Lenalidomide‐based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients

Abstract

A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a proinflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR21 Tregs are potent suppressors, targeting TNFR21 Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR21 T cells, including TNFR21 Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFNc production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR21 T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR21 T cells and TNFR21 Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR21 T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome.

A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia

“…Given that lenalidomide may modulate anti‐tumor immunity in AML, we evaluated T‐cell immune responses during treatment. Peripheral blood mononuclear cells (PBMC) were collected prior to therapy and at count recovery and were cryopreserved.…”

Maintenance lenalidomide in combination with 5‐azacitidine as post‐remission therapy for acute myeloid leukaemia

“…Defective T and NK cell function has been previously characterised in AML, including the persistence of aberrant NK cells among patients in CR (Le Dieu et al , ; Dauguet et al , ; Govindaraj et al , , ). There is a relative paucity of experimental data available regarding immune competency in the post‐remission period after intensive chemotherapy in AML.…”

TNFR2 and Regulatory T Cells: Potential Immune Checkpoint Target in Cancer Immunotherapy

“…Thalidomide and its analogues prevent the surface expression of TNFR2 on activated T cells, which is associated with the inhibition of TNFR2 protein trafficking to the cell membrane [67]. Treating acute myeloid leukemia patients with azacitidine and lenalidomide, a thalidomide derivative can reduce TNFR2 expression on T cells as well as TNFR2+ Treg in vivo, leading to enhanced effector immune function [68]. Cyclophosphamide is a DNA alkylating agent.…”