Devine SM, Vij R, Rettig M, et al. Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Blood (Impact Factor: 10.45). 05/2008; 112(4):990-8. DOI: 10.1182/blood-2007-12-130179
Source: PubMed

ABSTRACT Allografts from HLA-matched sibling donors were mobilized and collected without granulocyte colony-stimulating factor (G-CSF) using AMD3100, a direct antagonist of CXCR4/stromal-derived factor 1 (SDF-1/CXCL12). Donors (N = 25) were treated with AMD3100 at a dose of 240 mug/kg by subcutaneous injection, and leukapheresis was then initiated just 4 hours later. Two-thirds of the donors collected an allograft with a CD34(+) cell dose sufficient for transplantation after just one dose of AMD3100. No donor experienced more than grade 1 toxicity. After a myeloablative regimen, 20 patients with hematologic malignancies received allografts collected after AMD3100 alone. All patients engrafted neutrophils (median day 10) and platelets (median day 12) promptly. Acute graft-versus-host disease (GVHD) grades 2 through 4 occurred in 35% of patients. One patient died due to complications related to acute GVHD. No unexpected adverse events were observed in any of the recipients. All 14 patients surviving in remission have robust trilineage hematopoiesis and are transfusion-free with a median follow-up of 277 days (range, 139-964 days). Direct antagonism of CXCR4 by AMD3100 may provide a more rapid and possibly less toxic and cumbersome alternative to traditional G-CSF-based mobilization in normal donors. This trial was registered as no. NCT00241358 at

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Available from: Kiley Mcglauchlen, Sep 27, 2015
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    • "Please cite this article in press as: Zirafi et al., Discovery and Characterization of an Endogenous CXCR4 Antagonist, Cell Reports (2015), http:// far, however, only a single antagonist (plerixafor, AMD3100) has been approved for stem cell mobilization in patients who do not respond to chemotherapy or granulocyte colony-stimulating factor (G-CSF) (Devine et al., 2008). "
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    ABSTRACT: CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.061 · 8.36 Impact Factor
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    • "Recently, a pilot trial was performed with 20 patients with hematologic malignancies who received allografts collected after Plerixafor alone. In that report, 35% of the patients experienced grade 2 through 4 aGVHD, but the rates of acute and chronic GVHD observed were not significantly different from those of historical control patients receiving G-CSF-mobilized grafts at the same institution [14]. On the basis of this background, we characterized the graft content of T cells and DC after administration of plerixafor and G-CSF in murine models, with a special focus on the impact on acute GVHD. "
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    ABSTRACT: This study aimed to characterize the immune effectors contained in the grafts from donor mice mobilized by granulocyte colony-stimulating factor (G-CSF) and plerixafor and to evaluate their impact on the development of acute graft-versus-host-disease (aGVHD). Mobilization was done with G-CSF alone or G-CSF plus plerixafor (G+P). In grafts collected after G+P mobilization, we observed a significantly higher proportion of c-kit(+)Sca-1(+) hematopoietic stem cells compared with G-CSF. A significant increase in the percentage of plasmacytoid dendritic cells was detected in the G+P graft compared with G-CSF graft. We also studied the ability of stem cell grafts mobilized with G+P to induce GVHD in a mouse model. We observed higher mortality (P < 0.001) associated with increased aGVHD clinical score (P < 0.0001) as well as higher pathology score in the intestine of mice receiving G+P as compared with G-CSF grafts (P < 0.001). Moreover, the exacerbated aGVHD severity was associated with upregulation of CCR6 expression on both CD4(+) and CD8(+) T cells from the G+P grafts, as well as on T cells from mice transplanted with G+P grafts. In conclusion, we showed that grafts mobilized with G+P exhibited functional features different from those mobilized with G-CSF alone, which increase the severity of aGVHD in the recipients. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
    Cytotherapy 03/2015; 17(7). DOI:10.1016/j.jcyt.2015.02.009 · 3.29 Impact Factor
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    • "Plerixafor is a novel mobilizing agent and a reversible inhibitor of CXCR4–SDF-1 interaction resulting in rapid mobilization within hours after administration (Liles et al., 2003; Devine et al., 2004; Broxmeyer et al., 2005). When used as a single agent, plerixafor has been reported to result in modest or even inferior yields as compared with G-CSF (Liles et al., 2003; Broxmeyer et al., 2005; Devine et al., 2008); however, it exhibits marked synergism in combination with G-CSF, increasing CD34 + cell yields by several fold (Liles et al., 2005; DiPersio et al., 2009; Nademanee et al., 2012). Adult patients with severe thalassemia respond to G-CSF mobilization differently from the normal individuals for various reasons. "
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    ABSTRACT: Successful stem cellgene therapy requires high numbers of genetically-engineered hematopoietic stem cells collected using optimal mobilization strategies. Here we focus on stem cell mobilization strategies for thalassemia and present the results of a plerixafor-based mobilization trial with emphasis on the remobilization with G-CSF+plerixafor in those patients who have previously failed mobilization. Plerixafor rapidly mobilized CD34+cells without inducing hyperleukocytosis, however, 35% of patients failed to reach the target cell dose of ≥6X106CD34+cells/kg. Four subjects who failed either on plerixafor or G-CSF were remobilized with G-CSF+plerixafor. The combination proved highly synergistic; the target cell dose was readily reached and the per apheresis yield was significantly increased over initial mobilization, ultimately resulting in single-apheresis collections, despite a more than50% reduction of the dose of G-CSF in splenectomized patients to avoid hyperleukocytosis. The total stem and progenitor cells mobilized in G-CSF+plerixafor patients were higher than in patients treated by plerixafor-alone. Importantly, the G-CSF+plerixafor-mobilized cells displayed a primitive stem cell phenotype and higher clonogenic capacity over plerixafor-mobilized cells. G-CSF+plerixafor represents the optimal strategy when very high yields of stem cells or a single apheresis is required. The high yields and the favorable transplantation features, render the G-CSF+plerixafor-mobilized cells the optimal CD34+cell source for stem cell gene therapy applications.
    Human gene therapy 09/2013; 24(10). DOI:10.1089/hum.2013.163 · 3.76 Impact Factor
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