Activation of Th1 Immunity Within the Tumor Microenvironment is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia. Activation of Th1 Immunity Within the Tumor Microenvironment is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia

Immune stimulation contributes to lenalidomide’s anti-tumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T-cell function in vitro. Whether T-cell activation is required for clinical response to lenalidomide remains unclear. Here we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with anti-tumor response. Within days of starting lenalidomide, CD3+ cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pre-treatment and on-treatment lymph node biopsies revealed upregulation of IFN and many of its target genes in response to lenalidomide. The IFNγ-mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of T-cell receptor genes revealed decreasing diversity of the T-cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T-cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response. Overall design: Patients with relapsed CLL were enrolled on a phase 2 study of lenalidomide at 10 mg or 20 mg daily for 3 weeks followed by 3 weeks off for up to 8 cycles. Blood and lyphm node samples were collected from the patients prior treatment and treated on day 8 for studying change in expression of genes in blood and lymph nodes.