Cxcr4 Antagonist As A Sensitizing Agent For Anti-Tumor Therapies In Disseminated Lymphoma Models

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO CXCR4 is a chemokine receptor frequently over-expressed on hematological cancers and solid tumors. CXCR4 plays an important role in cancer metastasis, regulation of stem cell trafficking and neovascularization. The human B-lymphoma cell lines Raji and B-104 express high levels of human CXCR4 as well as CD52 and CD20, the targets of the monoclonal antibodies Campath and Rituxan, respectively. We hypothesized that the small molecule CXCR4 antagonists AMD3465 and AMD3100 could compromise tumor cell growth by inhibiting the survival signals delivered through the interaction of CXCR4 and SDF-1 in the tumor stroma and increase the susceptibility of the tumor cells to the cytotoxic effects of monoclonal antibody therapy. Lymphoma cells were seeded by intravenous injection and tumor-bearing mice were treated with multiple injections of AMD3465 or AMD3100. Interestingly, treatment with AMD3465 as a single agent was sufficient to increase survival of the animals compared to untreated controls. In addition, the combination of AMD3465 and Campath showed a synergistic effect with a prolongation of survival greater than that obtained with either agent alone. Similarly, combination of the CXCR4 antagonist AMD3100 and Rituxan also resulted in a significantly prolonged survival compared to either agent alone. The impact of treatment on tumor burden was confirmed by Xenogen imaging. These results suggest that there is a potential role for CXCR4 antagonists in combination with a B-cell targeted therapy in the treatment of B-cell malignancies. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-160.