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  • 1
    Online Resource
    Online Resource
    Infusion of Umbilical Cord Blood-Derived Natural Killer Cells in Immune-Deficient Mice for the Treatment of Resistant Acute Myeloid Leukaemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 5727-5727
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5727-5727
    Abstract: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against acute myeloid leukaemia (AML). Success of this NK cell immunotherapy is dependent on obtaining high numbers of functional NK cells that have the potential to survive in vivo. The use of umbilical cord blood (UCB) CD34+ cells as a source of allogenic NK cells is an interesting method that can generate a readily available, non-invasive, off the shelf cellular product. We developed a cytokine-based culture method for the generation of NK cell products derived from CD34+hematopoietic progenitor cells (HPC) isolated from fresh UCB units. Immuno-phenotyping of ex vivo expanded NK cells showed typical inhibitory and activating NK receptors except for CD16 and the KIR receptors. UCB-derived NK cells displayed good cytolytic activity against NK-sensitive K562 cells with a percentage of specific lysis varying from 30 to 50%. Cytolysis was directly correlated to CD94 expression since CD94-sorted NK cells were responsible for all the in vitro cytolytic function of differentiated NKs against K562 cells. There was an inconstant susceptibility of patient-derived primary AML cells to UCB-derived NK lysis in vitro with a specific lysis ranging from 0 to 25%. We further characterized UCB-derived NK cells by investigating their toxicity, biodistribution, and anti-leukemic potential in vivo. As adoptive transfer of NK cells is an attractive approach for treating refractory leukemia, immune deficient mice were engrafted with a patient derived AML strain resistant to NK-mediated lysis and doxorubicin. After successful engraftment and randomization, leukemic mice were injected with either UCB- derived NK cells or NK cells from healthy donors (NKhds) or doxorubicin, with one control group that didn't receive any treatment. Mice were sacrificed after 2 weeks of treatment and leukemia load along with NK distribution were evaluated by flow cytometry in the blood, bone marrow (BM) and spleen. There was no evidence of toxicity of UCB-derived or healthy donors NK cells in mice. Both types of cells were preferentially found in the blood and in the spleen, even though NKhds reached much higher levels than UCB-derived NKs. As for treatment efficacy, none of our treatment showed anti-leukemic potential based on the absence of decrease of leukemic cells in BM, blood, and spleen. In vivo microenvironment didn't overcome resistance of the patient derived AML cell to NK lysis or to doxorubicin. Remarkably, all of the UCB derived NK cells founded in vivo expressed the CD94 whereas not more than 20% of the injected cells were positive for this marker. Whether it was by in vivo selection or by in vivo differentiation must be investigated. Interestingly, a small cell population with CD56 and CD34 double staining was distinguished in UCB-derived NK and NK healthy donor treated leukemic mice suggesting in vivo interaction between leukemic and NK cells. Further characterization of this population may help to understand the molecular mechanism of leukemic recognition by NK cells and resistance of leukemic cells to cytolysis. In conclusion, UCB-derived NK generation is feasible. Investigation of the role of CD94 in these cells is needed, as cell sorting by CD94 selection in addition to the CD56 could be an interesting approach in the future to select highly functional expanded NK cells before therapeutic use. Furthermore, infusion of UCB-derived NK cells into immune-deficient mice is achievable and non-toxic. However, in vivo environment didn't overcome primary in vitro resistance of AML cells despite an established interaction. Additional elucidation of AML resistance mechanisms to NK lysis is mandatory before therapeutic application. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.5727.5727
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    The Thrombocytopenia of Wiskott Aldrich Syndrome Is Not Related to a Defect in Proplatelet Formation
    American Society of Hematology ; 1999
    In:  Blood Vol. 94, No. 2 ( 1999-07-15), p. 509-518
    Details
    In: Blood, American Society of Hematology, Vol. 94, No. 2 ( 1999-07-15), p. 509-518
    Abstract: The Wiskott-Aldrich syndrome (WAS) is an X-linked hereditary disease characterized by thrombocytopenia with small platelet size, eczema, and increased susceptibility to infections. The gene responsible for WAS was recently cloned. Although the precise function of WAS protein (WASP) is unknown, it appears to play a critical role in the regulation of cytoskeletal organization. The platelet defect, resulting in thombocytopenia and small platelet size, is a consistent finding in patients with mutations in the WASP gene. However, its exact mechanism is unknown. Regarding WASP function in cytoskeletal organization, we investigated whether these platelet abnormalities could be due to a defect in proplatelet formation or in megakaryocyte (MK) migration. CD34+ cells were isolated from blood and/or marrow of 14 WAS patients and five patients with hereditary X-linked thrombocytopenia (XLT) and cultured in serum-free liquid medium containing recombinant human Mpl-L (PEG-rHuMGDF) and stem-cell factor (SCF) to study in vitro megakaryocytopoiesis. In all cases, under an inverted microscope, normal MK differentiation and proplatelet formation were observed. At the ultrastructural level, there was also no abnormality in MK maturation, and normal filamentous MK were present. Moreover, the in vitro produced platelets had a normal size, while peripheral blood platelets of the same patients exhibited an abnormally small size. However, despite this normal platelet production, we observed that F-actin distribution was abnormal in MKs from WAS patients. Indeed, F-actin was regularly and linearly distributed under the cytoplasmic membrane in normal MKs, but it was found concentrated in the center of the WAS MKs. After adhesion, normal MKs extended very long filopodia in which WASP could be detected. In contrast, MKs from WAS patients showed shorter and less numerous filopodia. However, despite this abnormal filopodia formation, MKs from WAS patients normally migrated in response to stroma-derived factor-1 (SDF-1), and actin normally polymerized after SDF-1 or thrombin stimulation. These results suggest that the platelet defect in WAS patients is not due to abnormal platelet production, but instead to cytoskeletal changes occuring in platelets during circulation.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V94.2.509.414k09_509_518
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1999
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    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    CXCR4 Blockade as a New Targeted Therapy for Acute Myeloide Leukemia Characterised by High Cell Surface Density of CXCR4.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4570-4570
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4570-4570
    Abstract: Abstract 4570 Stromal cell-derived factor 1 (SDF-1)/CXCR4 axis plays key roles in hematopoiesis regulating the interactions between hematopoietic cells and their stromal microenvironment within the bone marrow, their trafficking from the bone marrow to blood, their proliferation and survival. SDF-1/CXCR4 interactions also participate in the development of leukemic blasts in acute myeloid leukaemia (AML) influencing their trafficking, survival and differentiation. We used the xenotransplantation model of nonobese diabetes/severe combined immunodeficiency γcnull (NOG) mice reconstituted with human primary cells from AML patients and 2 small molecule competitive antagonists of CXCR4, AMD3100 and TN140 to better define the role of CXCR4/SDF-1 on the leukemic blast burden within the bone marrow and in extramedullary sites. In a first set of experiments, we investigated whether there was a correlation between CXCR4 expression or function on leukemic blasts and their ability to engraft the bone marrow of NOG mice in 34 patients. Using flow cytometric analyses, we observed that CXCR4 membrane expression was highly variable between patients. This expression did not correlate with engraftment. In addition, SDF-1 responsiveness evaluated by transwell migration only marginally correlated with engraftment. However, in these initial analyses, we observed that the differences between engrafters and nonengrafters were significant if the cut-point migration is set to 20%. Patients with higher chemotactic response to SDF-1 had a significantly increased NOG repopulating ability. In further studies, NOG mice reconstituted with AML cells from 5 different patients were treated with optimal concentration of either AMD3100 or TN140 for 1 week. We observed that CXCR4 inhibition by TN140 (used as a single therapy) had profound inhibitory effects on the proliferation and the development of extramedullary dissemination of the disease in this xenotransplantation. This patient had FAB M1 leukemia and initially exhibits high CXCR4 level on blast. Our study demonstrated that CXCR4 inhibition in selected patients might be a potent therapy against leukemic development. Disclosures: Bouamar: Association pour la Recherche sur le Cancer: Employment; Cancéropôle IDF: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4570.4570
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
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    Online Resource
    CXCR4 Inhibitors Selectively Eliminate CXCR4 Expressing Human Acute Myeloid Leukemia Cells in NOG Mouse Model
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1881-1881
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1881-1881
    Abstract: Abstract 1881 The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates to pathogenesis is unclear. Here we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4high (25/47; 53%) from CXCR4neg/low (22/47, 47%) AML patients. Leukemic engraftment in NOD/Shi-scid/IL-2Rnull (NOG) mice was observed for both the CXCR4high and CXCR4neg/low groups. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOG leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to CXCL12. Mechanisms of this anti-leukemic effect included interference with the retention of LICs with their supportive bone marrow microenvironment niches, as indicated by a mobilization of LICs in response to drugs, and increased apoptosis of leukemic cells in vitro and in vivo. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1881.1881
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    Online Resource
    Reduced retention of radioprotective hematopoietic cells within the bone marrow microenvironment in CXCR4–/– chimeric mice
    American Society of Hematology ; 2006
    In:  Blood Vol. 107, No. 6 ( 2006-03-15), p. 2243-2251
    Details
    In: Blood, American Society of Hematology, Vol. 107, No. 6 ( 2006-03-15), p. 2243-2251
    Abstract: The physiologic role of CXCR4 on hematopoietic stem/progenitor cells (HSPCs) is not fully understood. Here, we show that radioprotection of lethally irradiated mice by embryonic day 14.5 (E14.5) CXCR4–/– fetal liver (FL) cells was markedly impaired when compared with CXCR4+/+ counterparts, but this defect was rescued when hosts were engrafted with high cell numbers. This quantitative defect contrasted with a similar content in hematopoietic colony-forming cells (CFCs), splenic colony-forming units (CFUs-S), and Lin– Sca-1+ c-kit+ cells in E14.5 CXCR4–/– and CXCR4+/+ livers. In addition, the homing of HSPCs in the bone marrow was not altered as detected with a CFSE-staining assay. In contrast, a 30-fold increase in CFCs was seen in the circulation of mice stably reconstituted with CXCR4–/– FL cells and this increment was already observed before hematopoiesis had reached a steady-state level. Together, the data strongly suggest that impaired retention may, at least in short-term hematopoietic reconstitution, lead to a diminution in the number of available progenitors required for radioprotection.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2005-02-0581
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Online Resource
    Targeting Acute Myeloid Leukemia with a New CXCR4 Antagonist IgG1 Antibody (PF-06747143)in NOD/SCID Mice
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1362-1362
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1362-1362
    Abstract: Chemoresistance represents a considerable barrier to improving outcomes for patients with acute myeloid leukemia (AML) and therapeutic approaches using multiple lines of therapy have been unsuccessful as cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. This vulnerable patient group needs individualizing therapy through careful selection of appropriate agents based on specific signaling pathways. The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow microenvironment, is highly expressed in 25-30% of patients with AML and its expression is correlated with poor prognosis and drug resistance. The purpose of this study was to investigate a new humanized monoclonal IgG1 antibody to CXCR4 (PF-06747143) and its effects as a monotherapy in AML primary patient samples and in chemotherapy resistant patient-derived xenotransplantation (PDX) models. This antibody was previously shown to be able to induce cell death through its effector function (CDC and ADCC) and to be efficacious in cell-based xenograft models of AML, NHL, CLL and MM. Here we have shown that PF-06747143 binds strongly and specifically to AML cell lines and to AML primary cells, by flow cytometry. Of 16 samples evaluated, 7 displayed low CXCR4 expression (CXCR4neg/low) whereas 9 displayed high expression (CXCR4high). A good correlation was observed between 12G5, a commercially available CXCR4 Ab, and PF-06747143 staining, indicating that PF-06747143 can be used to stratify AML patients. Chemotaxis in response to CXCL12 was significantly inhibited in all AML patient primary samples analyzed. Administration of PF-06747143 to mice engrafted with AML patient cells (PDX models) induced rapid malignant cell mobilization into the peripheral blood at 4 hrs after a single antibody dose, with mobilized cell levels going back down to baseline at 24 hrs post-dose. This is in line with the ability of the antibody to block malignant cell homing to the bone marrow, inducing cell mobilization, as well as induction of cell death through effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different models: 1) P15 model characterized by high CXCR4 expression, inducing aggressive disease, with rapid progression of leukemia and widespread dissemination and chemoresistance; 2) P17 model characterized by a low CXCR4 expression, a less aggressive disease and limited dissemination. Weekly administration of PF-06747143 to leukemic mice previously engrafted with P17 or P15 malignant cells induced a sharp reduction of leukemia cells in the bone marrow, spleen and blood leading to increased survival of leukemic mice in both models. Activity of the antibody as monotherapy was superior to daunorubicin in the P15 chemoresistant model. Secondary transplantation of bone marrow cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143 treatment, with slower tumor growth in mice transplanted with PF-06747143-treated cells. In summary, PF-06747143, a CXCR4 IgG1 antibody, is significantly efficacious as a monotherapy and superior to daunorubicin in AML chemoresistant PDX models. These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1362.1362
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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    detail.hit.zdb_id: 80069-7
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  • 7
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    Expression of CD94 by ex vivo -differentiated NK cells correlates with the in vitro and in vivo acquisition of cytotoxic features
    Informa UK Limited ; 2017
    In:  OncoImmunology Vol. 6, No. 10 ( 2017-10-03), p. e1346763-
    Details
    In: OncoImmunology, Informa UK Limited, Vol. 6, No. 10 ( 2017-10-03), p. e1346763-
    Type of Medium: Online Resource
    ISSN: 2162-402X
    URL: Article
    DOI: 10.1080/2162402X.2017.1346763
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2017
    detail.hit.zdb_id: 2645309-5
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  • 8
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    The Chemokine Receptor CXCR4 Strongly Promotes Neuroblastoma Primary Tumour and Metastatic Growth, but not Invasion
    Public Library of Science (PLoS) ; 2007
    In:  PLoS ONE Vol. 2, No. 10 ( 2007-10-10), p. e1016-
    Details
    In: PLoS ONE, Public Library of Science (PLoS), Vol. 2, No. 10 ( 2007-10-10), p. e1016-
    Type of Medium: Online Resource
    ISSN: 1932-6203
    URL: Article
    URL: Article
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    URL: Article
    DOI: 10.1371/journal.pone.0001016
    DOI: 10.1371/journal.pone.0001016.g001
    DOI: 10.1371/journal.pone.0001016.g002
    DOI: 10.1371/journal.pone.0001016.g003
    DOI: 10.1371/journal.pone.0001016.g004
    DOI: 10.1371/journal.pone.0001016.g005
    DOI: 10.1371/journal.pone.0001016.g006
    DOI: 10.1371/journal.pone.0001016.s001
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2007
    detail.hit.zdb_id: 2267670-3
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  • 9
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    Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines
    American Society of Hematology ; 2017
    In:  Blood Advances Vol. 1, No. 14 ( 2017-06-13), p. 972-979
    Details
    In: Blood Advances, American Society of Hematology, Vol. 1, No. 14 ( 2017-06-13), p. 972-979
    Abstract: Transgenic mice expressing 3 human cytokines enable expansion of CMML cells with limited stem cell engraftment. The mutational profile of CMML cells that expand in mice mirrors that of patient monocytes.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2017004903
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    detail.hit.zdb_id: 2876449-3
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  • 10
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    In vitro and in vivo efficacy of an anti-CD203c conjugated antibody (AGS-16C3F) in mouse models of advanced systemic mastocytosis
    American Society of Hematology ; 2019
    In:  Blood Advances Vol. 3, No. 4 ( 2019-02-26), p. 633-643
    Details
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 4 ( 2019-02-26), p. 633-643
    Abstract: Antibody-drug conjugates (ADCs) are a new class of therapeutics that use antibodies to deliver potent cytotoxic drugs selectively to cancer cells. CD203c, an ecto-nucleotide pyrophosphatase-phosphodiesterase 3, is overexpressed on neoplastic mast cells (MCs) in systemic mastocytosis (SM), thus representing a promising target for antibody-mediated therapy. In this study, we have found that human neoplastic MC lines (ROSAKIT D816V and ROSAKIT D816V-Gluc), which express high levels of CD203c, are highly and specifically sensitive to the antiproliferative effects of an ADC against CD203c (AGS-16C3F). In these cell lines, AGS-16C3F induced cell apoptosis at very low concentrations. To characterize the effects of AGS-16C3F on leukemia progression in vivo, ROSAKIT D816V-Gluc NOD-SCID γ mouse models of advanced SM (AdvSM) were treated with AGS-16C3F or an ADC control for 2 weeks. Whereas AGS-16C3F had no apparent toxicity in xenotransplanted mice, in vivo neoplastic MC burden significantly decreased in both hematopoietic and nonhematopoietic organs. Furthermore, animals treated with AGS-16C3F had prolonged survival compared with the animals treated with control ADC, and AGS-16C3F efficiently prevented disease relapse. In conclusion, these preclinical studies identified CD203c as a novel therapeutic target on neoplastic MCs, and AGS-16C3F as a promising ADC for the treatment of patients with AdvSM.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2018026179
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 2876449-3
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