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Introduction
Non-Hodgkin's lymphoma (NHL) is the fifth or sixth most common cancer in the US, and diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoma in the Western world (1,2). Currently, the standard front-line therapy for DLBCL is the combination of rituximab and chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) (R-CHOP), with expected 5- and 10-year overall survival (OS) rates of 58 and 43.5%, respectively (3). Rituximab is a chimeric monoclonal antibody (mAb) targeting CD20. Rituximab acts, in part, by engaging Fc receptors on immune effector cells, such as NK and macrophages, and induces cytotoxicity by antibody-dependent cellular cytotoxicity (ADCC). It also activates complement-dependent cytotoxicity (CDC) and rarely induces apoptosis (4). While therapeutic outcomes have improved in the post-rituximab era, there is evidence of patients exhibiting rituximab-resistance (RR). Thus, attempts to overcome RR have been a major focus of novel therapeutic developments. The mechanisms of resistances in vivo are not clear. Several mechanisms underlying RR have been postulated. These included resistance to antibody-mediated cytotoxicity mechanisms (ADCC, CDC, and induction of apoptosis), Fc-receptors polymorphisms, downregulation or loss of CD20 expression, altered antibody pharmacokinetics and altered molecular signaling pathways through CD20 (5).
We have explored the potential mechanisms of rituximab resistance by developing in vitro clones of rituximab-resistant (RR) variants in several B-NHL cell lines and characterized their properties. Briefly, unlike the parental wild-type, the RR clones express CD20 but no longer respond to treatments with rituximab or combination of rituximab and cytotoxic drugs. Further, the RR clones overexpressed the activity of several survival/anti-apoptotic pathways. Interference in the activity of these hyper-activated pathways reversed resistance (6). In the hope of overcoming rituximab resistance alternative therapies such as the use of HDAC or Bcl-2 inhibitors have also been demonstrated to enhance sensitization of tumor cells to rituximab (7). The efficacy of rituximab has also been shown to be augmented when used in combination with biological agents such as interferon-α-2a (IFN-α), specific interleukins, bortezomib and lenalidomide (8).
An alternative strategy for the management of patients with lymphoma has been to use biologic agents instead of chemotherapy in relapsed and refractory lymphoma patients. Clinical trials using rituximab alone or in combination with IFN-α have shown that T-cells are important for the survival for lymphoma patients (9). Preclinical studies have...