Strategies to enhance rituximab anti-tumor activity in the treatment of CD20-positive B-cell neoplasms

Rituximab is a chimeric monoclonal anti-CD20 antibody and was the first monoclonal antibody (mAb) therapy approved by FDA (Food and Drug Administration) for the treatment of B-cell lymphoma. It has revolutionized the treatment of patients with CD20-positive non-Hodgkin’s lymphoma and CLL. Rituximab is currently being used in virtually all patients with B-cell lymphomas either alone or in combination with chemotherapy. Despite its excellent safety and efficacy profile, only a small portion of B-cell lymphoma patients treated with rituximab as a single agent have sustained complete remissions. Combining rituximab with standard chemotherapy regimens is associated with higher response rates, and improved survival in a subset of patients. Unfortunately, a significant percentage of patients who initially respond to rituximab eventually relapse, and there are patients that demonstrate intrinsic resistance to initial therapy. In the last decade, ongoing scientific research has led to a better understanding of rituximab-associated cytotoxic mechanisms against lymphoma target cells. Scientific efforts are increasingly being focused in developing new strategies to improve mAb activity. Various strategies include the following: combining rituximab with different biologic agents (e.g. cytokines, immunomodulatory drugs); developing novel antibody constructs (including bi-specific antibodies); and/or inhibiting signaling pathways associated with lymphomagenesis and immuno-chemotherapy resistance. In this review article, we will provide an overview of various rituximab-associated cytotoxic mechanisms and novel strategies to improve mAb activity against B-cell lymphoma.