Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia

Abstract

The online version of this article contains a supplementary appendix. BackgroundIn chronic lymphocytic leukemia lenalidomide causes striking immune activation, possibly leading to clearance of tumor cells. We conducted this study to investigate the mechanism of action of lenalidomide and the basis for its unique toxicities in chronic lymphocytic leukemia. Design and MethodsPatients with relapsed chronic lymphocytic leukemia were treated with lenalidomide 20 mg (n=10) or 10 mg (n=8) daily for 3 weeks on a 6-week cycle. Correlative studies assessed expression of co-stimulatory molecules on tumor cells, T-cell activation, cytokine levels, and changes in lymphocyte subsets. ResultsLenalidomide upregulated the co-stimulatory molecule CD80 on chronic lymphocytic leukemia and mantle cell lymphoma cells but not on normal peripheral blood B cells in vitro. T-cell activation was apparent in chronic lymphocytic leukemia, weak in mantle cell lymphoma, but absent in normal peripheral blood mononuclear cells and correlated with the upregulation of CD80 on B cells. Strong CD80 upregulation and T-cell activation predicted more severe side effects, manifesting in 83% of patients as a cytokine release syndrome within 8-72 h after the first dose of lenalidomide. Serum levels of various cytokines, including tumor necrosis factor-α, increased during treatment. CD80 upregulation on tumor cells correlated with rapid clearance of leukemic cells from the peripheral blood. In contrast, neither the severity of the cytokine release syndrome nor the degree of T-cell activation in vitro correlated with clinical response. ConclusionsUpregulation of CD80 on tumor cells and T-cell activation correlate with unique toxicities of lenalidomide in chronic lymphocytic leukemia. However, T-cell activation appears to be dispensable for the drug's anti-tumor effects. This provides a rationale for combinations of lenalidomide with fludarabine or alemtuzumab.

Cereblon binding molecules in multiple myeloma

“…Innate immune function is improved by increasing the number of NK cells [71] and their cell-mediated and monocyte-mediated antibody-dependent cellular cytotoxicity [72][73][74]. Impaired T-cell function is reversed by CBMs including cytoskeletal reorganization of the immunological synapse [75][76][77], T-cell activation [78], by activating cytokine production and the degradation of the negative IL2 regulators Ikaros and Aiolos [10,11,79]. Enhanced activation of the transcription factor AP-1 further contributes to increased production of IL-2 from activated CD4+ and CD8+ T-cells, IFN gamma from TH1 cells, and IL5 and IL10 from TH2 cells [20,80,81].…”

Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21WAF1/Cip1-dependent mechanism independent of functional p53

“…10 Moreover, lenalidomide can reverse noted functional defects of T cells in patients with CLL. 11,12 Finally, lenalidomide can also induce CLL B cells to express higher levels of immunostimulatory molecules such as CD80, CD86, HLA-DR, CD95, and CD40 in vitro, 5,13 thereby potentially enhancing their capacity to engage T cells in cognate interactions that lead to immune activation in response to leukemia-associated antigen(s). 14 However, lenalidomide may also have direct antiproliferative effects on CLL cells that account in part for its clinical activity in patients with this disease.…”

Immune dysfunction in chronic lymphocytic leukemia T cells and lenalidomide as an immunomodulatory drug

“…This tumor flare reaction is manifested as an acute onset of swelling of involved lymph nodes with inflammation of the overlying skin, rash and fever. Aue et al, in a study published in this issue of the Journal, 9 show that when relapsed patients are treated with lenalidomide this flare reaction is associated with induction of CLL cell co-stimulatory molecules and T-cell activation. Their findings highlight the need to combine the current understanding of CLL biology, including immune dysfunction, with the results of correlative functional studies in order to identify the critical mechanisms of action of lenalidomide as a new agent in CLL.…”