GM1 Expression of Non-Hodgkin's Lymphoma Determines Susceptibility to Rituximab Treatment

Abstract

Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to lipid microdomains. We now show that the extent of CD20 recruitment to lipid rafts correlates with response to rituximab. In addition, expression of the raft-associated sphingolipid GM1 on lymphoma cells is associated with the susceptibility of lymphoma cells to rituximab. Furthermore, we show substantially different GM1 expression in various primary non-Hodgkin's lymphomas. Whereas chronic lymphocytic leukemia (CLL) cells have a low GM1 expression, marginal zone lymphoma cells exhibit much higher levels. Differences were not only detected among various lymphoma subgroups but also within one lymphoma subtype. Interestingly, whereas CLL cells from patients with high GM1 expression responded to rituximab, patients with low GM1 expressing CLL cells did not. These data show the importance of membrane microdomains in the effect of rituximab and may offer a predictive factor for the responsiveness of lymphoma cells to rituximab. [Cancer Res 2008;68(13):5414-22]

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

“…The binding of ofatumumab to a CD20 epitope close to the cell surface 3,[6][7][8] and the segregation of anti-CD20 monoclonal antibodies into lipid rafts may be among the factors that make ofatumumab less dependent than rituximab on CD20 expression. 42,43 In its present form, the application of SCR to improve ofatumumab is not feasible. The SCR do not only compete with fH, present at high concentrations in human serum, but also with fH-related proteins (CFHL-1 and CFHR1-5), all of which contain heparin-binding motifs.…”

Understanding and circumventing resistance to anticancer monoclonal antibodies

“…Meyer zum Buschenfelde et al have recently reported that the content in GM1, a raft-associated sphingolipid, in patient samples was correlated with sensitivity to rituximab. 33 Samples from patients with MZL, a subtype sensitive to rituximab, were found to have high GM1 content, while CLL samples had a lower GM1 content. 33 Deficient redistribution into rafts or alterations in the composition of rafts are thus likely mechanisms of resistance to rituximab, although this remains to be studied in greater detail.…”

“…33 Samples from patients with MZL, a subtype sensitive to rituximab, were found to have high GM1 content, while CLL samples had a lower GM1 content. 33 Deficient redistribution into rafts or alterations in the composition of rafts are thus likely mechanisms of resistance to rituximab, although this remains to be studied in greater detail. The fact that type II antibodies do not appear to require redistribution to rafts suggest that they may be active in models of resistance to rituximab.…”

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

“…However, it seems that the membrane lipid organization itself plays a role. Thus, the amount of GM1, a ganglioside and important sphingolipid constituent of lipid rafts, correlates with the susceptibility of NHL and CLL to rituximab in vitro, irrespective of the level of CD20 expression (32). GM1 may therefore represent a predictive factor for the response of lymphoma cells to rituximab (32).…”

“…Thus, the amount of GM1, a ganglioside and important sphingolipid constituent of lipid rafts, correlates with the susceptibility of NHL and CLL to rituximab in vitro, irrespective of the level of CD20 expression (32). GM1 may therefore represent a predictive factor for the response of lymphoma cells to rituximab (32). With the widespread use of cholesterol-lowering statins, which can interfere with the formation of cholesterol-rich lipid rafts (33), inhibit expression of GM1 (34), and induce conformational changes in CD20 in vitro (35), there has been some concern that patients who have been treated with statins may have an impaired response to rituximab (36).…”