Treatment with lenalidomide modulates T‐cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia

Abstract

BACKGROUND Lenalidomide, an immunomodulatory agent, has activity in lymphoproliferative disorders. The authors, therefore, evaluated its effects on T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia (CLL). METHODS To study the immunomodulatory effects of lenalidomide in CLL, the authors recruited 24 patients with untreated CLL enrolled in a phase 2 clinical trial of lenalidomide and obtained peripheral blood specimens for immunologic studies consisting of enumeration of T cells and assessing their ability to synthesize cytokines after activation through T-cell receptor (TCR). RESULTS After 3 cycles of therapy, patients had a significant reduction in percentage (%) and absolute lymphocyte count (ALC) and an increase in percentage of T cells, percentage of activated CD8+ T cells producing IFN-γ, and percentage of regulatory T (TR) cells when compared with their respective levels before treatment. After 15 cycles of treatment, responder patients had significant reduction in percentage of lymphocytes and ALC, percentage of activated CD4+ T cells producing IL-2, IFN-γ, or TNF-α, and percentage of TR cells when compared with their perspective levels after 3 cycles of treatment. Furthermore, the numbers of activated CD4+ T cells producing IL-2, IFN-γ, or TNF-α, activated CD8+ T cells producing IFN-γ, and TR cells normalized to the range of healthy subjects. CONCLUSIONS Treatment with lenalidomide resulted in the normalization of functional T-cell subsets in responders, suggesting that lenalidomide may modulate cell-mediated immunity in patients with CLL.

Lenalidomide reduces survival of chronic lymphocytic leukemia cells in primary cocultures by altering the myeloid microenvironment

“…17,18 In addition, lenalidomide treatment enhanced the levels of several inflammatory cytokines and induced expression of costimulatory molecules CD40, CD80, and CD86 in CLL cells. 14,15 Furthermore, lenalidomide was shown to promote CD40L (CD154) expression in CLL cells resulting in an activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. 16 Previous studies revealed an important role for monocytes and NLCs in maintaining viability of CLL cells.…”

“…14 Analysis of blood serum after lenalidomide treatment of CLL patients revealed changes in the levels of several inflammatory cytokines. 12,15 Further, an increased expression of several activation markers was observed. 14,16 By in vitro studies and in the murine TCL1 mouse model for CLL, lenalidomide treatment was shown to reverse a defect in immunologic synapse formation between T cells and CLL cells, which was induced by the malignant cells.…”

Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia

“…11 Intracellular cytokine synthesis by activated T cells was measured as previously described. 13,14 Measured cytokines were: interleukin (IL)-2, IL-6, IL-8, IL-10, IL-12p70, interferon-g, tumor necrosis factor-a, soluble IL-6 receptor, soluble tumor necrosis factor receptor, soluble vascular endothelial growth factor receptor-1, -2 and -3, fibroblast growth factor-b, chemokine (C-C motif) ligand 3, and IL-1Ra. As median time-to-treatment failure was 30 months, patients who had a response lasting more than 36 months were defined as long-term responders (LTRs).…”

Role of the tumor microenvironment in mature B-cell lymphoid malignancies

“…The binding of immunomodulatory drugs to CRBN therefore blocks survival signals to tumor cells and leads to increased IL-2 production and enhancement of T-cell co-stimulation. 138 Furthermore, lenalidomide induces type 1 T helper cell polarization, 141 reduces T reg cells, increases antigen presentation to effector T-cell populations, 142 repairs the immune synapse between tumor cells and cytotoxic T cells, 69 restores impaired T-cell motility and interferes with com-…”