In vivo Model of Follicular Lymphoma Resistant to Rituximab

Purpose: Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Rituximab is widely used alone or in combination therapy for the treatment of FL. Despite its well-established clinical efficacy, a subpopulation of patients does not respond to rituximab and most patients will relapse after therapy. The mechanisms of action and resistance to rituximab are not fully understood. Experimental Design: To study these mechanisms we developed an in vivo model of FL resistant to rituximab. This model was developed using the human RL line, isolated from a patient with FL, grown as xenotransplants in severe combined immunodeficient mice, exposed weekly to rituximab in vivo, followed by serial reimplantation and reexposure to rituximab, until a resistant phenotype was obtained. Results: RL-derived tumors unexposed to rituximab were grown as controls and compared with the resistant tumors. Although the expression of CD46 and CD55 antigens were not differently expressed in the resistant cells, the complement inhibitor CD59 was overexpressed in a subpopulation and CD20 was found to be expressed at a lower level in a minority of cells. BCl-X-L and YY1 were also found more highly expressed in rituximab-resistant cells. Conclusion: This model provides insight on potential in vivo resistance mechanisms to rituximab and could help contribute to the development of novel therapies in rituximab-refractory diseases.