The immunomodulatory (IMiD) drug Lenalidomide (Len) is known to stimulate natural killer (NK) cells and enhance anti-tumor responses. Len plus Dexamethasone (Dex) therapy (Len-Dex) is an effective treatment for multiple myeloma (MM). As part of a prospective clinical trial of monthly cycles of Len-Dex therapy we assessed NK cell number and function in 25 MM patients. Whilst NK numbers increased from a mean of 2×105/ml (baseline) to a mean of 3.9×105/ml (cycle 6) (p=0.05), the mean NK cell-mediated cytotoxicity in chromium assays against K562 significantly decreased from 48.9% to 27.6% respectively (p=0.0028). Further analysis showed that when NK cell cytotoxicity was assessed from MM patient peripheral blood mononuclear cells (PBMC) during therapy, no enhancement of cytotoxicity could be observed when cultured in vitro with Len. We hypothesized that Dex potently suppressed the Len-mediated enhancement of NK function. In vitro, Len increased normal donor (n=6) NK cytotoxicity from 38.5% (untreated) to 53.3%. Dex severely impaired NK cytotoxicity to <10%, this failed to increase (<13%) in the presence of Len. Only the addition of high dose IL-2 (500U/ml) rescued cytotoxicity of Dex-treated NK cells (28.6%). The suppressive effect of Dex on NK cytotoxicity was not permanent as NK function returned to normal levels within 3 days of drug removal. However, these dex-‘washout’ PBMCs could no longer respond to Len with increased NK function, suggesting a permanent Dex-induced NK impairment. In cell sorting and co-culture experiments we found that Len enhancement of NK cytotoxicity was only mediated by CD4+ T cells (NK alone 76.6% vs NK+CD4 85%) and the effect of CD4+ T cells was IL-2 dependent. Furthermore IL-2 production by CD4+ T cells in response to anti-CD3/CD28 was also suppressed by Dex. Following Len-Dex therapy in patients we observed less IL-2 and IFN-γ production from T cells in response to anti-CD3/CD28 at cycle 6 compared to baseline.

Therefore, Len-mediates enhanced NK function through CD4+ T cell production of IL-2. The NK impairment observed in MM patients receiving Len-Dex is due to CD4+ T cell suppression. Our findings indicate that in order to harness both the anti-tumor and immunomodulatory capacity of Len the dose and timing of Dex therapy should be carefully reconsidered.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5619.