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1. Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Author

Ruggeri, Annalisa, de Wreede, Liesbeth C., Müller, Carlheinz R., Crivello, Pietro, Bonneville, Edouard F., Petersdorf, Effie W., Socié, Gerard, Dubois, Valérie, Niittyvuopio, Riitta, Peräsaari, Juha, Yakoub-Agha, Ibrahim, Cornelissen, Jan J., Wieten, Lotte, Gedde-Dahl, Tobias, Forcade, Edouard, Crawley, Charles R., Marsh, Steven G.E., Gandemer, Virginie, Tholouli, Eleni, Bulabois, Claude-Eric, Huynh, Anne, Choi, Goda, Deconinck, Eric, Itäla-Remes, Maija, Lenhoff, Stig, Bengtsson, Mats, Johansson, Jan-Erik, van Gorkom, Gwendolyn, Hoogenboom, Jorinde D., Vago, Luca, Rocha, Vanderson, Bonini, Chiara, Chabannon, Christian, Fleischhauer, Katharina, Clausen, Johannes, Holter, Wolfgang, Kalhs, Peter, Beguin, Yves, Bron, Dominique, Deeren, Dries, Lung, Wu Ka, Kerre, Tessa, Poiré, Xavier, Selleslag, Dominik, Schroyens, Wilfried, Jindra, Pavel, Mayer, Jiri, Vydra, Jan, Zák, Pavel, Nielsen, Bendt, Sengeloev, Henrik, Kaare, Ain, Partanen, Anu, Bay, Jacques-Olivier, Bertrand, Yves, Blaise, Didier, Bourhis, Jean Henri, Chevallier, Patrice, Cluzeau, Thomas, Damaj, Gandhi, Fegueux, Nathalie, Guyotat, Denis, Hunault-Berger, Mathilde, Labussière-Wallet, Hélène, Leleu, Xavier, Lioure, Bruno, Maury, Sebastien, Michel, Gérard, Mohty, Mohamad, Rubio, Marie Thérèse, Tilly, Herve, Turlure, Pascal, Bethge, Wolfgang, Casper, Jochen, Einsele, Hermann, Ganser, Arnold, Kröger, Nicolaus, Martin, Sonja, Platzbecker, Uwe, Reinhardt, Christian, Schäfer-Eckart, Kerstin, Thurner, Lorenz, Valerius, Thomas, Wulf, Gerald G., Karakasis, Dimitrios, Spyridonidis, Alexandros, Hauser, Peter, Reményi, Péter, Reykdal, Sigrun, Mousavi, Ashrafsadat, Angelucci, Emanuele, Arcese, William, Benedetti, Fabio, Bernasconi, Paolo, Biondi, Andrea, Bonifazi, Francesca, Carella, Angelo Michele, Carluccio, Paola, Casini, Marco, Cavanna, Luigi, Ciceri, Fabio, Cimino, Giuseppe, Corradini, Paolo, Fanin, Renato, Galieni, Piero, Grillo, Giovanni, Iori, Anna Paola, La Nasa, Giorgio, Locatelli, Franco, Marotta, Giuseppe, Martino, Massimo, Mazza, Patrizio, Mordini, Nicola, Musso, Maurizio, Olivieri, Attilio, Pavone, Vincenzo, Pane, Fabrizio, Petrini, Mario, Pioltelli, Pietro, Rambaldi, Alessandro, Ruggeri, Marco, Saccardi, Riccardo, Santarone, Stella, Scimè, Rosanna, Sica, Simona, Tarella, Corrado, Velardi, Andrea, Visani, Giuseppe, Zecca, Marco, Tanase, Alina, Kulagin, Aleksandr, Savchenko, Valery, López, Carmen Albo, Amor, Adrián Alegre, López, Jose Luis Bello, Caballero, Dolores, Duarte, Rafael, Cascon, Maria Jesús Pascual, Porras, Rocio Parody, Pérez-Simón, Jose Antonio, Rovira, Montserrat, Sanz, Jaime, Carrete, Juan Pio Torres, Cammenga, Jörg, Isaksson, Cecilia, Mielke, Stephan, Chalandon, Yves, Passweg, Jakob, Schanz, Urs, Meijer, Ellen, Kuball, Jürgen, Veelken, Joan Hendrik, Apperley, Jane, Bloor, Adrian, Byrne, Jenny, Carpenter, Ben, Clark, Andrew, Collin, Matthew, Craddock, Charles, Gibson, Brenda E., Khan, Anjum, Martin, Murray, Medd, Patrick, Nicholson, Emma, Orchard, Kim, Patel, Amit, Peniket, Andy, Potter, Victoria, Snowden, John, Wilson, Keith M.O., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Transplant. Immunology/Tissue Typing lab, Interne Geneeskunde, MUMC+: MA Hematologie (9), Hematology, IRCCS San Raffaele Scientific Institute [Milan, Italie], EFS, CHU Lille, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Oslo University Hospital [Oslo], CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Groningen [Groningen], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), and Essen University Hospital

Subjects
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, [SDV]Life Sciences [q-bio], HSCT, Medizin, Hematology, Hematologi
Abstract

International audience; Not available.

Published
2023

2. Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control

Author

Johanna, Inez, Hernández-López, Patricia, Heijhuurs, Sabine, Scheper, Wouter, Bongiovanni, Laura, de Bruin, Alain, Beringer, Dennis X, Oostvogels, Rimke, Straetemans, Trudy, Sebestyen, Zsolt, Kuball, Jürgen, dPB RMSC, Pathobiologie, Dep Biomolecular Health Sciences, Sub Crystal and Structural Chemistry, dPB RMSC, Pathobiologie, Dep Biomolecular Health Sciences, and Sub Crystal and Structural Chemistry

Subjects
Adoptive cell transfer, CD8 Antigens, mouse model, medicine.medical_treatment, efficacy, Immunology, HLA-A24 Antigen, Mice, Transgenic, Spleen, Major histocompatibility complex, Immunotherapy, Adoptive, Mice, Cancer immunotherapy, Neoplasms, medicine, Animals, Humans, Immunology and Allergy, Receptor, Original Research, Receptors, Chimeric Antigen, cancer immunotherapy, biology, Chemistry, preclinical (in vivo) studies, Receptors, Antigen, T-Cell, gamma-delta, persistence, RC581-607, TCR engineering, Chimeric antigen receptor, medicine.anatomical_structure, human leukocyte antigens (HLA), Cancer research, biology.protein, Bone marrow, Immunologic diseases. Allergy, CD8, TEGs
Abstract

γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8+ TEG011. We subsequently explored the concept of additional redirection of CD4+ T cells through co-expression of the human CD8α gene into CD4+ and CD8+ TEG011 cells, later referred as TEG011_CD8α. Adoptive transfer of TEG011_CD8α cells in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mice injected with tumor HLA-A*24:02+ cells showed superior tumor control in comparison to TEG011, and to mock control groups. The total percentage of mice with persisting TEG011_CD8α cells, as well as the total number of TEG011_CD8α cells per mice, was significantly improved over time, mainly due to a dominance of CD4+CD8+ double-positive TEG011_CD8α, which resulted in higher total counts of functional T cells in spleen and bone marrow. We observed that tumor clearance in the bone marrow of TEG011_CD8α-treated mice associated with better human T cell infiltration, which was not observed in the TEG011-treated group. Overall, introduction of transgenic human CD8α receptor on TEG011 improves antitumor reactivity against HLA-A*24:02+ tumor cells and further enhances in vivo tumor control.

Published
2021

3. Cell-density independent increased lymphocyte production and loss rates post-autologous HSCT

Author

Baliu-Piqué, Mariona, van Hoeven, Vera, Drylewicz, Julia, van der Wagen, Lotte E., Janssen, Anke, Otto, Sigrid A., van Zelm, Menno C., de Boer, Rob J., Kuball, Jürgen, Borghans, Jose A.M., Tesselaar, Kiki, Sub Theoretical Biology, Theoretical Biology and Bioinformatics, Sub Theoretical Biology, and Theoretical Biology and Bioinformatics

Subjects
Male, 0301 basic medicine, autologous hematopoietic, medicine.medical_treatment, Cell, Hematopoietic stem cell transplantation, Biochemistry, Immunology and Inflammation, 0302 clinical medicine, lymphocyte dynamics, Cell density, Lymphocytes, deuterium labeling, Biology (General), General Neuroscience, Hematopoietic Stem Cell Transplantation, mathematical modeling, General Medicine, Middle Aged, lymphopenia, Lymphocyte production, medicine.anatomical_structure, Medicine, Female, medicine.symptom, Research Article, Human, Adult, QH301-705.5, Science, Neuroscience(all), Inflammation, Biology, Transplantation, Autologous, stem cell transplantation, General Biochemistry, Genetics and Molecular Biology, Normal cell, 03 medical and health sciences, In vivo, Immunology and Microbiology(all), medicine, Humans, Lymphocyte Count, General Immunology and Microbiology, Biochemistry, Genetics and Molecular Biology(all), Autologous hsct, 030104 developmental biology, Immunology, Genetics and Molecular Biology(all), 030215 immunology
Abstract

Lymphocyte numbers need to be quite tightly regulated. It is generally assumed that lymphocyte production and lifespan increase homeostatically when lymphocyte numbers are low and, vice versa, return to normal once cell numbers have normalized. This widely accepted concept is largely based on experiments in mice, but is hardly investigated in vivo in humans. Here we quantified lymphocyte production and loss rates in vivo in patients 0.5–1 year after their autologous hematopoietic stem cell transplantation (autoHSCT). We indeed found that the production rates of most T- and B-cell subsets in autoHSCT-patients were two to eight times higher than in healthy controls, but went hand in hand with a threefold to ninefold increase in cell loss rates. Both rates also did not normalize when cell numbers did. This shows that increased lymphocyte production and loss rates occur even long after autoHSCT and can persist in the face of apparently normal cell numbers.

Published
2021

4. Additional file 1 of Allogeneic hematopoietic cell transplantation with cord blood versus mismatched unrelated donor with post-transplant cyclophosphamide in acute myeloid leukemia

Author

Dholaria, Bhagirathbhai, Labopin, Myriam, Sanz, Jaime, Ruggeri, Annalisa, Cornelissen, Jan, Labussière-Wallet, Hélène, Blaise, Didier, Forcade, Edouard, Chevallier, Patrice, Grassi, Anna, Zubarovskaya, Ludmila, Kuball, Jürgen, Ceballos, Patrice, Ciceri, Fabio, Baron, Frederic, Bipin N. Savani, Nagler, Arnon, and Mohty, Mohamad

Abstract

Additional file 1. Supplementary material.

Published
2021
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5. A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance

Author

Langenhorst, Jurgen B., Boss, Jill, van Kesteren, Charlotte, Lalmohamed, Arief, Kuball, Jürgen, Egberts, Antoine C.G., Boelens, Jaap Jan, Huitema, Alwin D.R., van Maarseveen, Erik M., Afd Pharmacoepi & Clinical Pharmacology, and Pharmacoepidemiology and Clinical Pharmacology

Subjects
Pharmacology, drug safety – clinical pharmacology, therapeutic drug monitoring – clinical pharmacology, chemotherapy – oncology, Pharmacology (medical), pharmacokinetics
Abstract

Aim: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. Methods: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. Results: In both models, a similar clearance decrease of 7% (range −82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6–8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0–73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. Conclusion: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.

Published
2020

6. Prevention of Vγ9Vδ2 T cell activation by a Vγ9Vδ2 TCR nanobody

Author

de Bruin, Renée C G, Stam, Anita G M, Vangone, Anna, van Bergen En Henegouwen, Paul M P, Verheul, Henk M W, Sebestyén, Zsolt, Kuball, Jürgen, Bonvin, Alexandre M J J, de Gruijl, Tanja D, van der Vliet, Hans J, Celbiologie, Sub NMR Spectroscopy, Sub Cell Biology, NMR Spectroscopy, CCA - Cancer biology and immunology, Medical oncology laboratory, AII - Cancer immunology, Medical oncology, Celbiologie, Sub NMR Spectroscopy, Sub Cell Biology, and NMR Spectroscopy

Subjects
0301 basic medicine, T cell, Immunology, Biology, Lymphocyte Activation, Proinflammatory cytokine, Cell Line, 03 medical and health sciences, Immune system, Antigen, T-Lymphocyte Subsets, Journal Article, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, T-cell receptor, Models, Immunological, Receptors, Antigen, T-Cell, gamma-delta, Flow Cytometry, Molecular biology, Antibodies, Neutralizing, 3. Good health, Cell biology, Molecular Docking Simulation, 030104 developmental biology, medicine.anatomical_structure, Cell culture, CD8, Single-Chain Antibodies
Abstract

Vγ9Vδ2 T cell activation plays an important role in antitumor and antimicrobial immune responses. However, there are conditions in which Vγ9Vδ2 T cell activation can be considered inappropriate for the host. Patients treated with aminobisphosphonates for hypercalcemia or metastatic bone disease often present with a debilitating acute phase response as a result of Vγ9Vδ2 T cell activation. To date, no agents are available that can clinically inhibit Vγ9Vδ2 T cell activation. In this study, we describe the identification of a single domain Ab fragment directed to the TCR of Vγ9Vδ2 T cells with neutralizing properties. This variable domain of an H chain–only Ab (VHH or nanobody) significantly inhibited both phosphoantigen-dependent and -independent activation of Vγ9Vδ2 T cells and, importantly, strongly reduced the production of inflammatory cytokines upon stimulation with aminobisphosphonate-treated cells. Additionally, in silico modeling suggests that the neutralizing VHH binds the same residues on the Vγ9Vδ2 TCR as the Vγ9Vδ2 T cell Ag-presenting transmembrane protein butyrophilin 3A1, providing information on critical residues involved in this interaction. The neutralizing Vγ9Vδ2 TCR VHH identified in this study might provide a novel approach to inhibit the unintentional Vγ9Vδ2 T cell activation as a consequence of aminobisphosphonate administration.

Published
2017

7. Tyrosine kinase inhibitor levels matter in treating chronic GVHD

Author

van der Wagen, Lotte, Janssen, Julie, Raijmakers, Reinier, Petersen, Eefke, de Witte, Moniek, de Jong, Niels, Bellido, Mar, Meijer, Ellen, Bär, Brigitte, Jan Boelens, Jaap, Huitema, Alwin, and Kuball, Jürgen

Subjects
Transplantation, surgical procedures, operative, Hematology
Abstract

We observed a possible concentration effect relationship for nilotinib on resolution of chronic Graft versus Host disease.These data suggest therapeutic drug monitoring might be useful for patients receiving tyrosine kinase inhibitors for chronic GVHD.

Published
2019

8. Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells

Author

Johanna, Inez, Straetemans, Trudy, Heijhuurs, Sabine, Aarts-Riemens, Tineke, Norell, Håkan, Bongiovanni, Laura, de Bruin, Alain, Sebestyen, Zsolt, Kuball, Jürgen, LS Pathobiologie, dPB RMSC, Repositório da Universidade de Lisboa, LS Pathobiologie, and dPB RMSC

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Mice, 0302 clinical medicine, AML, Immunology and Allergy, Immunotherapy, Mice model, Preclinical, TCR engineering, TEGs, Toxicity, Immunology, Molecular Medicine, Oncology, Pharmacology, medicine.diagnostic_test, Histocytochemistry, Myeloid leukemia, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Leukemia, Haematopoiesis, 030220 oncology & carcinogenesis, Clone (B-cell biology), Research Article, Antineoplastic Agents, lcsh:RC254-282, Flow cytometry, 03 medical and health sciences, Antigens, CD, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Progenitor cell, Blood Cells, Butyrophilins, business.industry, Hematopoietic Stem Cells, medicine.disease, Xenograft Model Antitumor Assays, Hematopoiesis, Disease Models, Animal, 030104 developmental biology, Cancer research, business
Abstract

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated., Background: γ9δ2T cells, which express Vγ9 and Vδ2 chains of the T cell receptor (TCR), mediate cancer immune surveillance by sensing early metabolic changes in malignant leukemic blast and not their healthy hematopoietic stem counterparts via the γ9δ2TCR targeting joined conformational and spatial changes of CD277 at the cell membrane (CD277J). This concept led to the development of next generation CAR-T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. The high affinity γ9δ2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). However, exploring safety and efficacy against a target, which reflects an early metabolic change in tumor cells, remains challenging given the lack of appropriate tools. Therefore, we tested whether TEG001 is able to eliminate established leukemia in a primary disease model, without harming other parts of the healthy hematopoiesis in vivo. Methods: Separate sets of NSG mice were respectively injected with primary human acute myeloid leukemia (AML) blasts and cord blood-derived human progenitor cells from healthy donors. These mice were then treated with TEG001 and mock cells. Tumor burden and human cells engraftment were measured in peripheral blood and followed up over time by quantifying for absolute cell number by flow cytometry. Statistical analysis was performed using non-parametric 2-tailed Mann-Whitney t-test. Results: We successfully engrafted primary AML blasts and healthy hematopoietic cells after 6-8 weeks. Here we report that metabolic cancer targeting through TEG001 eradicated established primary leukemic blasts in vivo, while healthy hematopoietic compartments derived from human cord-blood remained unharmed in spite of TEGs persistence up to 50 days after infusion. No additional signs of off-target toxicity were observed in any other tissues. Conclusion: Within the limitations of humanized PD-X models, targeting CD277J by TEG001 is safe and efficient. Therefore, we have initiated clinical testing of TEG001 in a phase I first-in-human clinical trial (NTR6541; date of registration 25 July 2017).

Published
2019

9. Additional file 5: of Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells

Author

Johanna, Inez, Straetemans, Trudy, Heijhuurs, Sabine, Aarts-Riemens, Tineke, Norell, Håkan, Bongiovanni, Laura, Bruin, Alain De, Sebestyen, Zsolt, and Kuball, Jürgen

Abstract

Figure S3. In vivo efficacy profile of TEG001 in PD-X model of primary blast in NSG-SGM3 mice. (A) Schematic overview of in vivo experiment. NSG-SGM3 mice were irradiated at day 0 and engrafted with primary AML cells at day 1. AML cells were followed-up in the peripheral blood by flow cytometry. Mice received 2 injections of therapeutic TEG001 or TEG-LM1 mock in the presence of PAM (at Day 8 and 16) and IL-2 (at Day 8); (B) Tumor burden for primary AML was measured in peripheral blood by quantifying for absolute cell number by flow cytometry. Data represent mean ± SD of all mice per group (n = 5 mice/group). Statistical significances were calculated by non-parametric 2-tailed Mann-Whitney t-test; *, P

Published
2019
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10. Additional file 6: of Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells

Author

Johanna, Inez, Straetemans, Trudy, Heijhuurs, Sabine, Aarts-Riemens, Tineke, Norell, Håkan, Bongiovanni, Laura, Bruin, Alain De, Sebestyen, Zsolt, and Kuball, Jürgen

Abstract

Figure S4. Gating strategy for flow cytometry analysis of healthy hematopoietic compartments. A representative flow cytometry plot of murine peripheral blood. (A) Engraftment was determined by quantifying absolute cell number of viable huCD45+ of healthy stem cells; (B) Hematopoietic cellular compartments outgrowth were determined by quantifying absolute cell number for CD19+ B cells, CD3+ T cells, and CD14+ monocytes. Also, persistence of TEGs were determined by quantifying absolute cell number for γδTCR+ cells. (PPTX 225 kb)

Published
2019
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11. Additional file 4: of Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells

Author

Johanna, Inez, Straetemans, Trudy, Heijhuurs, Sabine, Aarts-Riemens, Tineke, Norell, Håkan, Bongiovanni, Laura, Bruin, Alain De, Sebestyen, Zsolt, and Kuball, Jürgen

Abstract

Figure S1. γδTCR expression of TEG001 and TEG-LM1 mock. A representative flow cytometry plot γδTCR expression of TEG001 and TEG-LM1 mock after transductions, after αβTCR depletion and prior to infusion into mice after 2 weeks expansion. (PPTX 191 kb)

Published
2019
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12. Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

Author

Geneugelijk, Kirsten, Thus, Kirsten A., Van Deutekom, Hanneke W.M., Calis, Jorg J.A., Borst, Eric, Keşmir, Can, Oudshoorn, Machteld, Van Der Holt, Bronno, Meijer, Ellen, Zeerleder, Sacha, De Groot, Marco R., Von Dem Borne, Peter A., Schaap, Nicolaas, Cornelissen, Jan, Kuball, Jürgen, Spierings, Eric, Sub Theoretical Biology & Bioinformatics, Sub Theoretical Biology, Theoretical Biology and Bioinformatics, AII - Inflammatory diseases, Hematology, CCA - Cancer biology and immunology, Sub Theoretical Biology & Bioinformatics, Sub Theoretical Biology, Theoretical Biology and Bioinformatics, Clinical Haematology, ACS - Pulmonary hypertension & thrombosis, and Faculteit Medische Wetenschappen/UMCG

Subjects
Male, 0301 basic medicine, Oncology, HLA mismatch, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Disease, Epitope, Epitopes, MOLECULES, 0302 clinical medicine, HLA Antigens, VERSUS-HOST-DISEASE, Immunology and Allergy, Child, Original Research, UNRELATED-DONOR, biology, Non-permissible mismatch, Hematopoietic Stem Cell Transplantation, HSCT-hematopoietic stem cell transplant, Middle Aged, HLA, HLA-DPB1, HISTOCHECK, Child, Preschool, PIRCHE, Cohort, Female, DETERMINES NONPERMISSIVE MISMATCHES, Antibody, Unrelated Donors, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, HSCT—hematopoietic stem cell transplant, Adolescent, Immunology, Human leukocyte antigen, ACUTE GVHD, Young Adult, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Transplantation Immunology, Internal medicine, medicine, Journal Article, Humans, Aged, Proportional Hazards Models, business.industry, Infant, CLASS-I MISMATCHES, HLA Mismatch, Transplantation, 030104 developmental biology, ANTIBODIES, biology.protein, lcsh:RC581-607, business, RECIPIENT, 030215 immunology
Abstract

HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient's mismatched-HLA molecules that can be presented by donor-patient shared HLA. We retrospectively scored PIRCHE numbers either presented on HLA class-I (PIRCHE-I) or class-II (PIRCHE-II) for a Dutch multicenter cohort of 103 patients who received a single HLA-mismatched (9/10) unrelated donor transplant in an early phase of their disease. These patients were divided into low and high PIRCHE-I and PIRCHE-II groups, based on their PIRCHE scores, and compared using multivariate statistical analysis methods. The high PIRCHE-II group had a significantly impaired OS compared to the low PIRCHE-II group and the 10/10 reference group (HR: 1.86, 95%-CI: 1.02-3.40; and HR: 2.65, 95%-CI: 1.53-4.60, respectively). Overall, PIRCHE-II seem to have a more prominent effect on OS than PIRCHE- I. This impaired OS is probably due to an increased risk for severe acute graft-vs.-host disease. These data suggest that high PIRCHE-II scores may be used to identify non-permissible HLA mismatches within single HLA-mismatched hematopoietic stem-cell transplantations.

Published
2019

13. Erratum : Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, Nimitha R, Baumgartner, Francis, Braun, Lukas, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Markus, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thomas, Schroeder, Thomas, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandros, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yves, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolaus, Ayuk, Francis, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, van der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andreas, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, McLornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Shah, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andreas, Neubauer, Andreas, Beelen, Dietrich, Mackensen, Andreas, von Bubnoff, Nikolas, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justus, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Abstract

This corrects the article DOI: 10.1038/nm.4484.

Published
2018

14. Manufacturing mesenchymal stromal cells for the treatment of graft-versus-host disease

Author

Trento, Cristina, Bernardo, Maria Ester, Nagler, Arnon, Kuçi, Selim, Bornhäuser, Martin, Köhl, Ulrike, Strunk, Dirk, Galleu, Antonio, Sanchez-Guijo, F., Gaipa, Giuseppe, Introna, Martino, Bukauskas, Adomas, Blanc, Katarina le, Apperley, Jane, Roelofs, Hélène, Campenhout, Ann van, Béguin, Yves P., Kuball, Jürgen H.E., Lazzari, Lorenza, Avanzini, Maria Antonietta, Fibbe, Willem E., Chabannon, Christian, Bonini, Chiara, Dazzi, Francesco, and Publica

Subjects
mesenchymal stem cells, mesenchymale Stammzelle, mesenchymale Zelle, Graft-Versus-Host-Disease
Abstract

The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients' stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.

Published
2018

15. Correction: Prevention of Vγ9Vδ2 T Cell Activation by a Vγ9Vδ2 TCR Nanobody

Author

de Bruin, Renée C G, Stam, Anita G M, Vangone, Anna, van Bergen En Henegouwen, Paul M P, Verheul, Henk M W, Sebestyén, Zsolt, Kuball, Jürgen, Bonvin, Alexandre M J J, de Gruijl, Tanja D, van der Vliet, Hans J, Sub Biomolecular Imaging, Sub NMR Spectroscopy, Sub Cell Biology, and NMR Spectroscopy

Subjects
Taverne
Published
2017

16. Correction: Prevention of Vγ9Vδ2 T Cell Activation by a Vγ9Vδ2 TCR Nanobody

Author

de Bruin, Renée C G, Stam, Anita G M, Vangone, Anna, van Bergen En Henegouwen, Paul M P, Verheul, Henk M W, Sebestyén, Zsolt, Kuball, Jürgen, Bonvin, Alexandre M J J, de Gruijl, Tanja D, van der Vliet, Hans J, Sub Biomolecular Imaging, Sub NMR Spectroscopy, Sub Cell Biology, and NMR Spectroscopy

Subjects
Taverne
Published
2017

18. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, Nimitha R, Baumgartner, Francis, Braun, Lukas, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Markus, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst Müller, Thomas Niklaus, Schroeder, Thomas, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandros, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-De-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yves, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolaus, Ayuk, Francis, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, Van Der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andreas, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, McLornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Shah, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andreas, Neubauer, Andreas, Beelen, Dietrich, Mackensen, Andreas, Von Bubnoff, Nikolas, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justus, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Subjects
hemic and lymphatic diseases, 610 Medicine & health, neoplasms, 3. Good health
Abstract

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

19. Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation

Author

Maria Ester Bernardo, Katarina Le Blanc, Yves Beguin, Martino Introna, Cristina Trento, Jane F. Apperley, Chiara Bonini, Francesco Dazzi, Fermín Sánchez-Guijo, Selim Kuçi, Ulrike Köhl, Helene Roelofs, Giuseppe Gaipa, Lorenza Lazzari, Jürgen Kuball, Dirk Strunk, Antonio Galleu, Martin Bornhäuser, Maria Antonietta Avanzini, Christian Chabannon, Arnon Nagler, Adomas Bukauskas, Willem E. Fibbe, Ann Van Campenhout, Trento, Cristina, Bernardo, Maria Ester, Nagler, Arnon, Kuçi, Selim, Bornhäuser, Martin, Köhl, Ulrike, Strunk, Dirk, Galleu, Antonio, Sanchez-Guijo, Fermin, Gaipa, Giuseppe, Introna, Martino, Bukauskas, Adoma, Le Blanc, Katarina, Apperley, Jane, Roelofs, Helene, Van Campenhout, Ann, Beguin, Yve, Kuball, Jürgen, Lazzari, Lorenza, Avanzini, Maria Antonietta, Fibbe, Willem, Chabannon, Christian, Bonini, Chiara, and Dazzi, Francesco

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Immunology, Cellular therapy, Mesenchymal stromal cells, Graft vs Host Disease, Umbilical cord, Graft-versus-host disease, Article, Cell therapy, 03 medical and health sciences, Release criteria, hematología, Internal medicine, Surveys and Questionnaires, medicine, Humans, Transplantation, Hematology, business.industry, 3205.04 Hematología, Mesenchymal stem cell, 1103 Clinical Sciences, Mesenchymal Stem Cells, medicine.disease, Clinical trial, Europe, Manufacturing, 030104 developmental biology, medicine.anatomical_structure, Product specification, células del estroma mesenquimatoso, enfermedad injerto contra huésped, Bone marrow, business
Abstract

Highlights • Seventeen EBMT centers participated to a questionnaire on MSC manufacturing. • 88% of centers manufacture MSC from bone marrow and only 2 centers from umbilical cord. • Human platelet lysate has replaced bovine serum as culture medium supplement. • Release criteria extensively differ among centers. • The results highlight the need to harmonize MSC manufacturing., The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients’ stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.

Published
2018

20. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

Author

Christophe Picard, Cécile Macquin, Sergi Querol, Catherine Paillard, Katharina Fleischhauer, Gaëlle Giacometti, Bronno van der Holt, Ibrahim Yakoub-Agha, Wassila Ilias, Anne Cesbron, Myriam Labopin, Masao Ota, Jorge Sierra, Fabio Ciceri, Dominique Charron, Ryad Tamouza, Régis Peffault de Latour, Xavier Lafarge, Katia Gagne, Seiamak Bahram, Myriam Maumy-Bertrand, Meiggie Untrau, Pascale Loiseau, Raphael Carapito, Jürgen Kuball, Bruno Lioure, Frans H.J. Claas, Noel Milpied, Antoine Toubert, Jan J. Cornelissen, Irina Kotova, Philippe Moreau, Eric Spierings, Mauricette Michallet, Arnon Nagler, Annette Schmitt-Graeff, Angélique Pichot, Petya Apostolova, Mohamad Mohty, Aurore Morlon, Myriam Labalette, Nicolas Jung, Didier Blaise, Yoshihiko Katsuyama, Hidetoshi Inoko, A. Parissiadis, Frédéric Bertrand, Marius Kwemou, Sandra Michel, Machteld Oudshoorn, Gérard Socié, Robert Zeiser, Peter A. von dem Borne, Valérie Dubois, Luca Vago, Carapito, Raphael, Jung, Nicola, Kwemou, Mariu, Untrau, Meiggie, Michel, Sandra, Pichot, Angélique, Giacometti, Gaëlle, Macquin, Cécile, Ilias, Wassila, Morlon, Aurore, Kotova, Irina, Apostolova, Petya, Schmitt Graeff, Annette, Cesbron, Anne, Gagne, Katia, Oudshoorn, Machteld, Van Der Holt, Bronno, Labalette, Myriam, Spierings, Eric, Picard, Christophe, Loiseau, Pascale, Tamouza, Ryad, Toubert, Antoine, Parissiadis, Anne, Dubois, Valérie, Lafarge, Xavier, Maumy Bertrand, Myriam, Bertrand, Frédéric, Vago, Luca, Ciceri, Fabio, Paillard, Catherine, Querol, Sergi, Sierra, Jorge, Fleischhauer, Katharina, Nagler, Arnon, Labopin, Myriam, Inoko, Hidetoshi, Von Dem Borne, Peter A., Kuball, Jürgen, Ota, Masao, Katsuyama, Yoshihiko, Michallet, Mauricette, Lioure, Bruno, De Latour, Régis Peffault, Blaise, Didier, Cornelissen, Jan J., Yakoub Agha, Ibrahim, Claas, Fran, Moreau, Philippe, Milpied, Noël, Charron, Dominique, Mohty, Mohamad, Zeiser, Robert, Socié, Gérard, Bahram, Seiamak, inconnu, Inconnu, Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'Etudes et de recherches en Statistiques et Développement (LERSTAD), Université Gaston Bergé Sénégal, Laboratoire d'Acoustique Environnementale (IFSTTAR/AME/LAE), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Lyon-PRES Université Nantes Angers Le Mans (UNAM), Physique des interactions ioniques et moléculaires (PIIM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Etablissement Français du Sang [Nantes], Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Service de pneumologie [Rennes] = Pneumology [Rennes], CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sociétés, Acteurs, Gouvernement en Europe (SAGE), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne (PRISME-GSPE), Centre National de la Recherche Scientifique (CNRS), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Ospedale San Raffaele, Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Barcelona Cord Blood Bank, Agrosystèmes tropicaux (ASTRO), Institut National de la Recherche Agronomique (INRA), Chaim Sheba Medical Center [Ramat Gan, Israel], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Université Paris Diderot - Paris 7 (UPD7), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigations Biomédicales-Hématologie, Oncologie et Greffes (CIB-HOG), Hôpital St Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Centre d'Investigations Biomédicales-Hématologie, Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-ENSIIE-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), ALWP-EBMT & Département d'hématologie et de thérapie cellulaire [AP-HP Hôpital Saint-Antoine], AP-HP - Hôpital Saint-Antoine, Hematology, Institut de Recherche Mathématique Avancée ( IRMA ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Mathématiques et Modélisation d'Evry ( LaMME ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -ENSIIE-Centre National de la Recherche Scientifique ( CNRS ), laboratoire d'Etudes et de recherches en Statistiques et Développement ( LERSTAD ), Laboratoire d'Acoustique Environnementale ( IFSTTAR/AME/LAE ), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université de Lyon-PRES Université Nantes Angers Le Mans ( UNAM ), Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré ( LHSP ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Physique des interactions ioniques et moléculaires ( PIIM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Functional Genomics and Cancer, Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne ( PRISME-GSPE ), Centre National de la Recherche Scientifique ( CNRS ), Centre de Transfusion Sanguine Aquitaine-Limousin ( CTS AQUITAINE-LIMOUSIN ), Géographie de l'environnement ( GEODE ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse - Jean Jaurès ( UT2J ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Agrosystèmes tropicaux ( ASTRO ), Institut National de la Recherche Agronomique ( INRA ), Hospices Civils de Lyon ( HCL ), IFR Saint-Louis, institut d'hématologie ( ISLIH ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC University medical Centre / Daniel den Hoed Cancer centre, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Laboratoire de Mathématiques et Modélisation d'Evry, PRES Université Nantes Angers Le Mans (UNAM)-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-ENSIIE-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, Graft vs Host Disease, Hematopoietic stem cell transplantation, Biochemistry, Linkage Disequilibrium, immune system diseases, HLA Antigens, Cytotoxic T cell, Child, ComputingMilieux_MISCELLANEOUS, HLA-DQB1, biology, Histocompatibility Testing, Incidence, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Allografts, 3. Good health, surgical procedures, operative, NK Cell Lectin-Like Receptor Subfamily K, Child, Preschool, Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, Adolescent, Immunology, Human leukocyte antigen, 03 medical and health sciences, MHC class I, medicine, Journal Article, Humans, Aged, Retrospective Studies, Transplantation, [ SDV ] Life Sciences [q-bio], Histocompatibility Antigens Class I, Infant, Newborn, Infant, Cell Biology, medicine.disease, Histocompatibility, stomatognathic diseases, 030104 developmental biology, Graft-versus-host disease, Chronic Disease, biology.protein
Abstract

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

Published
2016

21. Immune monitoring in allogeneic hematopoietic stem cell transplant recipients: a survey from the EBMT-CTIWP

Author

Fabio Ciceri, Jacopo Peccatori, Giacomo Oliveira, Jürgen Kuball, Maddalena Noviello, Ulrike Koehl, Antoine Toubert, Ebmt Cellular Therapy, Chiara Bonini, Katharina Fleischhauer, Christian Chabannon, Nicoletta Cieri, Francesco Dazzi, Attilio Bondanza, Dirk-Jan Eikema, Vanderson Rocha, Raffaella Greco, Steffie van der Werf, Annalisa Ruggeri, Luca Vago, Sofie Rosanne Terwel, Greco, Raffaella, Ciceri, Fabio, Noviello, Maddalena, Bondanza, Attilio, Vago, Luca, Oliveira, Giacomo, Peccatori, Jacopo, Cieri, Nicoletta, Ruggeri, Annalisa, Koehl, Ulrike, Fleischhauer, Katharina, Rocha, Vanderson, Dazzi, Francesco, van der Werf, Steffie Maria, Eikema, Dirk-Jan, Terwel, Sofie Rosanne, Kuball, Jürgen, Toubert, Antoine, Chabannon, Christian, and Bonini, Chiara

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Medizin, MEDLINE, Immune monitoring, 03 medical and health sciences, 0302 clinical medicine, Monitoring, Immunologic, Internal medicine, Surveys and Questionnaires, medicine, Humans, Transplantation, Homologous, Transplantation, Hematology, business.industry, Hematopoietic Stem Cell Transplantation, Transplant Recipients, 030104 developmental biology, Multicenter study, Transplantation, Haploidentical, Allogeneic hematopoietic stem cell transplant, business, Unrelated Donors, 030215 immunology
Published
2018

22. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Donald Bunjes, Sebastian Halbach, Dietmar Pfeifer, Philipp Hemmati, Robert S. Negrin, Fabio Ciceri, Jean-Yves Cahn, Markus Ditschkowski, Pavan Reddy, Kathrin Hanke, Daniela Dörfel, Susan Klaeger, Jürgen Finke, Zehan Hu, Gabriele Ihorst, Gérard Socié, Sanaz Taromi, Andreas Hochhaus, Glen A Kennedy, Omid Shah, Andreas Neubauer, Robert Thimme, Michael Schultheiss, Sabine Spath, Dietrich W. Beelen, Sandra Duquesne, Arnim Weber, Geoffrey R. Hill, Ronjon Chakraverty, Jürgen Kuball, Guido Kobbe, Nikolas von Bubnoff, Andrea S. Henden, Betul Oran, Burkhard Becher, Bernhard Kuster, Christoph Rummelt, Lena Osswald, Hartmut Bertz, Wolfgang Bethge, Eva-Maria Wagner, Arnon Nagler, Eliana Ruggiero, Saar Gill, Miguel Waterhouse, Andreas Mackensen, Dominik Bettinger, Francis Baumgartner, Florian Kuchenbauer, Anita Sarma, Takanori Teshima, Erika L. Pearce, Antonia M.S. Müller, Kathleen Stabla, John M. Magenau, Evelyn Ullrich, Nicolaus Kröger, Georg Häcker, Simone Thomas, Myriam Labopin, Ghulam J. Mufti, Jan E. Ehlert, Lutz P. Müller, Marie Follo, Dominik Wolf, Tony Andreas Müller, Michael Lübbert, Jacqueline Schnell, Christof Scheid, Takeshi Kondo, Donal P. McLornan, Thomas Pabst, Konrad Wilhelm, Chiara Bonini, Wolf Rösler, Simon Richardson, Cordula A. Jilg, Andrea Schmidts, Luca Vago, Joseph H. Antin, Annette Schmitt-Graeff, Yakup Tanriver, Michael A. Caligiuri, Wolfgang Herr, Kai-Li Yan, Lukas Braun, Daniel J. Weisdorf, Katayoun Rezvani, Giang Lam Vuong, Tilman Brummer, Stephan Meckel, Ralph Wäsch, Geoffroy Andrieux, Soroush Doostkam, Hauke Busch, Dennis Dong Hwan Kim, Sabine Gerull, Bruce R. Blazar, Robert Zeiser, Merav Bar, Flore Sicre-de-Fontbrune, Daniel Feger, Melanie Börries, Wolfgang Melchinger, Petya Apostolova, C. Leiber, Udo Holtick, Walter J.F.M. van der Velden, Renate Arnold, Rainer Claus, Justus Duyster, Nimitha R. Mathew, David O’Sullivan, Alexandros Spyridonidis, S K Metzelder, Thomas Schroeder, Jörg Halter, Johanna Haag, Friedrich Stölzel, Christoph Schmid, Anna Lena Illert, Claudia Lengerke, Björn Hackanson, Joern Dengjel, Francis Ayuk, Rainer Ordemann, Sonia Tugues, Marco Prinz, Inken Hilgendorf, Andreas Burchert, Mathew, Nimitha R, Baumgartner, Franci, Braun, Luka, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Marku, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thoma, Schroeder, Thoma, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandro, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yve, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolau, Ayuk, Franci, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, van der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andrea, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, Mclornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Sha, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andrea, Neubauer, Andrea, Beelen, Dietrich, Mackensen, Andrea, von Bubnoff, Nikola, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justu, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Subjects
0301 basic medicine, Sorafenib, medicine.drug_class, Interferon Regulatory Factor-7, Medizin, Graft vs Host Disease, CD8-Positive T-Lymphocytes, Article, General Biochemistry, Genetics and Molecular Biology, Tyrosine-kinase inhibitor, Mice, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Animals, Humans, Transplantation, Homologous, Medicine, ddc:610, neoplasms, Interleukin-15, business.industry, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, General Medicine, Cellular Reprogramming, medicine.disease, Activating Transcription Factor 4, 3. Good health, Gene Expression Regulation, Neoplastic, Transplantation, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, fms-Like Tyrosine Kinase 3, Tandem Repeat Sequences, Interleukin 15, 030220 oncology & carcinogenesis, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Cancer research, IRF7, business, CD8, medicine.drug
Abstract

Contains fulltext : 190745.pdf (Publisher’s version ) (Closed access) Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Published
2018
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