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. 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.