Treatment with the CXCR4 Antagonist AMD3100 Enhances Antibody Mediated Killing in Disseminated Lymphoma Models.

Abstract

2717 Poster Board II-693 Interactions between chemokines and their receptors play an important role in cancer biology and have been shown to influence several processes such as tumor growth and the development of metastatic lesions. Stromal cell derived factor-1 (SDF-1) is a chemokine that binds to the CXCR4 chemokine receptor and stimulates B cell growth. CXCR4 is frequently over-expressed on tumor cells and the SDF-1/CXCR4 axis has been reported to play a role in promoting survival, angiogenesis and metastasis. The role of the stroma, in particular SDF-1/CXCR4 interactions, in providing a “survival niche” for tumor cells is well described for both hematological and solid tumors. We hypothesized that disruption of the protective microenvironment of tumor cells through antagonism of the SDF-1/CXCR4 axis may enhance the sensitivity of the tumor cells to treatment with anti-cancer agents such as monoclonal antibodies. Mozobil (AMD3100) or its structurally related analog, AMD3465, were used in combination with either Campath (anti-CD52) or Rituxan (anti-CD20) in lymphoma xenograft models to determine whether enhanced tumor protection could be observed. Flow cytometry analysis of lymphoma cell lines confirmed the cell surface expression of high levels of CXCR4 as well as the CD20 and CD52 target antigens. Lymphoma cells were seeded by intravenous injection and tumor-bearing mice were treated with multiple injections of the CXCR4 antagonists AMD3465 or AMD3100 alone or in combination with monoclonal antibodies. 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 (p<0.01). Similarly, combination of AMD3100 and Rituxan also resulted in a significantly prolonged survival compared to either agent alone (p=0.0340). In vivo imaging using a Raji-luciferase cell line also confirmed the impact of treatment on tumor burden. 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 in the clinic. Disclosures: Siders: Genzyme Corporation: Employment. Hu:Genzyme: Employment. Gale:Genzyme: Employment. Jacques:Genzyme: Employment. Fogle:Genzyme: Employment. Shields:Genzyme: Employment. Garron:Genzyme: Employment. Kaplan:Genzyme: Employment.

Polyfunctionality of the CXCR4/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune‐mediated diseases

“…However, continuous administration of AMD3100 early in immunocompetent models did not improve survival and in some instances exacerbated disease (M Poznansky personal communication), likely due to the ongoing mobilization of immune cells and pre‐cursors. In a mouse model of lymphoma, co‐administration of AMD3100 with Rituxan, an anti‐B‐cell antibody targeting CD20, resulted in prolonged survival compared with either agent alone, suggesting a role for AMD3100 alongside immunotherapy to modulate the local tumor immune milieu 202 …”

“…In a mouse model of lymphoma, co-administration of AMD3100 with Rituxan, an anti-B-cell antibody targeting CD20, resulted in prolonged survival compared with either agent alone, suggesting a role for AMD3100 alongside immunotherapy to modulate the local tumor immune milieu. 202 More recently, strategies where AMD3100 is applied at a reduced dose in a pulsatile manner and combined with either taxol, αPD-1, or a mesothelin-targeted immune-activating single-chain variable fragment fusion protein has improved tumor suppression and overall survival in pre-clinical models of ovarian cancer or mesothelioma. [203][204][205] Interestingly, AMD3100 treatment appears to promote accumulation of activated CD8 cells within the tumor and promote Tregs to adopt a more T-helper-like phenotype.…”

Novel Therapies for Aggressive B-Cell Lymphoma

“…Stromal-cell-derived-factor-1 (SDF-1) is a chemokine that binds to the CXCR4 chemokine receptor and stimulates B-cell growth [ 229 ]. CXCR4 is frequently overexpressed on tumor cells, and the SDF-1/CXCR4 axis is thought to play a role in promoting survival, angiogenesis, and metastasis.…”