Direct Effect of Rituximab in B-Cell–Derived Lymphoid Neoplasias: Mechanism, Regulation, and Perspectives

Abstract

The anti-CD20 monoclonal antibody rituximab is the backbone of treatment for the B-cell malignancies nonHodgkin lymphoma and chronic lymphocytic leukemia. However, there is a wide variability in response to rituximab treatment, and some patients are refractory to current standard therapies. Rituximab kills B cells by multiple mechanisms of action, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which are immune-mediated mechanisms, as well as by direct effects on cell signaling pathways and cell membranes following CD20 binding. A large number of events that are affected by rituximab binding have been identified, including lipid raft modifications, kinase and caspase activation, and effects on transcription factors and apoptotic/antiapoptotic molecules. Studies on cell lines and isolated tumor cells have

Localized Store-Operated Calcium Influx Represses CD95-Dependent Apoptotic Effects of Rituximab in Non-Hodgkin B Lymphomas

“…RTX-induced apoptosis is mediated by a complex signaling pathway, including activation or downregulation of protein kinases, phosphatases, and Bcl-2 family members, as well as changes in lipid distribution in the cell membrane, triggering mitochondrial-and CD95-dependent cell death (5). However, it has been established that RTX induces only modest levels of apoptosis in NHL B.…”

Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

“…Anti-CD20 monoclonal antibodies (mAbs) such as chimeric rituximab and completely human ofatumumab are used in the treatment of both indolent and aggressive non-Hodgkin lymphomas (NHLs) 3 and have revealed a significant activity in patients with chronic lymphocytic leukemia (CLL) (1). These antibodies can trigger indirect effector mechanisms of the immune system such as activation of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and immunophagocytosis (1,2).…”

“…These antibodies can trigger indirect effector mechanisms of the immune system such as activation of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and immunophagocytosis (1,2). Despite the vast amounts of data on the mechanisms of anti-CD20 mAb-mediated cytotoxicity, their relative contribution to the therapeutic outcome is still difficult to predict in individual patients (1,2).…”

Review of Antibody-Based Immunotherapy in the Treatment of Non-Hodgkin Lymphoma and Patterns of Use

“…The chimeric antibody was chosen specifically for the purpose of increasing complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity (ADCC), which are the main mechanisms through which rituximab produces its antitumor effect. 5 Additionally, reports of increased cytotoxic T-cell response against the malignant clone in patients treated with rituximab suggest that rituximab may induce vaccine-like effects. 6 Finally, there is considerable evidence that the binding of rituximab to CD20 has the capability of interfering with a variety of intracellular processes, including Bcl-2 signaling, BCR signaling, and caspase signal cascades.…”

“…6 Finally, there is considerable evidence that the binding of rituximab to CD20 has the capability of interfering with a variety of intracellular processes, including Bcl-2 signaling, BCR signaling, and caspase signal cascades. 5 As a single agent, rituximab treatment produced durable response rates (RRs) in a large variety of cancers, including treated and untreated follicular lymphoma (FL), relapsed indolent lymphoma, relapsed diffuse large B-cell lymphoma (DLBCL), relapsed and untreated mantle cell lymphoma (MCL), and relapsed and untreated chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL), among others. Dillman presented summaries of all single-agent rituximab trials.…”