119 results on '"Bonig, Halvard"'
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2. Vertriebsweg von kommerziellen CAR-T-Zell-Präparaten: Apothekenpflicht oder Direktvertrieb?
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Bakhschai, Bita and Bonig, Halvard
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- 2024
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3. Cell-Based Therapy by Autologous Bone Marrow-Derived Mononuclear Cells for Bone Augmentation of Plate-Stabilized Proximal Humeral Fractures: A Multicentric, Randomized, Open Phase IIa study
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Seebach, Caroline, Nau, Christoph, Henrich, Dirk, Verboket, Rene, Bellen, Marlene, Frischknecht, Nadine, Moeck, Vivien, Eichler, Kathrin, Horlohé, Kay Hajo Schmidt, Hoffmann, Reinhard, Bonig, Halvard, Seifried, Erhard, Frank, Johannes, and Marzi, Ingo
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Proximal humerus fractures are common in an aging population. The standard operative treatment is open reduction internal fixation (ORIF) using an angular stable plate. However, this procedure has complications such as a relatively high rate of secondary dislocation, humeral head necrosis or nonunion caused by delayed bony consolidation. Autologous bone marrow mononuclear cells (BMC) combined with a β-TCP scaffold could support bone healing and is considered clinically safe.This multicentric, randomized, open phase IIa clinical trial (Clinical Trials. Gov Identifier: NCT02803177, Eudra CT No: 2015-001820-51) evaluated whether autologous BMC with β-TCP in addition to ORIF reduces the incidence of secondary dislocations in patients with proximal humerus fracture. Ninty-four patients equally divided between verum group (BMC+β-TCP) and control group (ß-TCP only) were targeted and calculated. At the time of planned interim evaluation, ie, enrolment of 56 patients, no statistical difference in secondary dislocations or complications was demonstrated in either group after an observation period of 12 weeks. Radiographic bone healing and DASH score to determine shoulder function were comparable between both groups. Bone marrow harvest and BMC transplantation did not result in any severe adverse events. Therefore, the study was terminated after the interim analysis, as no other result could be expected. From the study results, it can be concluded that the application of autologous BMC is well tolerated, and bone healing can be achieved. Augmentation of bone defects with β-TCP could be shown to be feasible and might be considered in other clinical situations.Graphical Abstract
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- 2024
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4. A guide to the collection of T-cells by apheresis for ATMP manufacturing—recommendations of the GoCART coalition apheresis working group
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Worel, Nina, Holbro, Andreas, Vrielink, Hans, Ootjers, Claudia, Le Poole, Kaatje, Beer-Wekking, Ingrid, Rintala, Tuula, Lozano, Miquel, and Bonig, Halvard
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Autologous chimeric antigen receptor-modified T-cells (CAR-T) provide meaningful benefit for otherwise refractory malignancies. As clinical indications for CAR-T cells are expanding, hospitals hitherto not active in the field of immune effector cell therapy will need to build capacity and expertise. The GoCART Coalition seeks to disseminate knowledge and skills to facilitate the introduction of CAR-T cells and to standardize management and documentation of CAR-T cell recipients, in order to optimize outcomes and to be able to benchmark clinical results against other centers. Apheresis generates the starting material for CAR-T cell manufacturing. This guide provides some initial suggestions for patient’s apheresis readiness and performance to collect starting material and should thus facilitate the implementation of a CAR-T-starting material apheresis facility. It cannot replace, of course, the extensive training needed to perform qualitative apheresis collections in compliance with national and international regulations and assess their cellular composition and biological safety.
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- 2023
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5. Impact of mesenchymal stromal cell–derived vesicular cargo on B-cell acute lymphoblastic leukemia progression
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Karantanou, Christina, Minciacchi, Valentina R., Kumar, Rahul, Zanetti, Costanza, Bravo, Jimena, Pereira, Raquel S., Tascher, Georg, Tertel, Tobias, Covarrubias-Pinto, Adriana, Bankov, Katrin, Pfeffermann, Lisa-Marie, Bonig, Halvard, Divieti-Pajevic, Paola, McEwan, David G., Giebel, Bernd, Münch, Christian, Dikic, Ivan, and Krause, Daniela S.
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Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance through the release of small extracellular vesicles (sEVs). In contrast, we show here that BMM deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via regulation of the cargo of sEVs released by BMM-derived mesenchymal stromal cells (MSCs). PLEKHM1-deficient MSCs and their sEVs carry increased amounts of syntenin and syndecan-1, resulting in a more immature B-cell phenotype and an increased number/function of leukemia-initiating cells (LICs) via focal adhesion kinase and AKT signaling in B-ALL cells. Ex vivo pretreatment of LICs with sEVs derived from PLEKHM1-deficient MSCs led to a strong trend toward acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL cell–derived tumor necrosis factor α or interleukin-1β condition murine and human MSCs in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSCs, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSCs. In summary, our data reveal an important role of BMM-derived sEVs for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared with BCR-ABL1− B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.
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- 2023
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6. Retained functional normal and preleukemic HSCs at diagnosis are associated with good prognosis in DNMT3AmutNPM1mut AMLs
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Donato, Elisa, Correia, Nadia, Andresen, Carolin, Karpova, Darja, Würth, Roberto, Klein, Corinna, Sohn, Markus, Przybylla, Adriana, Zeisberger, Petra, Rothfelder, Kathrin, Salih, Helmut, Bonig, Halvard, Stasik, Sebastian, Röllig, Christoph, Dolnik, Anna, Bullinger, Lars, Buchholz, Frank, Thiede, Christian, Hübschmann, Daniel, and Trumpp, Andreas
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Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of relapse and mortality. Current chemotherapies whilst successful in eradicating blasts, are less effective in eliminating relapse-causing leukemic stem cells (LSCs). Although LSCs are usually identified as CD34+CD38- cells, there is significant heterogeneity in surface marker expression, and CD34- LSCs exist particularly in NPM1mut AMLs. By analyzing diagnostic primary DNMT3AmutNPM1mut AML samples, we suggest a novel flow cytometry sorting strategy particularly useful for CD34neg AML subtypes. To enrich for LSCs independently of CD34 status, positive selection for GPR56 and negative selection for NKG2D ligands are used. We show that the functional reconstitution capacity of CD34- and CD34+ LSCs as well as their transcriptomes are very similar which support phenotypic plasticity. Furthermore, we show that although CD34+ subpopulations can contain next to LSCs also normal and/or preleukemic hematopoietic stem cells (HSCs), this is not the case in CD34-GPR56+NKG2DL- enriched LSCs which thus can be isolated with high purity. Finally, we show that patients with AML, who retain at the time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significantly longer relapse-free and overall survival than patients with AML in whom functional HSCs are no longer detectable.
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- 2023
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7. The EGR3 regulome of infant KMT2A-r acute lymphoblastic leukemia identifies differential expression of B-lineage genes predictive for outcome
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Külp, Marius, Larghero, Patrizia, Alten, Julia, Cario, Gunnar, Eckert, Cornelia, Caye-Eude, Aurélie, Cavé, Hélène, Schmachtel, Tessa, Bardini, Michela, Cazzaniga, Giovanni, De Lorenzo, Paola, Valsecchi, Maria Grazia, Bonig, Halvard, Meyer, Claus, Rieger, Michael A., and Marschalek, Rolf
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KMT2A-rearranged acute lymphoblastic infant leukemia (KMT2A-r iALL) is associated with outsize risk of relapse and relapse mortality. We previously reported strong upregulation of the immediate early gene EGR3in KMT2A::AFF1iALL at relapse; now we provide analyses of the EGR3 regulome, which we assessed through binding and expression target analysis of an EGR3-overexpressing t(4;11) cell culture model. Our data identify EGR3 as a regulator of early B-lineage commitment. Principal component analysis of 50 KMT2A-r iALL patients at diagnosis and 18 at relapse provided strictly dichotomous separation of patients based on the expression of four B-lineage genes. Absence of B-lineage gene expression translates to more than two-fold poorer long-term event-free survival. In conclusion, our study presents four B-lineage genes with prognostic significance, suitable for gene expression-based risk stratification of KMT2A-r iALL patients.
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- 2023
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8. The differential role of the lipid raft-associated protein flotillin 2 for progression of myeloid leukemia
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Kumar, Rahul, Pereira, Raquel S., Niemann, Julian, Azimpour, Alexander I., Zanetti, Costanza, Karantanou, Christina, Minka, Wahyu, Minciacchi, Valentina R., Kowarz, Eric, Meister, Melanie, Godavarthy, Parimala S., Maguer-Satta, Véronique, Lefort, Sylvain, Wiercinska, Eliza, Bonig, Halvard, Marschalek, Rolf, and Krause, Daniela S.
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Lipid raft-associated proteins play a vital role in membrane-mediated processes. The lipid microdomain-associated protein flotillin 2 (FLOT2), which has a scaffolding function, is involved in polarization, as well as in actin cytoskeletal organization of primitive and mature hematopoietic cells and has been associated with different malignancies. However, its involvement in myeloid leukemias is not well studied. Using murine transplantation models, we show here that the absence of FLOT2 from leukemia-initiating cells (LICs) altered the disease course of BCR-ABL1+chronic myeloid leukemia (CML), but not of MLL–AF9-driven acute myeloid leukemia (AML). While FLOT2 was required for expression of the adhesion molecule CD44 on both CML- and AML-LIC, a defect in the cytoskeleton, cell polarity, and impaired homing ability of LIC was only observed in FLOT2-deficient BCR-ABL1+compared with MLL-AF9+cells. Downstream of CD44, BCR-ABL1 kinase-independent discrepancies were observed regarding expression, localization, and activity of cell division control protein 42 homolog (CDC42) between wild-type (WT) and FLOT2-deficient human CML and AML cells. Inhibition of CDC42 by ML141 impaired the homing of CML LIC and, thereby, CML progression. This suggested that alteration of both CD44 and CDC42 may be causative of impaired CML progression in the absence of FLOT2. In summary, our data suggest a FLOT2-CD44-CDC42 axis, which differentially regulates CML vs AML progression, with deficiency of FLOT2 impairing the development of CML.
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- 2022
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9. Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients
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Bethge, Wolfgang A., Eyrich, Matthias, Mielke, Stephan, Meisel, Roland, Niederwieser, Dietger, Schlegel, Paul G., Schulz, Ansgar, Greil, Johann, Bunjes, Donald, Brecht, Arne, Kuball, Jurgen, Schumm, Michael, Vucinic, Vladan, Wiesneth, Markus, Bonig, Halvard, Westinga, Kasper, Biedermann, Stefanie, Holtkamp, Silke, Karitzky, Sandra, Malchow, Michaela, Siewert, Christiane, Handgretinger, Rupert, and Lang, Peter
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Hematopoietic stem cell transplantation (HSCT) from haploidentical donors is a viable option for patients lacking HLA-matched donors. Here we report the results of a prospective multicenter phase I/II trial of transplantation of TCRαβ and CD19-depleted peripheral blood stem cells from haploidentical family donors after a reduced-intensity conditioning with fludarabine, thiotepa, and melphalan. Thirty pediatric and 30 adult patients with acute leukemia (n= 43), myelodysplastic or myeloproliferative syndrome (n= 6), multiple myeloma (n= 1), solid tumors (n= 6), and non-malignant disorders (n= 4) were enrolled. TCR αβ/CD19-depleted grafts prepared decentrally at six manufacturing sites contained a median of 12.1 × 106CD34+cells/kg and 14.2 × 103TCRαβ+T-cells/kg. None of the patients developed grade lll/IV acute graft-versus-host disease (GVHD) and only six patients (10%) had grade II acute GVHD. With a median follow-up of 733 days 36/60 patients are alive. The cumulative incidence of non-relapse mortality at day 100, 1 and 2 years after HSCT was 5%, 15%, and 17% for all patients, respectively. Estimated probabilities of overall and disease-free survival at 2 years were 63% and 50%, respectively. Based on these promising results in a high-risk patient cohort, haploidentical HSCT using TCRαβ/CD19-depleted grafts represents a viable treatment option.
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- 2022
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10. Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization
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Bisht, Kavita, McGirr, Crystal, Lee, Seo-Youn, Tseng, Hsu-Wen, Fleming, Whitney, Alexander, Kylie A., Matsumoto, Taichi, Barbier, Valérie, Sims, Natalie A., Müller-Newen, Gerhard, Winkler, Ingrid G., Bonig, Halvard, and Lévesque, Jean-Pierre
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We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr−/−and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.
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- 2022
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11. Severe impairment of T-cell responses to BNT162b2 immunization in patients with multiple myeloma
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Enßle, Julius C., Campe, Julia, Schwenger, Amelie, Wiercinska, Eliza, Hellstern, Helen, Dürrwald, Ralf, Rieger, Michael A., Wolf, Sebastian, Ballo, Olivier, Steffen, Björn, Serve, Hubert, Bonig, Halvard, Rabenau, Holger F., Widera, Marek, Ciesek, Sandra, Metzler, Ivana von, and Ullrich, Evelyn
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- 2022
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12. Soluble Fas ligand and transforming growth factor beta(sub 2) in the aqueous humor of patients with endothelial immune reactions after penetrating keratoplasty
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Reinhard, Thomas, Bonig, Halvard, Mayweg, Susanne, Bohringer, Daniel, Gobel, Ulrich, and Sundmacher, Rainer
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Graft rejection -- Physiological aspects ,Transforming growth factors -- Physiological aspects ,Cornea -- Transplantation ,Health - Published
- 2002
13. CD19-CAR-T Cells Are Effective and Safe Treatment of Post-Transplant Relapse in Pediatric and Young Adult Patients with B-Lineage ALL: Real-World Data from Germany
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Bader, Peter, Rossig, Claudia, Hutter, Martin, Ayuk, Francis A., Baldus, Claudia D., Buecklein, Veit L, Bonig, Halvard, Cario, Gunnar, Einsele, Hermann, Holtick, Udo, Koenecke, Christian, Künkele, Annette, Meisel, Roland, Mueller, Fabian, Müller, Ingo, Penack, Olaf, Rettinger, Eva, Sauer, Martin G., Schlegel, Paul-Gerhardt, Soerensen, Jan, von Stackelberg, Arend, Feuchtinger, Tobias, and Jarisch, Andrea
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- 2022
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14. Additive effects of infection and neutropenia on the induction of granulocytopoietic activity in vivo
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Bonig, Halvard-B., Hannen, Martin, Lex, Christiane, Wolfel, Sonja, Banning, Ursula, Nurnberger, Wenzel, Korholz, Dieter, and Gobel, Ulrich
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Granulocyte colony-stimulating factor -- Physiological aspects ,Neutropenia -- Physiological aspects ,Health - Published
- 1999
15. Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia
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Jetani, Hardikkumar, Navarro-Bailón, Almudena, Maucher, Marius, Frenz, Silke, Verbruggen, Christina, Yeguas, Ana, Vidriales, María Belén, González, Marcos, Rial Saborido, Judit, Kraus, Sabrina, Mestermann, Katrin, Thomas, Simone, Bonig, Halvard, Luu, Maik, Monjezi, Razieh, Mougiakakos, Dimitrios, Sauer, Markus, Einsele, Hermann, and Hudecek, Michael
- Abstract
Acute myeloid leukemia (AML) is an attractive entity for the development of chimeric antigen receptor (CAR) T-cell immunotherapy because AML blasts are susceptible to T-cell–mediated elimination. Here, we introduce sialic acid–binding immunoglobulin-like lectin 6 (Siglec-6) as a novel target for CAR T cells in AML. We designed a Siglec-6–specific CAR with a targeting domain derived from the human monoclonal antibody JML-1. We found that Siglec-6 is commonly expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells. Treatment with Siglec-6 CAR T cells confers specific antileukemia reactivity that correlates with Siglec-6 expression in preclinical models, including induction of complete remission in a xenograft AML model in immunodeficient mice (NSG/U937). In addition, we confirmed Siglec-6 expression on transformed B cells in chronic lymphocytic leukemia (CLL), and specific anti-CLL reactivity of Siglec-6 CAR T cells in vitro. Of particular interest, we found that Siglec-6 is not detectable on normal hematopoietic stem and progenitor cells (HSPCs) and that treatment with Siglec-6 CAR T cells does not affect their viability and lineage differentiation in colony-formation assays. These data suggest that Siglec-6 CAR T-cell therapy may be used to effectively treat AML without the need for subsequent allogeneic hematopoietic stem cell transplantation. In mature normal hematopoietic cells, we detected Siglec-6 in a proportion of memory (and naïve) B cells and basophilic granulocytes, suggesting the potential for limited on-target/off-tumor reactivity. The lack of expression of Siglec-6 on normal HSPCs is a key to differentiating it from other Siglec family members (eg, Siglec-3 [CD33]) and other CAR target antigens (eg, CD123) that are under investigation in AML, and it warrants the clinical investigation of Siglec-6 CAR T-cell therapy.
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- 2021
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16. Preanalytic depletion of medicinal anti-CD38 antibody from patient plasma for immunohematology testing
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Ehrend, Elisabeth, Manns, Patricia, Harenkamp, Sabine, Seifried, Erhard, Geisen, Christof, and Bonig, Halvard
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- 2021
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17. CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beautygene transfer to treat multiple myeloma
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Prommersberger, Sabrina, Reiser, Michael, Beckmann, Julia, Danhof, Sophia, Amberger, Maximilian, Quade-Lyssy, Patricia, Einsele, Hermann, Hudecek, Michael, Bonig, Halvard, and Ivics, Zoltán
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Clinical development of chimeric antigen receptor (CAR)-T-cell therapy has been enabled by advances in synthetic biology, genetic engineering, clinical-grade manufacturing, and complex logistics to distribute the drug product to treatment sites. A key ambition of the CARAMBA project is to provide clinical proof-of-concept for virus-free CAR gene transfer using advanced Sleeping Beauty(SB) transposon technology. SB transposition in CAR-T engineering is attractive due to the high rate of stable CAR gene transfer enabled by optimized hyperactive SB100X transposase and transposon combinations, encoded by mRNA and minicircle DNA, respectively, as preferred vector embodiments. This approach bears the potential to facilitate and expedite vector procurement, CAR-T manufacturing and distribution, and the promise to provide a safe, effective, and economically sustainable treatment. As an exemplary and novel target for SB-based CAR-T cells, the CARAMBA consortium has selected the SLAMF7 antigen in multiple myeloma. SLAMF7 CAR-T cells confer potent and consistent anti-myeloma activity in preclinical assays in vitro and in vivo. The CARAMBA clinical trial (Phase-I/IIA; EudraCT: 2019-001264-30) investigates the feasibility, safety, and anti-myeloma efficacy of autologous SLAMF7 CAR-T cells. CARAMBA is the first clinical trial with virus-free CAR-T cells in Europe, and the first clinical trial that uses advanced SB technology worldwide.
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- 2021
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18. Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia
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Gang, Eun Ji, Kim, Hye Na, Hsieh, Yao-Te, Ruan, Yongsheng, Ogana, Heather A., Lee, Solomon, Pham, Jennifer, Geng, Huimin, Park, Eugene, Klemm, Lars, Willman, Cheryl L., Carroll, William L., Mittelman, Steven D., Orgel, Etan, Oberley, Matthew J., Parekh, Chintan, Abdel-Azim, Hisham, Bhojwani, Deepa, Wayne, Alan S., De Arcangelis, Adèle, Georges-Labouesse, Elisabeth, Wayner, Elizabeth, Bonig, Halvard, Minasyan, Aspram, ten Hoeve, Johanna, Graeber, Thomas G., Müschen, Markus, Heisterkamp, Nora, and Kim, Yong-Mi
- Abstract
Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.
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- 2020
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19. ATIR101 administered after T-cell-depleted haploidentical HSCT reduces NRM and improves overall survival in acute leukemia
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Roy, Denis Claude, Walker, Irwin, Maertens, Johan, Lewalle, Philippe, Olavarria, Eduardo, Selleslag, Dominik, Lachance, Sylvie, Buyse, Marc, Wang, Kun, Rovers, Jeroen, Santi, Irene, Bonig, Halvard, Sandler, Andrew, Velthuis, Jurjen, and Mielke, Stephan
- Abstract
Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n= 35), matched unrelated donor (MUD; n= 64), mismatched unrelated donor (MMUD; n= 37), and umbilical cord blood (UCB; n= 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P= 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P< 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.
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- 2020
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20. Automatic Generation of Alloreactivity-Reduced Donor Lymphocytes and Hematopoietic Stem Cells from the Same Mobilized Apheresis Product
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Wiercinska, Eliza, Quade-Lyssy, Patricia, Hümmer, Christiane, Beifuß, Josephine, Akarach, Karima, Poppe, Carolin, Olevska, Valeriya, Lahnor, Heike, Dzionek, Julia, Bosio, Andreas, Papanikolaou, Eleni, and Bonig, Halvard
- Abstract
In vitroor in vivodepletion of alloreactive T cells can facilitate haplo-identical hematopoietic stem cell transplantation (HSCT). Very satisfactory transplant outcomes were thus reported for TCRαβ/CD19-depleted hematopoietic stem/progenitor cell (HSPC) grafts. However, the current semi-automatic manufacturing process, although robust, still requires a significant amount of time to be completed. Towards advancing and further facilitating large scale cell processing, a new TCRαβ/CD19 depletion module combined with a, previously described, CD45RA depletion module (to serve as allo-reactivity attenuated donor lymphocyte infusion) was established on the CliniMACS Prodigy.
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- 2023
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21. Real-World Data Suggest Effectiveness of Allogeneic Mesenchymal Stromal (MSC-FFM) Cells in Ruxolitinib-Refractory Acute Graft-Versus-Host Disease
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Bader, Peter, Verbeek, Mareike, Herhaus, Peter, Pachzelt, Lavinia, Beutel, Gernot, Schmid, Christoph, Müller, Nadine, Bug, Gesine, von Stackelberg, Arend, Tischer, Johanna, Ayuk, Francis A., Wulf, Gerald G., Pfeffermann, Lisa-Marie, Jahrsdörfer, Bernd, Schrezenmeier, Hubert, Kuci, Selim, Kuci, Zyrafete, Zens, Anke, Tribanek, Michael, Zeiser, Robert, Huenecke, Sabine, and Bonig, Halvard
- Abstract
Introduction:
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- 2023
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22. Single Cell Analysis Identifies Expression of PD-L2 on Human Bone Marrow Hematopoietic Stem Cells
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Schmachtel, Tessa, Külp, Marius, Yu, Weijia, Komic, Hana, Simoes, Catia, Nilsson, Malin S., Prosper, Felipe, Schroeder, Timm, Bonig, Halvard, Paiva, Bruno, Thorén, Fredrik B., and Rieger, Michael A.
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The identification of specific and reliable markers for human hematopoietic stem cells (HSCs) is crucial to enable their prospective isolation allowing the investigation of unique physiological HSC functions within the blood cell hierarchy. Despite significant advancements in identification of surface markers for human bone marrow HSC isolation, the enriched populations remain heterogeneous. Here we applied single cell CITE-Seq (cellular indexing of transcriptomes and epitopes) of FACS-enriched hematopoietic stem and progenitor cells (HSPCs) to decipher differentiation hierarchies and to identify markers of most immature populations.
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- 2023
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23. Cancer-induced inflammation and inflammation-induced cancer in colon: a role for S1P lyase
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Schwiebs, Anja, Herrero San Juan, Martina, Schmidt, Katrin G., Wiercinska, Eliza, Anlauf, Martin, Ottenlinger, Florian, Thomas, Dominique, Elwakeel, Eiman, Weigert, Andreas, Farin, Henner F., Bonig, Halvard, Scholich, Klaus, Geisslinger, Gerd, Pfeilschifter, Josef M., and Radeke, Heinfried H.
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A role of sphingolipids for inflammatory bowel disease and cancer is evident. However, the relative and separate contribution of sphingolipid deterioration in inflammation versus carcinogenesis for the pathophysiology of colitis-associated colon cancer (CAC) was unknown and therefore examined in this study. We performed isogenic bone marrow transplantation of inducible sphingosine-1-phosphate (S1P) lyase knockout mice to specifically modulate sphingolipids and associated genes and proteins in a compartment-specific way in a DSS/AOM mediated CAC model. 3D organoid cultures were used in vitro. S1P lyase (SGPL1) knockout in either immune cells or tissue, caused local sphingolipid accumulation leading to a dichotomic development of CAC: Immune cell SGPL1 knockout (I-SGPL−/−) augmented massive immune cell infiltration initiating colitis with lesions and calprotectin increase. Pathological crypt remodeling plus extracellular S1P-signaling caused delayed tumor formation characterized by S1P receptor 1, STAT3 mRNA increase, as well as programmed cell death ligand 1 expression, accompanied by a putatively counter regulatory STAT1S727phosphorylation. In contrast, tissue SGPL1 knockout (T-SGPL−/−) provoked immediate occurrence of epithelial-driven tumors with upregulated sphingosine kinase 1, S1P receptor 2 and epidermal growth factor receptor. Here, progressing carcinogenesis was accompanied by an IL-12 to IL-23 shift with a consecutive development of a Th2/GATA3-driven, tumor-favoring microenvironment. Moreover, the knockout models showed distinct lymphopenia and neutrophilia, different from the full SGPL1 knockout. This study shows that depending on the initiating cellular S1P source, the pathophysiology of inflammation-induced cancer versus cancer-induced inflammation develops through separate, discernible molecular steps.
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- 2019
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24. A Proof of the Low Speed Centrifugation Concept in Rodents: New Perspectives for In VivoResearch
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Ghanaati, Shahram, Al-Maawi, Sarah, Herrera-Vizcaino, Carlos, Alves, Gutemberg Gomes, Calasans-Maia, Mônica Diuana, Sader, Robert, Kirkpatrick, C. James, Choukroun, Joseph, Bonig, Halvard, and Mourão, Carlos Fernando de Almeida Barros
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Blood concentrates are obtained by centrifugation of the patient's own peripheral blood. These concentrates revealed increasing importance in the regenerative medicine and tissue engineering. Many limitations are faced in preclinical research concerning the volume of blood needed to produce platelet-rich fibrin (PRF) matrices (10 mL). This study evaluated for the first time three different centrifugation protocols to obtain injectable PRF (i-PRF) matrices using a small blood volume of 3 mL. Small tubes were specially produced for this study. Blood was collected from 24 Wistar rats (ca. 200 g) for this study using the cardiac puncture technique. From each animal, two tubes were collected: the first was prepared according to the standard PRF protocol without anticoagulation and used for in vitroculturing and histology; the second was anticoagulated and used for automated cell count. Three different relative centrifugation forces (RCFs; high [710 g], medium [177 g], and low [44 g]) were evaluated in this study (n= 8 per RCF). The obtained PRF matrices were cultured over 10 days, and the supernatants were collected for quantification of growth factors (GFs), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-β1), and platelet-derived growth factor-BB (PDGF-BB). The results showed that it is possible to produce i-PRF using a small blood volume of 3 mL. Reducing the RCF led to a significant increase in the number of platelets and leukocytes, specifically lymphocytes, within the i-PRF matrices. GF release (VEGF, TGF-β1, and PDGF-BB) was continuously measurable in all evaluated i-PRF matrices over 10 days. The i-PRF matrices prepared using low RCF released significantly more GF compared to those prepared using a medium or high RCF over 10 days (p< 0.05). These findings are in accordance with the previously described low-speed centrifugation concept (LSCC), which was first established using human blood, and may serve as a proof of concept of the LSCC in another species, that is, rats. Reducing the initial blood volume provides many possibilities to implement PRF matrices in preclinical research as an autologous system. However, further studies are needed to evaluate the therapeutic effects of PRF matrices obtained using 10 mL blood compared to those obtained using 3 mL blood.Impact StatementThis study evaluated for the first time the composition and bioactivity of platelet-rich fibrin (PRF) produced from small animal blood by reducing the initial blood volume needed for the preparation of PRF from 10 to 3 mL. The results showed that different preparation protocols of PRF produced using 3 mL of animal blood exhibit the same composition, properties, and bioactivity as PRF prepared using 10 mL human blood.
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- 2018
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25. Frequent Whole Blood Donations Select for DNMT3Avariants Mediating Enhanced Response to Erythropoietin
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Karpova, Darja, Huerga Encabo, Hector, Donato, Elisa, Kotova, Iuliia, Calderazzo, Silvia, Leppä, Aino-Maija, Jasper, Panten, Przybylla, Adriana, Seifried, Erhard, Kopp-Schneider, Annette, Wong, Terrence N, Bonnet, Dominique, Bonig, Halvard, and Trumpp, Andreas
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- 2022
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26. Frequent Whole Blood Donations Select for DNMT3A variants Mediating Enhanced Response to Erythropoietin
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Karpova, Darja, Huerga Encabo, Hector, Donato, Elisa, Kotova, Iuliia, Calderazzo, Silvia, Leppä, Aino-Maija, Jasper, Panten, Przybylla, Adriana, Seifried, Erhard, Kopp-Schneider, Annette, Wong, Terrence N, Bonnet, Dominique, Bonig, Halvard, and Trumpp, Andreas
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- 2022
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27. Sars-Cov-2 Fails to Infect Mesenchymal Stromal Cells (MSCs) - Pre-Clinical Investigations in Support of Therapeutic Use of MSCs for Severe COVID-19
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Pfeffermann, Lisa-Marie, Bojkova, Denisa, Kandler, Joshua, Huenecke, Sabine, Bremm, Melanie, Piede, Natascha, Kuci, Selim, Kuci, Zyrafete, Harenkamp, Sabine, Bonig, Halvard, and Bader, Peter
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- 2022
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28. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM)
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Bader, Peter, Kuçi, Zyrafete, Bakhtiar, Shahrzad, Basu, Oliver, Bug, Gesine, Dennis, Michael, Greil, Johann, Barta, Aniko, Kállay, Krisztián, Lang, Peter, Lucchini, Giovanna, Pol, Raj, Schulz, Ansgar, Sykora, Karl-Walter, Luettichau, Irene, Herter-Sprie, Grit, Uddin, Mohammad, Jenkin, Phil, Alsultan, Abdulrahman, Buechner, Jochen, Stein, Jerry, Kelemen, Agnes, Jarisch, Andrea, Soerensen, Jan, Salzmann-Manrique, Emilia, Hutter, Martin, Schäfer, Richard, Seifried, Erhard, Klingebiel, Thomas, Bonig, Halvard, and Kuçi, Selim
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The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as “MSC-Frankfurt am Main (MSC-FFM)”. Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1–5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16–38); leukemia relapse mortality was 2% (range, 0–5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61–83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.
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- 2018
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29. CAR T-cells targeting FLT3 have potent activity against FLT3−ITD+AML and act synergistically with the FLT3-inhibitor crenolanib
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Jetani, Hardikkumar, Garcia-Cadenas, Irene, Nerreter, Thomas, Thomas, Simone, Rydzek, Julian, Meijide, Javier, Bonig, Halvard, Herr, Wolfgang, Sierra, Jordi, Einsele, Hermann, and Hudecek, Michael
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FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein expressed on normal hematopoietic stem and progenitor cells (HSC) and retained on malignant blasts in acute myeloid leukemia (AML). We engineered CD8+and CD4+T-cells expressing a FLT3-specific chimeric antigen receptor (CAR) and demonstrate they confer potent reactivity against AML cell lines and primary AML blasts that express either wild-type FLT3or FLT3with internal tandem duplication (FLT3-ITD). We also show that treatment with the FLT3-inhibitor crenolanib leads to increased surface expression of FLT3 specifically on FLT3-ITD+AML cells and consecutively, enhanced recognition by FLT3-CAR T-cells in vitro and in vivo. As anticipated, we found that FLT3-CAR T-cells recognize normal HSCs in vitro and in vivo, and disrupt normal hematopoiesis in colony-formation assays, suggesting that adoptive therapy with FLT3-CAR T-cells will require subsequent CAR T-cell depletion and allogeneic HSC transplantation to reconstitute the hematopoietic system. Collectively, our data establish FLT3 as a novel CAR target in AML with particular relevance in high-risk FLT3-ITD+AML. Further, our data provide the first proof-of-concept that CAR T-cell immunotherapy and small molecule inhibition can be used synergistically, as exemplified by our data showing superior antileukemia efficacy of FLT3-CAR T-cells in combination with crenolanib.
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- 2018
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30. Efficient Non-viral Gene Delivery into Human Hematopoietic Stem Cells by Minicircle Sleeping BeautyTransposon Vectors
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Holstein, Marta, Mesa-Nuñez, Cristina, Miskey, Csaba, Almarza, Elena, Poletti, Valentina, Schmeer, Marco, Grueso, Esther, Ordóñez Flores, Juan Carlos, Kobelt, Dennis, Walther, Wolfgang, Aneja, Manish K., Geiger, Johannes, Bonig, Halvard B., Izsvák, Zsuzsanna, Schleef, Martin, Rudolph, Carsten, Mavilio, Fulvio, Bueren, Juan A., Guenechea, Guillermo, and Ivics, Zoltán
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The Sleeping Beauty(SB) transposon system is a non-viral gene delivery platform that combines simplicity, inexpensive manufacture, and favorable safety features in the context of human applications. However, efficient correction of hematopoietic stem and progenitor cells (HSPCs) with non-viral vector systems, including SB, demands further refinement of gene delivery techniques. We set out to improve SB gene transfer into hard-to-transfect human CD34+cells by vectorizing the SB system components in the form of minicircles that are devoid of plasmid backbone sequences and are, therefore, significantly reduced in size. As compared to conventional plasmids, delivery of the SB transposon system as minicircle DNA is ∼20 times more efficient, and it is associated with up to a 50% reduction in cellular toxicity in human CD34+cells. Moreover, providing the SB transposase in the form of synthetic mRNA enabled us to further increase the efficacy and biosafety of stable gene delivery into hematopoietic progenitors ex vivo. Genome-wide insertion site profiling revealed a close-to-random distribution of SB transposon integrants, which is characteristically different from gammaretroviral and lentiviral integrations in HSPCs. Transplantation of gene-marked CD34+cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution, which was most efficient when the SB transposase was supplied as mRNA and nucleofected cells were maintained for 4–8 days in culture before transplantation. Collectively, implementation of minicircle and mRNA technologies allowed us to further refine the SB transposon system in the context of HSPC gene delivery to ultimately meet clinical demands of an efficient and safe non-viral gene therapy protocol.
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- 2018
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31. Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B
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Miesbach, Wolfgang, Meijer, Karina, Coppens, Michiel, Kampmann, Peter, Klamroth, Robert, Schutgens, Roger, Tangelder, Marco, Castaman, Giancarlo, Schwäble, Joachim, Bonig, Halvard, Seifried, Erhard, Cattaneo, Federica, Meyer, Christian, and Leebeek, Frank W. G.
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Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 × 1012 or 2 × 1013 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.
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- 2018
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32. Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells
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Karpova, Darja, Ritchey, Julie K., Holt, Matthew S., Abou-Ezzi, Grazia, Monlish, Darlene, Batoon, Lena, Millard, Susan, Spohn, Gabriele, Wiercinska, Eliza, Chendamarai, Ezhil, Yang, Wei, Christ, Stephanie, Gehrs, Leah, Schuettpelz, Laura G., Dembowsky, Klaus, Pettit, Allison R., Rettig, Michael P., Bonig, Halvard, and DiPersio, John F.
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Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool.
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- 2017
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33. CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany
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Bader, Peter, Rossig, Claudia, Hutter, Martin, Ayuk, Francis Ayuketang, Baldus, Claudia D., Bücklein, Veit L., Bonig, Halvard, Cario, Gunnar, Einsele, Hermann, Holtick, Udo, Koenecke, Christian, Bakhtiar, Shahrzad, Künkele, Annette, Meisel, Roland, Müller, Fabian, Müller, Ingo, Penack, Olaf, Rettinger, Eva, Sauer, Martin G., Schlegel, Paul-Gerhardt, Soerensen, Jan, von Stackelberg, Arend, Strahm, Brigitte, Hauer, Julia, Feuchtinger, Tobias, and Jarisch, Andrea
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•Most patients with refractory B-ALL could achieve remission with a single infusion of CAR T cells.•Survival probability is excellent for patients who relapsed >6 months posttransplant and poor for patients who relapsed before 6 months.
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- 2023
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34. Spleen Size Is Significantly Influenced by Body Height and Sex: Establishment of Normal Values for Spleen Size at US with a Cohort of 1200 Healthy Individuals
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Chow, Kai Uwe, Luxembourg, Beate, Seifried, Erhard, and Bonig, Halvard
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This study describes sex- and height-adjusted normal values, including lower and upper limits of normal, for spleen length as measured with two-dimensional US.
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- 2016
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35. Update on biosimilars of granulocyte colony-stimulating factor – when no news is good news
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Schulz, Miriam and Bonig, Halvard
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- 2016
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36. Co-culture of primary human T cells with leukemia cells to measure regulatory T cell expansion
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Külp, Marius, Diehl, Laura, Bonig, Halvard, and Marschalek, Rolf
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The expansion of regulatory T cells (Tregs) is known to be mediated by cytokines including IL-10 and TGFβ but has additionally been shown to depend on the interaction of the immune receptors ICOSLG and ICOS. Here, we describe a co-culture system which enables quantification of the ability of leukemia cells to induce Treg expansion through secreted cytokines and direct receptor interactions. The protocol is applicable for MHC-matched and -unmatched experiments and allows assessment of Treg expansion without using a mouse model.
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- 2022
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37. Concise Review: CXCR4/CXCL12 Signaling in Immature Hematopoiesis—Lessons From Pharmacological and Genetic Models
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Karpova, Darja and Bonig, Halvard
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Dominant, although nonexclusive roles of CXCR4 and its chief ligand CXCL12 in bone marrow (BM) retention and preservation of the relative quiescence of hematopoietic stem/progenitor cells (HSPCs), along with their involvement in human immunodeficiency virus infection, in trafficking of mature hematopoietic cells to sites of inflammation and in orderly migration of nonhematopoietic cells during embryogenesis, explain the significant interest of the scientific community in the mode of action of this receptor–ligand pair. In this focused review, we seek to distil from the large body of information that has become available over the years some of the key findings about the role of CXCR4/CXCL12 in normal immature hematopoiesis. It is hoped that understanding the mechanistic insights gained there from will help generate hypotheses about potential avenues in which cancer/leukemia cell behavior can be modified by interference with this pathway. StemCells2015;33:2391–2399
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- 2015
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38. RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation
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Kuvardina, Olga N., Herglotz, Julia, Kolodziej, Stephan, Kohrs, Nicole, Herkt, Stefanie, Wojcik, Bartosch, Oellerich, Thomas, Corso, Jasmin, Behrens, Kira, Kumar, Ashok, Hussong, Helge, Urlaub, Henning, Koch, Joachim, Serve, Hubert, Bonig, Halvard, Stocking, Carol, Rieger, Michael A., and Lausen, Jörn
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The activity of antagonizing transcription factors represents a mechanistic paradigm of bidirectional lineage–fate control during hematopoiesis. At the megakaryocytic/erythroid bifurcation, the crossantagonism of krueppel-like factor 1 (KLF1) and friend leukemia integration 1 (FLI1) has such a decisive role. However, how this antagonism is resolved during lineage specification is poorly understood. We found that runt-related transcription factor 1 (RUNX1) inhibits erythroid differentiation of murine megakaryocytic/erythroid progenitors and primary human CD34+progenitor cells. We show that RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation by epigenetic repression of the erythroid master regulator KLF1. RUNX1 binding to the KLF1locus is increased during megakaryocytic differentiation and counterbalances the activating role of T-cell acute lymphocytic leukemia 1 (TAL1). We found that corepressor recruitment by RUNX1 contributes to a block of the KLF1-dependent erythroid gene expression program. Our data indicate that the repressive function of RUNX1 influences the balance between erythroid and megakaryocytic differentiation by shifting the balance between KLF1 and FLI1 in the direction of FLI1. Taken together, we show that RUNX1 is a key player within a network of transcription factors that represses the erythroid gene expression program.
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- 2015
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39. Discovery and Characterization of an Endogenous CXCR4 Antagonist
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Zirafi, Onofrio, Kim, Kyeong-Ae, Ständker, Ludger, Mohr, Katharina B., Sauter, Daniel, Heigele, Anke, Kluge, Silvia F., Wiercinska, Eliza, Chudziak, Doreen, Richter, Rudolf, Moepps, Barbara, Gierschik, Peter, Vas, Virag, Geiger, Hartmut, Lamla, Markus, Weil, Tanja, Burster, Timo, Zgraja, Andreas, Daubeuf, Francois, Frossard, Nelly, Hachet-Haas, Muriel, Heunisch, Fabian, Reichetzeder, Christoph, Galzi, Jean-Luc, Pérez-Castells, Javier, Canales-Mayordomo, Angeles, Jiménez-Barbero, Jesus, Giménez-Gallego, Guillermo, Schneider, Marion, Shorter, James, Telenti, Amalio, Hocher, Berthold, Forssmann, Wolf-Georg, Bonig, Halvard, Kirchhoff, Frank, and Münch, Jan
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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.
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- 2015
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40. Retained functional normal and preleukemic HSCs at diagnosis are associated with good prognosis in DNMT3AmutNPM1mutAMLs
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Donato, Elisa, Correia, Nadia, Andresen, Carolin, Karpova, Darja, Würth, Roberto, Klein, Corinna, Sohn, Markus, Przybylla, Adriana, Zeisberger, Petra, Rothfelder, Kathrin, Salih, Helmut, Bonig, Halvard, Stasik, Sebastian, Röllig, Christoph, Dolnik, Anna, Bullinger, Lars, Buchholz, Frank, rth, Christian, Hübschmann, Daniel, and Trumpp, Andreas
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AML is a heterogeneous disease characterized by high rate of relapse and mortality. While chemotherapies may eradicate blasts, they are less effective in eliminating relapse-causing Leukemic Stem Cells (LSCs). Although LSCs are usually identified as CD34+CD38-cells, there is significant heterogeneity in surface marker expression and CD34-LSCs exist particularly in NPM1mutAMLs. By analyzing diagnostic primary DNMT3AmutNPM1mutAML samples, we suggest a novel flow cytometry sorting strategy particularly useful for CD34negAML subtypes. To enrich for LSCs independently of CD34 status, positive selection for GPR56 and negative selection for NKG2D-Ligands are employed. We demonstrate that the functional reconstitution capacity of CD34-and CD34+LSCs as well as their transcriptomes are very similar supporting phenotypic plasticity. Furthermore, we show that while CD34+subpopulations can contain next to LSCs also normal and/or pre-leukemic Hematopoietic Stem Cells (HSCs), this is not the case in CD34-GPR56+NKG2DL-enriched LSCs which thus can be isolated with high purity. Finally, we show that AML patients, who retain at time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significant longer relapse-free and overall survival compared to AML patients in whom functional HSCs are no longer detectable.
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- 2022
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41. Immune Responses to SARS-CoV-2 Vaccination in Young Patients with Anti-CD19 Chimeric Antigen Receptor T Cell-Induced B Cell Aplasia
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Jarisch, Andrea, Wiercinska, Eliza, Huenecke, Sabine, Bremm, Melanie, Cappel, Claudia, Hauler, Julian, Rettinger, Eva, Soerensen, Jan, Hellstern, Helen, Klusmann, Jan-Henning, Ciesek, Sandra, Bonig, Halvard, and Bader, Peter
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•For patients after immune cell therapy, the risks of Coronavirus disease 19-associated complications are much higher than for the general population, supporting prioritization of vaccine access.•No previous studies have reported cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients after anti-CD19 chimeric antigen receptor (CAR) T cell therapy.•SARS-CoV-2 mRNA vaccines induce robust and potentially clinically meaningful T cell responses to SARS-CoV-2 vaccines in patients with anti-CD19 CAR T cell therapy-mediated humoral immunodeficiency.•No severe vaccine-related grade 3 or 4 adverse events, graft-versus-host exacerbation, or relapse were observed in our cohort.
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- 2022
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42. On the adaptation of endosteal stem cell niche function in response to stress
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Jiang, Yi, Bonig, Halvard, Ulyanova, Tatiana, Chang, KaiHsin, and Papayannopoulou, Thalia
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Although the influence of microenvironmental “niche” on the function of a variety of stem cells is undisputed, the details of hematopoietic stem cell/niche interactions at the cellular and molecular level have sparked a continuous debate. We studied the microanatomic partitioning of transplanted normal and α4 integrin-deficient Lin−kit+ cells in trabecular and compact bone before and after irradiation and present robust quantitative data on both. We found that (1) the microanatomic distribution of normal highly enriched progenitor cells is random in nonirradiated recipients based on area distribution analyses, (2) in contrast, in irradiated hosts normal cells distribute preferentially near the endosteum, (3) the overall cell seeding efficiency was higher in trabecular versus compact bone both before and after irradiation, and (4) α4 integrin-deficient cells not only lodge with reduced overall efficiency confirming previous data, but fail to preferentially partition themselves into endosteal regions in irradiated hosts, as normal cells do. A similar phenotype was observed with cells rendered Gi-protein signaling incompetent by pertussis toxin treatment, supporting an active stromal-derived factor 1 (SDF-1) gradient near endosteum after irradiation.
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- 2009
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43. Implication of ICOSLG on Relapse in Infant T(4;11) Acute Lymphoblastic Leukemia
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Külp, Marius, Siemund, Anna Lena, Meyer, Claus, Larghero, Patrizia, Dietz, Alissa, Alten, Julia, Cario, Gunnar, Caye-Eude, Aurélie, Cavé, Hélène, Bardini, Michela, De Lorenzo, Paola, Cazzaniga, Giovanni, Diehl, Laura, Bonig, Halvard, and Marschalek, Rolf
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Infant t(4;11) acute lymphoblastic leukemia (ALL) is associated with a high relapse rate with 4-year event-free survival (EFS) of only 36%. Relapse has been shown to be the major cause of death as 83% of relapsed infant t(4;11) ALL patients die within three years of diagnosis. Therefore, it is of utmost therapeutic interest to elucidate molecular mechanisms of relapse.
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- 2021
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44. The p67 laminin receptor identifies human erythroid progenitor and precursor cells and is functionally important for their bone marrow lodgment
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Bonig, Halvard, Chang, Kai-Hsin, Nakamoto, Betty, and Papayannopoulou, Thalia
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The laminins are a group of extracellular matrix proteins with constitutive expression in all tissues, including bone marrow stroma. A functional role for the nonintegrin laminin receptor p67 has been described for cancer metastasis and lymphocyte trafficking. Expression of p67 was also reported for other subsets of mature leukocytes and for malignant hematopoietic or nonhematopoietic cells. We explored p67 expression on normal hematopoietic progenitor cells (HPCs) and its putative role in bone marrow retention of transplanted HPCs. We found p67 expression on a subset of primary human CD34+ cells coexpressing erythroid markers. Of importance, p67 recognizes early erythroid progenitors, since sorted p67+ cells were significantly enriched for burst-forming units–erythroid (BFU-Es) and depleted of colony-forming units–granulocyte/macrophage (CFU-GMs). Blockade of p67 binding of donor cells, using antifunctional antibody, reduced bone marrow homing of BFU-Es. These studies identify p67 as a novel phenotypic marker for erythroid HPCs of functional importance for lineage-specific homing/retention among adult transplanted HPCs.
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- 2006
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45. Hierarchy of molecular-pathway usage in bone marrow homing and its shift by cytokines
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Bonig, Halvard, Priestley, Gregory V., and Papayannopoulou, Thalia
- Abstract
Efficient bone marrow (BM) homing is a prerequisite for successful engraftment of transplanted hematopoietic cells (HPCs). Contradictory conclusions about the contribution of SDF-1/CXCR4 have clouded our understanding of its role within the molecular pathway cooperation needed for BM homing, particularly with the well-defined hierarchic network of adhesion molecules. In the present study we sought to unravel cooperative and compensatory molecular pathways guiding BM homing. Fresh BM-HPCs, rendered either SDF-1 unresponsive or Gi-signaling refractory, homed quite efficiently, because of compensation by α4-integrin interacting with VCAM-1. The contribution of SDF-1/CXCR4- or Gi-protein-mediated signals to BM homing became apparent after their blockade was combined with deletion of α4-integrin, leading to dramatic reduction in BM homing. Similar conclusions were revealed when VCAM-1-deficient hosts were used. Cytokine incubation changed the functional properties of BM-HPCs and hierarchy of molecular pathway usage in homing, by shifting the dominance among the homing mediators: loss of CXCR4 or Gi-signaling now significantly reduced BM homing, with only partial compensation through α4/VCAM-1 and endothelial selectins. These studies depict a flexible hierarchy of cooperating homing pathways, in which dominant players are repositioned with changing cytokine milieu, and possibly source of HPCs.
- Published
- 2006
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46. PTX-sensitive signals in bone marrow homing of fetal and adult hematopoietic progenitor cells
- Author
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Bonig, Halvard, Priestley, Gregory V., Nilsson, Lina M., Jiang, Yi, and Papayannopoulou, Thalia
- Abstract
Several examples suggest a relationship between in vitro migratory capacity and bone marrow (BM) homing. Pertussis toxin (PTX) is a potent inhibitor of serpentine receptor–associated inhibitory trimeric guanidine nucleotide binding (Gi) protein signals. As such, it blocks hematopoietic progenitor cell migration in vitro, but contrary to expectation, no effects on BM homing were observed in previous studies. We therefore re-examined the effect of PTX on homing of murine BM and fetal liver (FL). We found that BM homing of PTX-incubated progenitor cells (colony-forming cells in culture [CFU-Cs]) from BM or FL in irradiated and nonirradiated recipients was reduced by more than 75%, with a concomitant increase in circulating CFU-Cs in peripheral blood. Additional studies confirmed the functional significance of this reduction in homing: PTX-treated cells did not provide radioprotection, and their short-term engraftment in BM and spleen was drastically reduced. Furthermore, several approaches show that cell-intrinsic rather than host-derived mechanisms are responsible for the PTX-induced homing defect. In summary, we show that Gi protein signals are required for BM homing and, as such, provide a new example of the association between BM homing and in vitro migration. Moreover, our data suggest that the behavior of hematopoietic progenitors in obeying Gi signaling does not diverge from that of mature leukocytes.
- Published
- 2004
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47. The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization
- Author
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Papayannopoulou, Thalia, Priestley, Gregory V., Bonig, Halvard, and Nakamoto, Betty
- Abstract
The directed migration of mature leukocytes to inflammatory sites and the lymphocyte trafficking in vivo are dependent on G protein–coupled receptors and delivered through pertussis toxin (Ptx)–sensitive Gi-protein signaling. In the present study, we explored the in vivo role of G-protein signaling on the redistribution or mobilization of hematopoietic stem/progenitor cells (HPCs). A single injection of Ptx in mice elicits a long-lasting leukocytosis and a progressive increase in circulating colony-forming unit-culture (CFU-C) and colony-forming unit spleen (CFU-S). We found that the prolonged effect is sustained by a continuous slow release of Ptx bound to red blood cells or other cells and is potentially enhanced by an indirect influence on cell proliferation. Plasma levels of certain cytokines (interleukin 6 [IL-6], granulocyte colony-stimulating factor [G-CSF]) increase days after Ptx treatment, but these are unlikely initiators of mobilization. In addition to normal mice, mice genetically deficient in monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 9 (MMP-9), G-CSF receptor, β2 integrins, or selectins responded to Ptx treatment, suggesting independence of Ptx-response from the expression of these molecules. Combined treatments of Ptx with anti–very late activation antigen (anti-VLA-4), uncovered potentially important insight in the interplay of chemokines/integrins, and the synergy of Ptx with G-CSF appeared to be dependent on MMP-9. As Ptx-mobilized kit+ cells display virtually no response to stromal-derived factor 1 (SDF-1) in vitro, our data suggest that disruption of CXCR4/SDF-1 signaling may be the underlying mechanism of Ptx-induced mobilization and indirectly reinforce the notion that active signaling through this pathway is required for continuous retention of cells within the bone marrow. Collectively, our data unveil a novel example of mobilization through pharmacologic modulation of signaling.
- Published
- 2003
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48. Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab
- Author
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Bonig, Halvard, Wundes, Annette, Chang, Kai-Hsin, Lucas, Sylvia, and Papayannopoulou, Thalia
- Abstract
Blockade of CD49d-mediated lymphocyte trafficking has been used therapeutically for certain autoimmune diseases, such as multiple sclerosis (MS). In addition to negative effects on the trafficking of mature lymphocytes to sites of inflammation, CD49d blockade in mice and monkeys rapidly mobilizes hematopoietic stem/progenitor cells (HSPCs) capable of short- and long-term engraftment. Here we aimed to ascertain the effects of treatment with antifunctional anti-CD49d antibody in humans (MS patients receiving infusions of the CD49d-blocking antibody natalizumab) on levels of circulating HSPCs after a single dose of antibody or after long-term treatment. On average, 6-fold elevated levels of circulating CD34+ cells and colony-forming unit-culture (CFU-C) were achieved within 1 day of the first dose of natalizumab, and similar levels were continuously maintained under monthly natalizumab infusions. The blood of natalizumab-treated subjects also contained SCID-repopulating cells. The fate of these circulating HSPCs and their clinical relevance for MS patients remains to be determined.
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- 2008
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49. Cell Adhesion of ALL to Stromal Cells May Mediate CAR T-Cell Resistance: A Novel Escape Mechanism for Immunotherapy
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Kim, Hye Na, Jiang, Enzi, Yongsheng, Ruan, Ogana, Heather, Abdel-Azim, Nour, Le, Justin, Luong, Annie, Bonig, Halvard, Ahmed, Nabil, Babak, Moghimi, Pulsipher, Michael A., Bhojwani, Deepa, Wayne, Alan S., Parekh, Chintan, Abdel-Azim, Hisham, Heisterkamp, Nora, and Kim, Yong-Mi
- Abstract
Backgroud:Despite advances in therapy and improved survival, relapsed and refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL) in pediatric and adult patients still remains a problem. Chimeric antigen receptor T cells against CD19 (CD19 CAR T) show promising results in patients with r/r BCP-ALL. However, relapse of the disease still occurs with appreciable frequency even with this novel therapy. As a significant number of relapses post-CAR T lack surface CD19 expression, further CD19-directed therapy is not an option for these cases.
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- 2019
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50. Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation
- Author
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Ortmann, Christina A., Dorsheimer, Lena, Abou-El-Ardat, Khalil, Hoffrichter, Jennifer, Assmus, Birgit, Bonig, Halvard, Scholz, Anica, Pfeifer, Heike, Martin, Hans, Schmid, Tobias, Brüne, Bernhard, Scheich, Sebastian, Steffen, Björn, Riemann, Julia, Hermann, Stella, Dukat, Alexandra, Bug, Gesine, Brandts, Christian H., Wagner, Sebastian, Serve, Hubert, and Rieger, Michael A.
- Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.
- Published
- 2019
- Full Text
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