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3. Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease

Author

Bonig, Halvard, Verbeek, Mareike, Herhaus, Peter, Braitsch, Krischan, Beutel, Gernot, Schmid, Christoph, Müller, Nadine, Bug, Gesine, Döring, Michaela, von Stackelberg, Arend, Tischer, Johanna, Ayuk, Francis, Wulf, Gerald, Holtick, Udo, Pfeffermann, Lisa-Marie, Jahrsdörfer, Bernd, Schrezenmeier, Hubert, Kuci, Selim, Kuci, Zyrafete, Zens, Anke, Tribanek, Michael, Zeiser, Robert, Huenecke, Sabine, and Bader, Peter

Published
2023
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4. CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany

Author

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

Published
2023
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5. Impact of mesenchymal stromal cell–derived vesicular cargo on B-cell acute lymphoblastic leukemia progression

Author

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.

Published
2023
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6. Retained functional normal and preleukemic HSCs at diagnosis are associated with good prognosis in DNMT3AmutNPM1mut AMLs

Author

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

Published
2023
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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

Author

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

Published
2022
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13. The activating receptor NKp65 is selectively expressed by human ILC3 and demarcates ILC3 from mature NK cells.

Author

Kühnel, Ines, Vogler, Isabel, Spreu, Jessica, Bonig, Halvard, Döring, Claudia, and Steinle, Alexander

Abstract

Innate lymphocytes comprise cytotoxic natural killer (NK) cells and tissue‐resident innate lymphoid cells (ILC) that are subgrouped according to their cytokine profiles into group 1 ILC (ILC1), ILC2, and ILC3. However, cell surface receptors unambiguously defining or specifically activating such ILC subsets are scarcely known. Here, we report on the physiologic expression of the human activating C‐type lectin‐like receptor (CTLR) NKp65, a high‐affinity receptor for the CTLR keratinocyte‐associated C‐type lectin (KACL). Tracking rare NKp65 transcripts in human blood, we identify ILC3 to selectively express NKp65. NKp65 expression not only demarcates "bona fide" ILC3 from likewise RORγt‐expressing ILC precursors and lymphoid tissue inducer cells but also from mature NK cells which acquire the NKp65‐relative NKp80 during a Notch‐dependent differentiation from NKp65+ precursor cells. Hence, ILC3 and NK cells mutually exclusively and interdependently express the genetically coupled sibling receptors NKp65 and NKp80. Much alike NKp80, NKp65 promotes cytotoxicity by innate lymphocytes which may become relevant during pathophysiological reprogramming of ILC3. Altogether, we report the selective expression of the activating immunoreceptor NKp65 by ILC3 demarcating ILC3 from mature NK cells and endowing ILC3 with a dedicated immunosensor for the epidermal immune barrier. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells

Author

Karpova, Darja, Rettig, Michael P., Ritchey, Julie, Cancilla, Daniel, Gehrs, Stephanie ChrisLeah, Chendamarai, Ezhilarasi, Evbuomwan, Moses O., Zhang, Matthew HolJingzhu, Abou-Ezzi, Grazia, Celik, Hamza, Wiercinska, Eliza, Yang, Wei, Gao, Feng, Eissenberg, Linda G., Heier, Richard F., Arnet, Stacy D., Meyers, Marvin J., Prinsen, Michael J., Griggs, David W., Trumpp, Andreas, Ruminski, Peter G., Morrow, Dwight M., Bonig, Halvard B., Link, Daniel C., and DiPersio, John F.

Subjects
R and D Systems, Hematopoietic stem cells, Combination drug therapy, Software industry, Hematopoietic stem cell transplantation, Integrins, Plerixafor, Stem cells, Antigens, Surgery, Stem cell transplantation, Granulocyte colony-stimulating factor, Health care industry, Washington University. School of Medicine
Abstract

Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a 5-day course of granulocyte colony-stimulating factor (G-CSF) as the most common regimen used for HSPC mobilization. The CXCR4 inhibitor plerixafor is a more rapid mobilizer, yet not potent enough when used as a single agent, thus emphasizing the need for faster acting agents with more predictable mobilization responses and fewer side effects. We sought to improve hematopoietic stem cell transplantation by developing a new mobilization strategy in mice through combined targeting of the chemokine receptor CXCR2 and the very late antigen 4 (VLA4) integrin. Rapid and synergistic mobilization of HSPCs along with an enhanced recruitment of true HSCs was achieved when a CXCR2 agonist was coadministered in conjunction with a VLA4 inhibitor. Mechanistic studies revealed involvement of CXCR2 expressed on BM stroma in addition to stimulation of the receptor on granulocytes in the regulation of HSPC localization and egress. Given the rapid kinetics and potency of HSPC mobilization achieved by the VLA4 inhibitor and CXCR2 agonist combination in mice compared with currently approved HSPC mobilization methods, the combination represents an exciting potential strategy for clinical development in the future., Introduction In postnatal mammals, the vast majority of hematopoietic stem and progenitor cells (HSPCs) reside in the protective environment of the bone marrow (BM) (1, 2). Accordingly, only very few [...]

Published
2019
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29. Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells

Author

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.

Published
2017
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30. Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System.

Author

Yalcin, Burak H., Macas, Jadranka, Wiercinska, Eliza, Harter, Patrick N., Fawaz, Malak, Schmachtel, Tessa, Ghiro, Ilaria, Bieniek, Ewa, Kosanovic, Djuro, Thom, Sonja, Fruttiger, Marcus, Taketo, Makoto M., Schermuly, Ralph T., Rieger, Michael A., Plate, Karl H., Bonig, Halvard, and Liebner, Stefan

Subjects
HEMATOPOIETIC system, BLOOD cells, RUNX proteins, PLATELET-derived growth factor, HEMATOPOIETIC stem cells, WNT signal transduction, ERYTHROCYTES, BONE marrow
Abstract

The bone marrow (BM) hematopoietic system (HS) gives rise to blood cells originating from hematopoietic stem cells (HSCs), including megakaryocytes (MKs) and red blood cells (erythrocytes; RBCs). Many steps of the cell-fate decision remain to be elucidated, being important for cancer treatment. To explore the role of Wnt/β-catenin for MK and RBC differentiation, we activated β-catenin signaling in platelet-derived growth factor b (Pdgfb)-expressing cells of the HS using a Cre-lox approach (Ctnnb1BM-GOF). FACS analysis revealed that Pdgfb is mainly expressed by megakaryocytic progenitors (MKPs), MKs and platelets. Recombination resulted in a lethal phenotype in mutants (Ctnnb1BM-GOFwt/fl, Ctnnb1BM-GOFfl/fl) 3 weeks after tamoxifen injection, showing an increase in MKs in the BM and spleen, but no pronounced anemia despite reduced erythrocyte counts. BM transplantation (BMT) of Ctnnb1BM-GOF BM into lethally irradiated wildtype recipients (BMT-Ctnnb1BM-GOF) confirmed the megakaryocytic, but not the lethal phenotype. CFU-MK assays in vitro with BM cells of Ctnnb1BM-GOF mice supported MK skewing at the expense of erythroid colonies. Molecularly, the runt-related transcription factor 1 (RUNX1) mRNA, known to suppress erythropoiesis, was upregulated in Ctnnb1BM-GOF BM cells. In conclusion, β-catenin activation plays a key role in cell-fate decision favoring MK development at the expense of erythroid production. [ABSTRACT FROM AUTHOR]

Published
2023
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31. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM)

Author

Bader, Peter, Kuçi, Zyrafete, Bakhtiar, Shahrzad, Basu, Oliver, Bug, Gesine, Dennis, Michael, Greil, Johann, Barta, Aniko, Kállay, Krisztián M., Lang, Peter, Lucchini, Giovanna, Pol, Raj, Schulz, Ansgar, Sykora, Karl-Walter, von Luettichau, Irene, Herter-Sprie, Grit, Uddin, Mohammad Ashab, 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

Published
2018
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34. Simulating Space Conditions Evokes Different DNA Damage Responses in Immature and Mature Cells of the Human Hematopoietic System.

Author

Handwerk, Leonie, Schreier, Heike Katrin, Kraft, Daniela, Shreder, Kateryna, Hemmersbach, Ruth, Hauslage, Jens, Bonig, Halvard, Wiesmüller, Lisa, Fournier, Claudia, and Rall-Scharpf, Melanie

Subjects
HEMATOPOIETIC system, DOUBLE-strand DNA breaks, ASTROPHYSICAL radiation, CD45 antigen, PROGENITOR cells, REDUCED gravity environments, SINGLE-stranded DNA, DNA damage
Abstract

The impact of space radiation and microgravity on DNA damage responses has been discussed controversially, largely due to the variety of model systems engaged. Here, we performed side-by-side analyses of human hematopoietic stem/progenitor cells (HSPC) and peripheral blood lymphocytes (PBL) cultivated in a 2D clinostat to simulate microgravity before, during and after photon and particle irradiation. We demonstrate that simulated microgravity (SMG) accelerates the early phase of non-homologous end joining (NHEJ)-mediated repair of simple, X-ray-induced DNA double-strand breaks (DSBs) in PBL, while repair kinetics in HSPC remained unaltered. Repair acceleration was lost with increasing LET of ion exposures, which increases the complexity of DSBs, precluding NHEJ and requiring end resection for successful repair. Such cell-type specific effect of SMG on DSB repair was dependent on the NF-кB pathway pre-activated in PBL but not HSPC. Already under unperturbed growth conditions HSPC and PBL suffered from SMG-induced replication stress associated with accumulation of single-stranded DNA and DSBs, respectively. We conclude that in PBL, SMG-induced DSBs promote repair of radiation-induced damage in an adaptive-like response. HSPC feature SMG-induced single-stranded DNA and FANCD2 foci, i.e., markers of persistent replication stress and senescence that may contribute to a premature decline of the immune system in space. [ABSTRACT FROM AUTHOR]

Published
2023
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35. ErbB2 (HER2)-CAR-NK-92 cells for enhanced immunotherapy of metastatic fusion-driven alveolar rhabdomyosarcoma.

Author

Heim, Catrin, Moser, Laura M., Kreyenberg, Herman, Bonig, Halvard B., Tonn, Torsten, Wels, Winfried S., Gradhand, Elise, Ullrich, Evelyn, Meister, Michael T., Koerkamp, Marian Groot, Holstege, Frank C. P., Drost, Jarno, Klusmann, Jan-Henning, Bader, Peter, Merker, Michael, and Rettinger, Eva

Subjects
RHABDOMYOSARCOMA, CHIMERIC antigen receptors, IMMUNOTHERAPY, METASTASIS, KILLER cells
Abstract

Introduction: Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for novel therapeutic strategies. Applying chimeric antigen receptor (CAR) technology to natural killer (NK) cells may offer safe, effective, and affordable therapies that enhance cancer immune surveillance. Methods: Here, we assess the efficacy of clinically usable CAR-engineered NK cell line NK-92/5.28.z against ErbB2-positive RMS in vitro and in a metastatic xenograft mouse model. Results: Our results show that NK-92/5.28.z cells effectively kill RMS cells in vitro and significantly prolong survival and inhibit tumorprogression inmice. The persistence of NK-92/5.28.z cells at tumor sites demonstrates efficient antitumor response, which could help overcome current obstacles in the treatment of solid tumors. Discussion: These findings encourage further development of NK-92/5.28.z cells as off-the-shelf immunotherapy for the treatment of metastatic RMS. [ABSTRACT FROM AUTHOR]

Published
2023
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41. Donor‐type red blood cell transfusion to deplete isoagglutinins prior to allogeneic stem cell transplantation from ABO major incompatible bone marrow donors.

Author

Jarisch, Andrea, Salzmann‐Manrique, Emilia, Soerensen, Jan, Sach, Gudrun, Rettinger, Eva, Willasch, Andre, Bakhtiar, Shahrzad, Klarmann, Dieter, Bräuninger, Susanne, Moser, Laura, Fekadu, Julia, Hutter, Martin, Klingebiel, Thomas, Klusmann, Jan‐Henning, Bader, Peter, and Bonig, Halvard

Subjects
RED blood cell transfusion, BLOOD group incompatibility, STEM cell transplantation, BONE marrow, ERYTHROCYTES
Abstract

Summary: ABO incompatibility affects approximately 40% of allogeneic stem cell transplants in Caucasian patient populations. Because bone marrow (BM), the preferred graft from paediatric sibling donors and for non‐malignant diseases, has a red blood cell (RBC) content similar to blood, anti‐donor isoagglutinins must either be depleted from the recipient or RBCs removed from the graft. To achieve tolerability of unmanipulated BM grafts, we used controlled infusions of donor ABO‐type RBC units to deplete isoagglutinins before the transplant. This retrospective study evaluates the outcomes of 52 ABO major incompatible BM transplants performed at our centre between 2007 and 2019. The use of donor‐type RBC transfusions was well tolerated. They effectively reduced isoagglutinins levels, typically achieving target titres after one (60%) or two (29%) transfusions. The approach allowed for successful and uneventful infusions of unmanipulated BM which provided timely engraftment. The transplant outcomes were not inferior to those of a matched‐pair control group of patients with ABO‐identical donors. [ABSTRACT FROM AUTHOR]

Published
2023
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42. Validation of an ICH Q2 Compliant Flow Cytometry-Based Assay for the Assessment of the Inhibitory Potential of Mesenchymal Stromal Cells on T Cell Proliferation.

Author

Piede, Natascha, Bremm, Melanie, Farken, Anne, Pfeffermann, Lisa-Marie, Cappel, Claudia, Bonig, Halvard, Fingerhut, Theres, Puth, Laura, Vogelsang, Kathrin, Peinelt, Andreas, Marschalek, Rolf, Müller, Matthias, Bader, Peter, Kuçi, Zyrafete, Kuçi, Selim, and Huenecke, Sabine

Subjects
MONONUCLEAR leukocytes, T cells, STROMAL cells, CELL proliferation
Abstract

Mesenchymal stromal cells (MSCs) have the potential to suppress pathological activation of immune cells and have therefore been considered for the treatment of Graft-versus-Host-Disease. The clinical application of MSCs requires a process validation to ensure consistent quality. A flow cytometry-based mixed lymphocyte reaction (MLR) was developed to analyse the inhibitory effect of MSCs on T cell proliferation. Monoclonal antibodies were used to stimulate T cell expansion and determine the effect of MSCs after four days of co-culture based on proliferation tracking with the violet proliferation dye VPD450. Following the guidelines of the International Council for Harmonisation (ICH) Q2 (R1), the performance of n = 30 peripheral blood mononuclear cell (PBMC) donor pairs was assessed. The specific inhibition of T cells by viable MSCs was determined and precision values of <10% variation for repeatability and <15% for intermediate precision were found. Compared to a non-compendial reference method, a linear correlation of r = 0.9021 was shown. Serial dilution experiments demonstrated a linear range for PBMC:MSC ratios from 1:1 to 1:0.01. The assay was unaffected by PBMC inter-donor variability. In conclusion, the presented MLR can be used as part of quality control tests for the validation of MSCs as a clinical product. [ABSTRACT FROM AUTHOR]

Published
2023
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43. S111: TREATMENT OF POST‐TRANSPLANT RELAPSE IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH BCP ALL USING CD19‐CAR‐T: A EUROPEAN RETROSPECTIVE ANALYSIS OF REAL‐WORLD DATA.

Author

Bader, Peter, Alsonso, Anna, Attarbaschi, Andishe, Bodmer, Nicole, Bonig, Halvard, Burridge, Saskia, Bourquin, Jean‐Pierre, Bücklein, Veit, Cario, Gunnar, Oporto Espuelas, Macarena, Feuhtinger, Tobias, Fuereder, Anna, Hauer, Julia, Hutter, Martin, Kałwak, Krzysztof, Künkele, Annette, Meisel, Roland, Mielcarek‐Siedziuk, Monika, Müller, Ingo, and Napolitano, Sara

Published
2023
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46. HIV-1 Infection of Long-Lived Hematopoietic Precursors In Vitro and In Vivo.

Author

Renelt, Sebastian, Schult-Dietrich, Patrizia, Baldauf, Hanna-Mari, Stein, Stefan, Kann, Gerrit, Bickel, Markus, Kielland-Kaisen, Ulrikke, Bonig, Halvard, Marschalek, Rolf, Rieger, Michael A., Dietrich, Ursula, and Duerr, Ralf

Subjects
HIV, HEMATOPOIETIC stem cells
Abstract

Latent reservoirs in human-immunodeficiency-virus-1 (HIV-1)-infected individuals represent a major obstacle in finding a cure for HIV-1. Hematopoietic stem and progenitor cells (HSPCs) have been described as potential HIV-1 targets, but their roles as HIV-1 reservoirs remain controversial. Here we provide additional evidence for the susceptibility of several distinct HSPC subpopulations to HIV-1 infection in vitro and in vivo. In vitro infection experiments of HSPCs were performed with different HIV-1 Env-pseudotyped lentiviral particles and with replication-competent HIV-1. Low-level infection/transduction of HSPCs, including hematopoietic stem cells (HSCs) and multipotent progenitors (MPP), was observed, preferentially via CXCR4, but also via CCR5-mediated entry. Multi-lineage colony formation in methylcellulose assays and repetitive replating of transduced cells provided functional proof of susceptibility of primitive HSPCs to HIV-1 infection. Further, the access to bone marrow samples from HIV-positive individuals facilitated the detection of HIV-1 gag cDNA copies in CD34+ cells from eight (out of eleven) individuals, with at least six of them infected with CCR5-tropic HIV-1 strains. In summary, our data confirm that primitive HSPC subpopulations are susceptible to CXCR4- and CCR5-mediated HIV-1 infection in vitro and in vivo, which qualifies these cells to contribute to the HIV-1 reservoir in patients. [ABSTRACT FROM AUTHOR]

Published
2022
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50. SARS‐CoV‐2‐specific T cells are generated in less than half of allogeneic HSCT recipients failing to seroconvert after COVID‐19 vaccination.

Author

Jarisch, Andrea, Wiercinska, Eliza, Daqiq‐Mirdad, Shabnam, Hellstern, Helen, Ajib, Salem, Cremer, Anjali, Nguyen, Ngoc Thien Thu, Dukat, Alexandra, Ullrich, Evelyn, Ciesek, Sandra, Chow, Kai‐Uwe, Serve, Hubert, Seifried, Erhard, Bader, Peter, Bonig, Halvard, and Bug, Gesine

Subjects
T cells, COVID-19 vaccines, HEMATOPOIETIC stem cell transplantation, LYMPHOCYTE subsets
Abstract

We conclude that the majority of allogeneic HSCT patients not showing humoral responses to SARS-CoV-2 vaccination also fail to mount antigen-specific T-cell responses. Patients 2, 4, and 1 demonstrated isolated helper T-cell, cytotoxic T-cell, and combined T-cell responses; the total probability of SARS-CoV-2-specific T-cell responses was 7/17 (41%), 5/13, and 2/3 after 2xComirnaty and 2xVaxzevria. SARS-CoV-2-specific T cells are generated in less than half of allogeneic HSCT recipients failing to seroconvert after COVID-19 vaccination Keywords: HSCT; SARS-CoV-2; SARS-CoV-2-specific T cells; vaccination EN HSCT SARS-CoV-2 SARS-CoV-2-specific T cells vaccination 1194 1197 4 07/13/22 20220701 NES 220701 Little is known about the cellular immune response to SARS-CoV-2 vaccination in patients after HSCT and B-NHL with iatrogenic B-cell aplasia. [Extracted from the article]

Published
2022
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