Cancer Therapy: Preclinical Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140

Purpose:Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal andmalignant B lymphocytes.Here,we investigated the effect of high-affinityCXCR4antagonist BKT140on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo. Experimental Design: In vitro efficacy of BKT140 alone or in combination with rituximab was determined in non-Hodgkin lymphoma (NHL) cell lines and primary samples from bonemarrow aspirates of patients with NHL. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with bone marrow involvement. Results: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20þ lymphoma cell growth and in the induction of cell death, respectively. Combination of BKT140with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells, suggesting the possible interaction between CD20 and CXCR4 pathways in NHL. Primary bone marrow stromal cells (BMSC) further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, whereas BKT140 abrogated this protective effect. Furthermore, BKT140 showed efficient antilymphoma activity in vivo in the xenograft model of disseminated NHL with bone marrow involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the bone marrow. Combined treatment of BKT140with rituximab further decreased the number of viable lymphoma cells in the bone marrow, achieving 93% reduction. Conclusions: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL. Clin Cancer Res; 19(13); 3495–507. 2013 AACR.