Non-Hodgkin's Lymphomas: Biology and New Therapies
In our laboratory, we used cDNA arrays to compare the gene expression of germinal center (GC) B cells with follicular lymphoma (FL) cells, and confirmed differentially expressed genes by qRT-PCR. Among the genes upregulated in FL were cell cycle regulator proteins CDK10, p120, p21CIP1, and p16INK4a; transcription factors/regulators Pax-5 and Id-2; and genes involved in cell-cell interactions: TNF-alpha, IL-2R,-g and IL-4R. We also demonstrated that cytogenetic changes in FL cells correlates with the altered expression of some of these genes at their known loci. These findings provide a basis for future studies of the pathogenesis and pathophysiology of follicular lymphoma, and may lead to the identification of potential therapeutic targets as well as antigens for immunotherapeutic strategies. Based upon our array studies and other work, we are focusing on TNF-alpha, which is overexpressed by FL cells, as a therapeutic target in FL. TNF-alpha upregulates expression of adhesion molecules, cytokines, and chemokines that are critical to interactions between FL cells and follicular dendritic cells (FDC). We are currently conducting a clinical trial of etanercept - which binds to TNF-alpha, reducing its biological activities - in patients with relapsed and refractory follicular lymphoma, and also evaluating a variety of surrogate markers of the microenvironment and T cell function in these patients.In other research, we are attempting to modulate the effects of the anti-CD20 monoclonal antibody (mAb) rituximab. We completed a trial of low dose IL-2 with rituximab in which the numbers of natural killer cells increased in the peripheral blood of treated patients. We have also investigated the combination of rituximab with immunostimulatory DNA sequences (ISS), which enhance antigen presentation and costimulatory molecule expression, stimulate dendritic cell maturation, and induce cytokines, resulting in increased cell-mediated cytotoxicity. Through these effects on both the adaptive and innate immune response, ISS are excellent candidates to enhance the cytotoxicity of mAbs such as rituximab. We completed a phase I study of 1018 ISS in combination with rituximab in patients with relapsed non-Hodgkin's lymphoma (NHL), demonstrating safety and biological activity. Given this favorable data, we plan to test the efficacy of combination immunotherapy in a phase II study in patients with relapsed follicular NHL, and to further analyze the immunologic effects of this combination in vitro and in vivo.