Unique toxicities and resistance mechanisms associated with monoclonal antibody therapy.
Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.
Friedberg
Jonathan W
JW
James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA. jonathan_friedberg@urmc.rochester.edu
D000911:Antibodies, Monoclonal / Q000627:therapeutic use* / Q000633:toxicity; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D017209:Apoptosis; D015922:Complement C1q / Q000187:drug effects / Q000502:physiology; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D000069283:Rituximab; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab; D015922:Complement C1q