Journal
ONCOLOGIST
Volume 13, Issue 9, Pages 954-966Publisher
WILEY
DOI: 10.1634/theoncologist.2008-0089
Keywords
Rituximab; CD20; Mechanism; Resistance; Complement; B-cell non-Hodgkin's lymphoma
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Funding
- U.S. National Institutes of Health [RO1 AI061174]
- Harvard Technology Development Accelerator Fund
- American Heart Association [0435483N]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI061174] Funding Source: NIH RePORTER
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Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U. S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why similar to 50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding beta-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed. The Oncologist 2008; 13: 954-966
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