotherapy responses in MM patients, stimulating T-cell proliferation, enhancing IL-2, interferon-gamma and tumor necrosis factor-alpha secretion by T helper-1 cells, as well as downregulating regulatory T cells and upregulating cytotoxic effects of natural killer (NK) cells. To determine the effects of lenalidomide on NK cells, we evaluated the numbers of circulating NK cells in 15 MM patients (12 males and 3 females), with a median age of 75 years (range, 56-86), during treatment with continuous low-dose of lenalidomide (LDR). Seven of these 15 MM patients were newly diagnosed MM patients receiving continuous alternate-day LD-R (10 mg on alternate days) in combination with low dose steroids (15 mg/day), the remaining were MM patients receiving continuous alternate-day LD-R maintenance therapy after autologous stem cell transplantation. Flow cytometry analysis was performed using the Cytomics FC500 (Coulter, Miami, FL) to determine the expression of T-cell antigens (CD3, CD4, CD8), NK-cell antigen (CD56) and NK-cell–activation antigens (CD2, HLA DR). All antibodies were obtained from Beckman Coulter. Phenotypic analysis of all these T- and NK-cell antigens were performed before and at month +1, +3, +6, +9 and +12 during R therapy. All MM patients showed a progressive increase in the percentage of CD3+ CD56+ NK cells during the first 6 months of R therapy reaching a plateau maintained until month +12 after initiation of therapy: the median percentage of NK cells was 4% before R treatment versus 10%, 13%, 30%, 31% and 27% at +1, +3, +6, +9 and +12 months, respectively. Mean fold increase of NK cells during R therapy was 1.5, 2.5 and 6.5 at +1, +3, and +6 months, respectively. Progressive increase of NK cells was concomitantly associated with reduction in tumor-linked monoclonal immunoglobulin in all patients. Our preliminary data document that prolonged low-dose R treatment in MM patients increases circulating NK cells further supporting that this drug may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4238454
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact