Postulated mechanisms of resistance of B-cell non-Hodgkin lymphoma to rituximab treatment regimens: strategies to overcome resistance

Abstract

Antibody-mediated immunotherapy has gained significant momentum since 1997 when the US Food and Drug Administration approved the first monoclonal antibody (mAb) for the treatment of B-cell non-Hodgkin lymphoma (B-NHL), namely, rituximab (chimeric anti-CD20 mAb). Subsequently, more than 20 approved mAbs have been in use clinically for the treatment of various cancers and several non-cancer-related diseases. Further, the combination treatment of mAbs with chemotherapy, immunotherapy, proteaosome inhibitors, and other inhibitors has resulted in synergistic anti-tumor activity with significant objective clinical responses. Despite their successful clinical use, the underlying mechanisms of rituximab's in vivo activities remain elusive. Further, it is not clear why a subset of patients is initially unresponsive and many responding patients become refractory and resistant to further treatments; hence, the underlying mechanisms of resistance are not known, Attempts have been made to develop model systems to investigate resistance to mAb therapy with the hope to apply the findings in both the generation of new therapeutics and in their use as new prognostic biomarkers. This review focuses on the development of resistance to rituximab treatments and discusses possible underlying mechanisms of action, postulated mechanisms of resistance in model systems, and suggested means to overcome resistance. Several prior reviews on the subject of rituximab resistance have been published and the present review both complements as well as adds new topics of relevance.

Figure 1

Schematic diagram of the molecular mechanisms that regulate resistance to rituximab and approaches to overcome resistance. Briefly, the unresponsive B-NHL cells exhibit hyperactivated survival/anti-apoptotic pathways which regulate downstream anti-apoptotic gene products that result in the development of resistance to both rituximab, chemotherapy and combination. The intervention to inhibit the survival pathways may be achieved by targeted chemical inhibitors, proteasome inhibitors, selective chemical inhibitors for the anti-apoptotic gene products, as well as HDAC inhibitors and microRNAs. In addition, the potential application for the development of a new generation of CD20 mABs, alone or conjugated with various agents to enhance their activities.