Lenalidomide and CC-4047 are second generation IMiDs® having immunomodulatory properties and have shown promising results in recent clinical trials in patients with multiple myeloma. Partial or complete responses have been observed in up to 85% of patients. Many IMiDs® are strongly anti-angiogenic compounds and have also been shown to exhibit direct and immune related anti-tumor activities in vitro and in vivo, although the mechanisms of action of these drugs are still not clear. It is known that the drugs have CD4+ and CD8+ T cell co-stimulatory activity and can enhance the innate cytotoxic activity of NK and γδ T cells. In the current study we have assessed the ability of these compounds to influence the activity of thymus-derived peripheral blood “natural” Treg cells in vitro. These cells are key suppressor cells that promote tumour cell growth by inhibition of anti-tumour immune responses. We found that lenalidomide and CC-4047, but not thalidomide, inhibit the expansion of CTLA4 positive CD25+CD4+ Treg in an activated PBMC population by up to 50%. Both compounds abolish the suppressor function of Treg cells at 1 μM, which is a physiologically relevant concentration achievable well below the established maximum tolerated dose (MTD) for lenalidomide in particular. This is shown in an assay in which the ability of isolated Treg cells to suppress anti-CD3 mAb activated autologous CD4+CD25- cells is assessed. Pre-incubation of Treg cells with lenalidomide or CC-4047, but not thalidomide, strongly inhibits the suppressive function of these cells. The inhibition of Treg cell function and production by these compounds is not due to any cytotoxic or apoptotic effects of the IMiDs on the cells, nor is it due to a change in FOXP3 expression in the Treg cells. The inhibition of Treg cell expression and function are possible mechanisms by which some IMiDs®, and in particular lenalidomide, can increase anti-tumour immunity and augment NK cytotoxicity in vivo.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]