474 results on '"Kuball, Jürgen"'
Search Results
152. Re-targeting T-cells against cancer by gene-transfer of tumor-reactive receptors
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Marcu-Malina, Victoria, primary, van Dorp, Suzanne, additional, and Kuball, Jürgen, additional
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- 2009
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153. Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain
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Kuball, Jürgen, primary, Hauptrock, Beate, additional, Malina, Victoria, additional, Antunes, Edite, additional, Voss, Ralf-Holger, additional, Wolfl, Matthias, additional, Strong, Roland, additional, Theobald, Matthias, additional, and Greenberg, Philip D., additional
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- 2009
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154. Hepatitis C Virus Immune Escape via Exploitation of a Hole in the T Cell Repertoire
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Wölfl, Matthias, primary, Rutebemberwa, Alleluiah, additional, Mosbruger, Timothy, additional, Mao, Qing, additional, Li, Hong-mei, additional, Netski, Dale, additional, Ray, Stuart C., additional, Pardoll, Drew, additional, Sidney, John, additional, Sette, Alessandro, additional, Allen, Todd, additional, Kuntzen, Thomas, additional, Kavanagh, Daniel G., additional, Kuball, Jürgen, additional, Greenberg, Philip D., additional, and Cox, Andrea L., additional
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- 2008
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155. Use of CD137 to study the full repertoire of CD8+ T cells without the need to know epitope specificities
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Wölfl, Matthias, primary, Kuball, Jürgen, additional, Eyrich, Matthias, additional, Schlegel, Paul G., additional, and Greenberg, Philip D., additional
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- 2008
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156. Molecular Design of the Cαβ Interface Favors Specific Pairing of Introduced TCRαβ in Human T Cells
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Voss, Ralf-Holger, primary, Willemsen, Ralph A., additional, Kuball, Jürgen, additional, Grabowski, Margarete, additional, Engel, Renate, additional, Intan, Ratna S., additional, Guillaume, Philippe, additional, Romero, Pedro, additional, Huber, Christoph, additional, and Theobald, Matthias, additional
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- 2008
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157. Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities
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Wolfl, Matthias, primary, Kuball, Jürgen, additional, Ho, William Y., additional, Nguyen, Hieu, additional, Manley, Thomas J., additional, Bleakley, Marie, additional, and Greenberg, Philip D., additional
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- 2007
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158. Processing and MHC class I presentation of human cytomegalovirus pp65-derived peptides persist despite gpUS2–11-mediated immune evasion
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Besold, Katrin, primary, Frankenberg, Nadine, additional, Pepperl-Klindworth, Sandra, additional, Kuball, Jürgen, additional, Theobald, Matthias, additional, Hahn, Gabriele, additional, and Plachter, Bodo, additional
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- 2007
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159. Orchestrating an immune response against cancer with engineered immune cells expressing αβTCRs, CARs, and innate immune receptors: an immunological and regulatory challenge.
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Witte, Moniek, Kierkels, Guido, Straetemans, Trudy, Britten, Cedrik, and Kuball, Jürgen
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IMMUNE response ,CANCER immunotherapy ,NATURAL immunity ,IMMUNOLOGY ,HOMOGRAFTS ,STEM cell transplantation - Abstract
Over half a century ago, the first allogeneic stem cell transplantation (allo-SCT) initiated cellular immunotherapy. For several decades, little progress was made, and toxicity of allo-SCT remained a major challenge. However, recent breakthroughs have opened new avenues to further develop this modality and to provide less toxic and equally efficient interventions for patients suffering from hematological or solid malignancies. Current novel cellular immune interventions include ex vivo expansion and adoptive transfer of tumor-infiltrating immune cells or administration of drugs which antagonize tolerizing mechanisms. Alternatively, transfer of immune cells engineered to express defined T cell receptors (TCRs) and chimeric antigen receptors (CARs) has shown its potential. A valuable addition to 'engineered' adaptive immunity has emerged recently through the improved understanding of how innate immune cells can attack cancer cells without substantial side effects. This has enabled the development of transplantation platforms with limited side effects allowing early immune interventions as well as the design of engineered immune cells expressing innate immune receptors. Here, we focus on innate immune interventions and their orchestration with TCR- and CAR-engineered immune cells. In addition, we discuss how the exploitation of the full potential of cellular immune interventions is influenced by regulatory frameworks. Finally, we highlight and discuss substantial differences in the current landscape of clinical trials in Europe as compared to the USA. The aim is to stimulate international efforts to support regulatory authorities and funding agencies, especially in Europe, to create an environment that will endorse the development of engineered immune cells for the benefit of patients. [ABSTRACT FROM AUTHOR]
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- 2015
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160. Cancer immunotherapy using γδT cells: dealing with diversity.
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Scheper, Wouter, Sebestyen, Zsolt, and Kuball, Jürgen
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T cells ,CANCER immunotherapy ,ANTIBODY diversity ,NATURAL immunity ,MONOCLONAL antibodies ,LYMPHOCYTES ,THERAPEUTICS - Abstract
The broad and potent tumor-reactivity of innate-like γδT cells makes them valuable additions to current cancer immunotherapeutic concepts based on adaptive immunity, such as monoclonal antibodies and αβT cells. However, clinical success using γδT cells to treat cancer has so far fallen short. Efforts of recent years have revealed a striking diversity in γδT cell functions and immunobiology, putting these cells forward as true "swiss army knives" of immunity. At the same time, however, this heterogeneity poses new challenges to the design of γδT cell-based therapeutic concepts and could explain their rather limited clinical efficacy in cancer patients. This review outlines the recent new insights into the different levels of γδT cell diversity, including the myriad of γδT cell-mediated immune functions, the diversity of specificities and affinities within the γδT cell repertoire, and the multitude of complex molecular requirements for γδT cell activation. A careful consideration of the diversity of antibodies and αβT cells has delivered great progress to their clinical success; addressing also the extraordinary diversity in γδT cells will therefore hold the key to more effective immunotherapeutic strategies with γδT cells as additional and valuable tools to battle cancer. [ABSTRACT FROM AUTHOR]
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- 2014
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161. Facilitating matched pairing and expression of TCR chains introduced into human T cells
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Kuball, Jürgen, primary, Dossett, Michelle L., additional, Wolfl, Matthias, additional, Ho, William Y., additional, Voss, Ralf-Holger, additional, Fowler, Carla, additional, and Greenberg, Philip D., additional
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- 2006
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162. Nitric Oxide Promotes Resistance to Tumor Suppression by CTLs
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Su, Zhanhai, primary, Kuball, Jürgen, additional, Barreiros, Ana-Paula, additional, Gottfried, Daniela, additional, Ferreira, Edite Antunes, additional, Theobald, Matthias, additional, Galle, Peter R., additional, Strand, Dennis, additional, and Strand, Susanne, additional
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- 2006
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163. Cytomegalovirus Interleukin-10 Expression in Infected Cells Does Not Impair MHC Class I Restricted Peptide Presentation on Bystanding Antigen-Presenting Cells
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Pepperl-Klindworth, Sandra, primary, Besold, Katrin, additional, Frankenberg, Nadine, additional, Farkas, Mildred, additional, Kuball, Jürgen, additional, Theobald, Matthias, additional, and Plachter, Bodo, additional
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- 2006
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164. Designing TCR for Cancer Immunotherapy.
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Ludewig, Burkhard, Hoffmann, Matthias W., Voss, Ralf-Holger, Kuball, Jürgen, and Theobald, Matthias
- Abstract
Reprogramming T-cell populations by T-cell receptor (TCR) gene transfer is a new therapeutic tool for adoptive tumor immunotherapy. Gene transfer of human leukocyte antigen (HLA)-transgenic mice-derived TCR into human T-cells allows the circumvention of tolerance to tumor-associated (self) antigens (TAA). This chapter reports on the identification of the α and β chains of the heterodimeric TCR derived from a mouse T-cell clone. The related DNA fragments are inserted into a retroviral vector for heterologous expression of the TAA-specific TCR in human T-cells. Polymerase chain reaction (PCR)-based cloning protocols are provided for the tailor-made customization of murine TCR. We describe the humanization and chimerization of such TCR as well as their expression in human T-cells. [ABSTRACT FROM AUTHOR]
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- 2005
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165. Indirectly recognized HLA-C mismatches and their potential role in transplant outcome.
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Thus, Kirsten A., Te Boome, Liane, Kuball, Jürgen, and Spierings, Eric
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TRANSPLANTATION immunology ,EPITOPES ,T cells ,STEM cell transplantation ,HEMATOPOIETIC stem cells - Abstract
HLA-C mismatches are clearly associated to alloreactivity after hematopoietic stem-cell transplantation; in a number of large cohorts, HLA-C mismatches are correlated to an increased risk of acute graft-versus-host disease (GVHD) or even impaired survival. While for HLA-A and -B, both antigenic as well as allelic mismatches are associated with an increased risk of acute GVHD, such an increased risk is only observed for antigenic HLA-C mismatches and not for allelic mismatches. These observations raise the question what sets HLA-C apart from HLA-A and -B. The difference may well be related to the reduced levels of cell-surface expression of HLA-C as compared to HLA-A and -B, possibly due to, among other factors, a limited peptide-binding capacity. This limited peptide-binding capacity may retain HLA-C in the ER and enhance degradation of the HLA-C protein. Once degraded, HLA-C-derived peptides can be presented to the immune system via other HLA alleles and are thus available for indirect recognition. Indeed, such HLA-C-derived peptides have previously been eluted from other HLA alleles.We have recently developed an approach to predict indirect recognition of HLA molecules, by establishing the numbers of predicted indirectly recognizable HLA epitopes (PIRCHES). The number of PIRCHES presented on HLA class I and II (PIRCHE-I and -II, respectively), are highly correlated to clinical measures of alloreactivity, such as acute GVHD. In the present "Hypothesis &Theory," we reviewed the current knowledge on HLA-C mismatches and alloreactivity. Moreover, we speculate about the role of direct and indirect recognition of HLA-C and the consequences for donor selection in HLA-C mismatched stem-cell transplantation. [ABSTRACT FROM AUTHOR]
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- 2014
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166. Cooperation of Human Tumor-Reactive CD4+ and CD8+ T Cells after Redirection of Their Specificity by a High-Affinity p53A2.1-Specific TCR
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Kuball, Jürgen, Schmitz, Frank W., Voss, Ralf-Holger, Ferreira, Edite Antunes, Engel, Renate, Guillaume, Philippe, Strand, Susanne, Romero, Pedro, Huber, Christoph, Sherman, Linda A., and Theobald, Matthias
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T cell receptors , *LYMPHOCYTES , *HLA histocompatibility antigens , *TRANSGENIC animals - Abstract
Efficient immune attack of malignant disease requires the concerted action of both CD8+ CTL and CD4+ Th cells. We used human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic mice, in which the mouse CD8 molecule cannot efficiently interact with the α3 domain of A2.1, to generate a high-affinity, CD8-independent T cell receptor (TCR) specific for a commonly expressed, tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the human p53 tumor suppressor protein. Retroviral expression of this CD8-independent, p53-specific TCR into human T cells imparted the CD8+ T lymphocytes with broad tumor-specific CTL activity and turned CD4+ T cells into potent tumor-reactive, p53A2.1-specific Th cells. Both T cell subsets were cooperative and interacted synergistically with dendritic cell intermediates and tumor targets. The intentional redirection of both CD4+ Th cells and CD8+ CTL by the same high-affinity, CD8-independent, tumor-specific TCR could provide the basis for novel broad-spectrum cancer immunotherapeutics. [Copyright &y& Elsevier]
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- 2005
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167. Correction to: Predictive factors for vaccine failure to guide vaccination in allogeneic hematopoietic stem cell transplant recipients
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Janssen, Michelle J. M., Bruns, Anke H. W., Verduyn Lunel, Frans M., Raijmakers, Reinier A. P., de Weijer, Roel J., Nanlohy, Nening M., Smits, Gaby P., van Baarle, Debbie, and Kuball, Jürgen
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- 2022
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168. Posttransplant Cyclophosphamide for Prevention of Graft-versus-Host Disease: Results of the Prospective Randomized HOVON-96 Trial
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Broers, Annoek E.C., de Jong, Cornelis N., Bakunina, Katerina, Hazenberg, Mette D., van Marwijk Kooy, Marinus, de Groot, Marco R., van Gelder, Michel, Kuball, Jürgen, van der Holt, Bronno, Meijer, Ellen, and Cornelissen, Jan J.
- Abstract
Graft versus host disease (GVHD) is the most important complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). We performed a prospective randomized, multicenter, phase III trial to study whether posttransplant cyclophosphamide (PT-Cy) combined with a short course of cyclosporine A (CsA) would result in a reduction of severe GVHD and improvement of GVHD-free, relapse free survival (GRFS) as compared to the combination of CsA and mycophenolic acid (MPA) after non-myeloablative (NMA) matched related and unrelated peripheral blood alloHSCT. Between October 2013 and June 2018, 160 patients diagnosed with a high-risk hematological malignancy and having a matched related or at least 8 out of 8 HLA matched unrelated donor were randomized and allocated in a 1:2 ratio to CsA/MPA or PT-Cy/CsA. A total of 151 patients was transplanted (52 versus 99 patients). The cumulative incidence of grade II-IV acute GVHD at six months was 48% in recipients of CsA/MPA versus 30% following PT-Cy/CsA (Hazard ratio (HR): 0.48, 95% confidence interval (CI): 0.29-0.82, p=0.007). The two-year cumulative incidence of chronic extensive GVHD was 48% versus 16% (HR: 0.36, 95%CI: 0.21-0.64, p<0.001). The one-year estimate of GRFS was 21% (11%-32%) versus 45% (35%-55%), p<0.001.With a median follow-up of 56.4 months, relapse incidence, progression-freeand overall survival were not significantly different between the two treatment arms. PT-Cy combined with a short course of CsAafter NMA matched alloHSCTsignificantly improves GRFS due to a significant reduction in severe acute and chronic GVHD.The trial was registered as number NL2128 in the Dutch trial registry (www.trialregister.nl).
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- 2022
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169. In vitro T cell responses to PD-1 blockade are reduced by IFN-α but do not predict therapy response in melanoma patients.
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Timmerman, Laura M., Hensen, Lobke C. M., van Eijs, Mick J. M., Verheijden, Rik J., Suijkerbuijk, Karijn P. M., Meyaard, Linde, van der Vlist, Michiel, Kuball, Jürgen H. E., Oldenburg, Bas, and Leusen, Jeanette H. W.
- Abstract
PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients. [ABSTRACT FROM AUTHOR]
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- 2024
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170. Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+T cells responding to antigen without requiring knowledge of epitope specificities
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Wolfl, Matthias, Kuball, Jürgen, Ho, William Y., Nguyen, Hieu, Manley, Thomas J., Bleakley, Marie, and Greenberg, Philip D.
- Abstract
CD137 is a member of the TNFR-family with costimulatory function. Here we show that it also has many favorable characteristics as a surrogate marker for antigen-specific activation of human CD8+T cells. Although undetectable on unstimulated CD8+T cells, it is uniformly up-regulated 24 hours after stimulation on virtually all responding cells regardless of differentiation stage or profile of cytokine secretion, which circumvents limitations of current surrogate markers for defining the repertoire of responding cells based on only individual functions. Antibody-labeled responding CD137+cells can be easily and efficiently isolated by flow sorting or magnetic beads to substantially enrich antigen-specific T cells. To test this approach for epitope discovery, we examined in vitro priming of naive T cells from healthy donors to Wilms tumor antigen 1 (WT1), a protein overexpressed in various malignancies. Two overlapping pentadecamers were identified as immunogenic, and further analysis defined WT1(286–293)as the minimal amino acid sequence and HLA-Cw07 as the HLA restriction element. In conclusion, this approach appears to be an efficient and sensitive in vitro technique to rapidly identify and isolate antigen-specific CD8+T cells present at low frequencies and displaying heterogeneous functional profiles, and does not require prior knowledge of the specific epitopes recognized or the HLA-restricting elements.
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- 2007
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171. Facilitating matched pairing and expression of TCR chains introduced into human T cells
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Kuball, Jürgen, Dossett, Michelle L., Wolfl, Matthias, Ho, William Y., Voss, Ralf-Holger, Fowler, Carla, and Greenberg, Philip D.
- Abstract
Adoptive transfer of T lymphocytes is a promising treatment for a variety of malignancies but often not feasible due to difficulties generating T cells that are reactive with the targeted antigen from patients. To facilitate rapid generation of cells for therapy, T cells can be programmed with genes encoding the α and β chains of an antigen-specific T-cell receptor (TCR). However, such exogenous α and β chains can potentially assemble as pairs not only with each other but also with endogenous TCR α and β chains, thereby generating αβTCR pairs of unknown specificity as well as reducing the number of exogenous matched αβTCR pairs at the cell surface. We demonstrate that introducing cysteines into the constant region of the α and β chains can promote preferential pairing with each other, increase total surface expression of the introduced TCR chains, and reduce mismatching with endogenous TCR chains. This approach should improve both the efficacy and safety of ongoing efforts to use TCR transfer as a strategy to generate tumor-reactive T cells.
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- 2007
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172. Correction: Benchmarking of survival outcomes following haematopoietic stem cell transplantation: A review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE)
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Snowden, John A., Saccardi, Riccardo, Orchard, Kim, Ljungman, Per, Duarte, Rafael F., Labopin, Myriam, McGrath, Eoin, Brook, Nigel, de Elvira, Carmen Ruiz, Gordon, Debra, Poirel, Hélène A., Ayuk, Francis, Beguin, Yves, Bonifazi, Francesca, Gratwohl, Alois, Milpied, Noel, Moore, John, Passweg, Jakob, Rizzo, J. Douglas, Spellman, Stephen R., Sierra, Jorge, Solano, Carlos, Sanchez-Guijo, Fermin, Worel, Nina, Gusi, Andreu, Adams, Gillian, Balan, Theodor, Baldomero, Helen, Macq, Gilles, Marry, Evelyne, Mesnil, Florence, Oldani, Elena, Pearce, Rachel, Perry, Julia, Raus, Nicole, Schanz, Urs, Tran, Steven, Wilcox, Leonie, Basak, Grzegorz W., Chabannon, Christian, Corbacioglu, Selim, Dolstra, Harry, Kuball, Jürgen, Mohty, Mohamad, Lankester, Arjan, Montoto, Sylvia, Nagler, Arnon, Styczynski, Jan, Yakoub-Agha, Ibrahim, de Latour, Regis Peffault, Kroeger, Nicolaus, Brand, Ronald, de Wreede, Liesbeth C., van Zwet, Erik, and Putter, Hein
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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173. Control Of Organ Transplant-Associated Graft-versus-Host Disease By Activated Host Lymphocyte Infusions
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Kuball, Jürgen, Theobald, Matthias, Ferreira, Edite Antunes, Hess, Georg, Burg, Jürgen, Maccagno, Giancarlo, Barreiros, Ana P., Lüth, Stefan, Schimanski, Carl C., Schuchmann, Markus, Schwarting, Andreas, Neurath, Markus, Otto, Gerd, Galle, Peter R., and Lohse, Ansgar W.
- Abstract
Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal.
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- 2004
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174. Improving Tumor Immunotherapy by Using Distinct Subpopulations of the γδT Cell Repertoire with High Anti-Tumor Reactivity.
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van Dorp, Suzanne, Hol, Samantha, Marcu-Malina, Victoria, Thuss, Nicole, Lokhorst, Henk, and Kuball, Juergen
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- 2009
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175. Increasing Functional Avidity of T Cell Receptor (TCR)-Redirected T Cells by Removing Defined N-Glycoslyation Sites in the Constant Domain of Introduced TCR Chains.
- Author
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Kuball, Juergen, Hauptrock, Beate, Wolfl, Matthias, Voss, Ralf Holger, Strong, Roland, Theobald, Matthias, and Greenberg, Phil
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- 2007
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176. Reactivation of Multidrug-Resistant HSV-1 in a Post–Allogenic Hematopoietic Stem Cell Transplant Patient: Dynamic Detection of the Rare A605V Mutation by Next-Generation Sequencing.
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Zheng, Shuxuan, Rümke, Lidewij L W, Rubio, Bruno Tello, Rogers, Malbert R C, Sluis, Geerte L van, Kuball, Jürgen H E, Riezebos-Brilman, Annelies, Lebbink, Robert Jan, and Lunel, Frans M Verduyn
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HEMATOPOIETIC stem cells , *STEM cell transplantation , *NUCLEOTIDE sequencing , *HUMAN herpesvirus 1 , *VIRAL DNA - Abstract
We present an immunocompromised patient with a multiresistant herpes simplex virus–1 reactivation with a rare mutation (A605V) in the viral DNA polymerase gene. Next-generation sequencing suggests the presence of multiple drug-resistant strains before treatment and altered ratios during treatment, affecting the clinical response to aciclovir and foscarnet. [ABSTRACT FROM AUTHOR]
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- 2024
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177. Playing the Game Together: Coexpression of a Single Chain T Cell Receptor and a T Cell Receptor Constant-Alpha Domain Triggers Tumor Reactivity.
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Thomas, Simone, Voss, Ralf H., Intan, Ratna, Engel, Renate, Kuball, Juergen, Huber, Christoph, and Theobald, Matthias
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- 2006
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178. Vaccination with WT1 and PR3 Derived Peptides in Patients with AML/MDS and MUC1 Peptides in Patients with Multiple Myeloma - Preliminary Results.
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Wagner, Eva M., Kuball, Juergen, Wattad, Mohamed, Huber, Christoph, Heit, Wolfgang, and Theobald, Matthias
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- 2006
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179. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
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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
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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.
180. Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.
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Baron, Frédéric, Nagler, Arnon, Galimard, Jacques‐Emmanuel, Sanz, Jaime, Versluis, Jurjen, Forcade, Edouard, Chevallier, Patrice, Sirvent, Anne, Anthias, Chloe, Kuball, Jürgen, Furst, Sabine, Rambaldi, Alessandro, Sierra, Jorge, von dem Borne, Peter A., Gallego Hernanz, Maria Pilar, Cluzeau, Thomas, Robinson, Stephen, Raiola, Anna Maria, Labussière‐Wallet, Hélène, and Byrne, Jenny L.
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CORD blood transplantation , *ACUTE myeloid leukemia , *ACUTE leukemia , *CELL transplantation - Abstract
Summary: We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T‐cell depletion and no post‐transplant cyclophosphamide. The primary end‐point of the study was leukaemia‐free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non‐significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non‐relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non‐significantly different LFS following CBT in adult patients with secondary versus de novo AML. [ABSTRACT FROM AUTHOR]
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- 2024
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181. A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells.
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de Bruin, Renée C. G., Veluchamy, John P., Lougheed, Sinéad M., Schneiders, Famke L., Lopez-Lastra, Silvia, Lameris, Roeland, Stam, Anita G., Sebestyen, Zsolt, Kuball, Jürgen, Molthoff, Carla F. M., Hooijberg, Erik, Roovers, Rob C., Santo, James P. Di, van Bergen en Henegouwen, Paul M. P., Verheul, Henk M. W., de Gruijl, Tanja D., and van der Vliet, Hans J.
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CANCER immunotherapy ,T cells ,CANCER treatment ,THERAPEUTICS - Abstract
Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis bothin vitroand in anin vivomouse xenograft model. Tumor cell lysis was independent ofKRASandBRAFtumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients. [ABSTRACT FROM PUBLISHER]
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- 2018
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182. Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition.
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van Eijs, Mick J. M., Verheijden, Rik J., van der Wees, Stefanie A., Nierkens, Stefan, van Lindert, Anne S. R., Suijkerbuijk, Karijn P. M., van Wijk, Femke, the UNICIT consortium, Meyaard, Linde, Kuball, Jürgen H. E., Oldenburg, Bas, and Leusen, Jeanette H. W.
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IMMUNE checkpoint inhibitors , *B cells , *T cells , *T helper cells , *DRUG side effects - Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Mechanistic studies can aid the transition from expert-opinion to evidence-based irAE treatment strategies. We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients by multicolor flow cytometry and serum multiplex immunoassay at baseline, ± 3 weeks and ± 6 weeks or upon clinically relevant irAEs. We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1/anti-CTLA-4; cICI), of whom 21 developed irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly (CD4+) CD27− effector memory T cells, as well as Th17-associated immune responses and germinal center activation (reflected by CXCL13 and IL-21 increases). We observed no changes in CD21lo, memory, class-switched or newly activated B cell subsets. Particularly double-positive PD-1+LAG-3+ CD8+ T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. Within anti-PD-1 monotherapy, irAEs were associated with modestly enhanced Th1-associated responses reflected by increased serum CXCL9 and CXCL10. In conclusion, ICI-induced toxicity is dominated by enhanced Th1-associated responses, but in cICI we also found evidence for Th17-associated responses and germinal center activation. Together, our data add to the growing body of evidence that irAEs may be driven by newly activated CD4+ helper T cells, specifically after cICI. This study also supports tailored irAE treatment, based on ICI regimen, and to deploy specific strategies such as Th17 inhibition especially in cICI-associated irAEs. [ABSTRACT FROM AUTHOR]
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- 2023
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183. The next step toward GMP-grade production of engineered immune cells.
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Kierkels, Guido J. J., Straetemans, Trudy, de Witte, Moniek A., and Kuball, Jürgen
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CELLULAR immunity ,GUANYLIC acid ,T cells ,CANCER immunotherapy ,TREATMENT effectiveness ,THERAPEUTICS - Abstract
Removing less potent T cell subsets as well as poorly- or non-engineered cells can optimize effectiveness of engineered T cell therapy against cancer. We have recently described a novel, GMP-ready method for the purification of engineered immune cells that might further boost the clinical success of cancer immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2016
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184. Influence of Donor Cytomegalovirus (CMV) Status on Severity of Viral Reactivation after Allogeneic Stem Cell Transplantation in CMV-Seropositive Recipients.
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Pietersma, Floor L., van Dorp, Suzanne, Minnema, Monique C., Kuball, Jürgen, Meijer, Ellen, Schuurman, Rob, and van Baarle, Debbie
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CYTOMEGALOVIRUSES ,VIRUS reactivation ,STEM cells ,CELL transplantation ,VIRUS diseases ,IMMUNITY ,PATIENTS - Abstract
We investigated the role of donor cytomegalovirus (CMV) serostatus on reactivation of CMV infection in CMV-infected transplant recipients. Reactivation of CMV infection occurred more frequently in patients receiving a CMV positive graft but was less severe than in patients receiving a CMV-negative graft. These data suggest roles for both virus as well as CMV-specific immunity present in the graft.We investigated the role of donor cytomegalovirus (CMV) serostatus on reactivation of CMV infection in CMV-infected transplant recipients. Reactivation of CMV infection occurred more frequently in patients receiving a CMV-positive graft but was less severe than in patients receiving a CMV-negative graft. These data suggest roles for both virus as well as CMV-specific immunity present in the graft. [ABSTRACT FROM AUTHOR]
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- 2011
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185. Outcome of allogeneic haematopoietic cell transplantation in eosinophilic disorders: A retrospective study by the chronic malignancies working party of the EBMT.
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McLornan, Donal P., Gras, Luuk, Martin, Ivonne, Sirait, Tiarlan, Schroeder, Thomas, Blau, Igor Wolfgang, Kuball, Jürgen, Byrne, Jenny, Collin, Matthew, Stadler, Michael, Desmier, Déborah, Salmenniemi, Urpu, Jindra, Pavel, Mikhailova, Natalia, Lenhoff, Stig, Rifón, Jose, Robin, Marie, Rovira, Montserrat, Veelken, Hendrik, and Sadowska‐Klasa, Alicja
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HYPEREOSINOPHILIC syndrome , *CELL transplantation , *GRAFT versus host disease - Abstract
Patients were transplanted with a median time to allo-HCT of 15.1 months (IQR, 9.8-27.9) for CEL, NOS patients, and 22.2 months (IQR, 11.5-55.8; I p i = 0.01) for HES. Helbig et al. reported on 10 patients with CEL, NOS with a median age of 62 (23-73 years), frequently with an aggressive clinical course, five of whom developed acute transformation within two years from the time of diagnosis.6 Here, only one patient in the chronic phase successfully underwent allo-SCT. Keywords: allogeneic stem cell transplant; chronic eosinophilic leukaemia; conditioning; hypereosinophilic syndrome; non-relapse mortality EN allogeneic stem cell transplant chronic eosinophilic leukaemia conditioning hypereosinophilic syndrome non-relapse mortality 209 213 5 06/27/22 20220701 NES 220701 Hypereosinophilic syndrome (HES) and chronic eosinophilic leukaemia (CEL), not otherwise specified (NOS) are rare haematological disorders.1 Allogeneic haematopoietic cell transplantation (allo-HCT) has been reported in single case reports or small case series only for both refractory HES or CEL, NOS and outcomes remain ill-defined.1-3 HES normally demonstrates a male predominance, likely underrecognized, with a variable clinical course. [Extracted from the article]
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- 2022
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186. Allogeneic hematopoietic cell transplantation with cord blood versus mismatched unrelated donor with post-transplant cyclophosphamide in acute myeloid leukemia.
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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, Savani, Bipin N., Nagler, Arnon, and Mohty, Mohamad
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CORD blood transplantation , *HEMATOPOIETIC stem cell transplantation , *ACUTE myeloid leukemia , *HLA histocompatibility antigens , *CYCLOPHOSPHAMIDE - Abstract
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) using a mismatched unrelated donor (MMUD) and cord blood transplantation (CBT) are valid alternatives for patients without a fully human leukocyte antigen (HLA)-matched donor. Here, we compared the allo-HCT outcomes of CBT versus single-allele-mismatched MMUD allo-HCT with post-transplant cyclophosphamide (PTCy) in acute myeloid leukemia. Methods: Patients who underwent a first CBT without PTCy (N = 902) or allo-HCT from a (HLA 9/10) MMUD with PTCy (N = 280) were included in the study. A multivariate regression analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score-based 1:1 matching of patients (177 pairs) with known cytogenetic risk. Results: The incidence of grade II–IV and grade III–IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% (p = 0.07) and 15% versus 11% (p = 0.16) for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%, p < 0.01) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%, p < 0.01) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR = 2.09, 95% CI 1.46–2.99, p < 0.0001), and relapse (HR = 1.35, 95% CI 1–1.83, p = 0.05), which resulted in worse leukemia-free survival (LFS) (HR = 1.68, 95% CI 1.34–2.12, p < 0.0001), overall survival (OS) (HR = 1.7, 95% CI 1.33–2.17, p < 0.0001), and GVHD-free, relapse-free survival (GRFS) (HR = 1.49, 95% CI 1.21–1.83, p < 0.0001) compared to MMUD. The risk of grade II–IV acute GVHD (p = 0.052) and chronic GVHD (p = 0.69) did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis. Conclusions: CBT was associated with lower LFS, OS, and GRFS due to higher NRM, compared to MMUD allo-HCT with PTCy. In the absence of a fully matched donor, 9/10 MMUD with PTCy may be preferred over CBT. [ABSTRACT FROM AUTHOR]
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- 2021
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187. Thrombocytopenia and the effect of platelet transfusions on the occurrence of intracranial hemorrhage in patients with acute leukemia – a nested case-control study.
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Cornelissen, Loes L., Kreuger, Aukje L., Caram-Deelder, Camila, Middelburg, Rutger A., Kerkhoffs, Jean Louis H., von dem Borne, Peter A., Beckers, Erik A. M., de Vooght, Karen M. K., Kuball, Jürgen, Zwaginga, J. J., and van der Bom, Johanna G.
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BLOOD platelet transfusion , *ACUTE leukemia , *CASE-control method , *HEMORRHAGE , *PLATELET count - Abstract
We designed a study to describe the incidence of intracranial hemorrhage according to severity and duration of thrombocytopenia and to quantify the associations of platelet transfusions with intracranial hemorrhage in patients with acute leukemia. In this case-control study nested in a cohort of 859 leukemia patients, cases (n = 17) were patients diagnosed with intracranial hemorrhage who were matched with control patients (n = 55). We documented platelet counts and transfusions for seven days before the intracranial hemorrhage in cases and in a "matched" week for control patients. Three measures of platelet count exposure were assessed in four potentially important time periods before hemorrhage. Among these leukemia patients, we observed the cumulative incidence of intracranial hemorrhage of 3.5%. Low platelet counts were, especially in the three to seven days preceding intracranial hemorrhage, associated with the incidence of intracranial hemorrhage, although with wide confidence intervals. Platelet transfusions during the week preceding the hemorrhage were associated with higher incidences of intracranial hemorrhage; rate ratios (95% confidence interval) for one or two platelet transfusions and for more than two transfusions compared with none were 4.04 (0.73 to 22.27) and 8.91 (1.53 to 51.73) respectively. Thus, among acute leukemia patients, the risk of intracranial hemorrhage was higher among patients with low platelet counts and after receiving more platelet transfusions. Especially, the latter is likely due to clinical factors leading to increased transfusion needs. [ABSTRACT FROM AUTHOR]
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- 2021
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188. Evaluating in vivo efficacy -- toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells.
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Johanna, Inez, Straetemans, Trudy, Heijhuurs, Sabine, Aarts-Riemens, Tineke, Norell, Håkan, Bongiovanni, Laura, de Bruin, Alain, Sebestyen, Zsolt, and Kuball, Jürgen
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T cell receptors , *ACUTE myeloid leukemia , *PRELEUKEMIA , *XENOGRAFTS , *BLAST injuries , *PROGENITOR cells , *MICE - Abstract
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). [ABSTRACT FROM AUTHOR]
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- 2019
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189. Population Pharmacokinetics of Fludarabine in Children and Adults during Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.
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Langenhorst, Jurgen B., Dorlo, Thomas P. C., van Maarseveen, Erik M., Nierkens, Stefan, Kuball, Jürgen, Boelens, Jaap Jan, van Kesteren, Charlotte, and Huitema, Alwin D. R.
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CELL transplantation , *ADULT-child relationships , *FLUDARABINE , *MATERNAL exposure , *BODY surface area , *GLOMERULAR filtration rate , *BIOCONVERSION - Abstract
Background: Fludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used.Objective: We sought to describe the population PK of fludarabine in HCT recipients of all ages.Methods: From 258 HCT recipients aged 0.3-74 years, 2605 samples were acquired on days 1 (42%), 2 (17%), 3 (4%) and 4 (37%) of conditioning. Herein, the circulating metabolite of fludarabine was quantified, and derived concentration-time data were used to build a population PK model using non-linear mixed-effects modelling.Results: Variability was extensive where area under the curve ranged from 10 to 66 mg h/L. A three-compartment model with first-order kinetics best described the data. Actual body weight (BW) with standard allometric scaling was found to be the best body-size descriptor for all PK parameters. Estimated glomerular filtration rate (eGFR) was included as a descriptor of renal function. Thus, clearance was differentiated into a non-renal (3.24 ± 20% L/h/70 kg) and renal (eGFR × 0.782 ± 11% L/h/70 kg) component. The typical volumes of distribution of the central (V1), peripheral (V2), and second peripheral (V3) compartments were 39 ± 8%, 20 ± 11%, and 50 ± 9% L/70 kg respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 8.6 ± 8% and 3.8 ± 13% L/h/70 kg, respectively.Conclusion: BW and eGFR are important predictors of fludarabine PK. Therefore, current linear BSA-based dosing leads to highly variable exposure, which may lead to variable treatment outcome. [ABSTRACT FROM AUTHOR]- Published
- 2019
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190. Haematopoietic stem cell transplantation for autoimmune diseases.
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Swart, Joost F., Delemarre, Eveline M., van Wijk, Femke, Boelens, Jaap-Jan, Kuball, Jürgen, van Laar, Jacob M., and Wulffraat, Nico M.
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HEMATOPOIETIC stem cell transplantation , *AUTOIMMUNE disease treatment , *STEM cell transplantation , *CELL transplantation , *CANCER chemotherapy , *RHEUMATISM treatment , *AUTOGRAFTS , *AUTOIMMUNE diseases , *CELL receptors , *RHEUMATISM , *T cells - Abstract
Autologous haematopoietic stem cell transplantation (HSCT) is the only treatment that is able to induce long-term, drug-free and symptom-free remission in several refractory autoimmune rheumatic diseases. Over 3,000 HSCT procedures for rheumatic and nonrheumatic severe autoimmune diseases have been performed worldwide. Specific conditioning regimens are currently used to eradicate the autoreactive immunological memory of patients. Although in vivo immune cell depletion with antithymocyte globulin or anti-CD52 is the norm for many regimens, ex vivo selection of CD34+ stem cells from the graft is controversial. Following the extensive immune depletion associated with serotherapy and chemotherapy, HSCT effectively resets the immune system by renewing the CD4+ T cell compartment, especially the regulatory T cell population. The risk of transplant-related mortality (TRM) within the first 100 days should be weighed against the risk of disease-related mortality, and the careful selection and screening of patients before transplantation is essential. Systemic sclerosis is the first autoimmune disease for which HSCT has been shown, in a randomized, controlled trial, to be associated with increased TRM in the first year but a significant long-term, event-free survival benefit afterwards. In this Review, we discuss the immunological mechanisms of HSCT in various autoimmune diseases and current HSCT regimens. After carefully taking into consideration the risks and benefits of HSCT and alternative therapies, we also discuss the efficacy, complications and proposed indications of this procedure. [ABSTRACT FROM AUTHOR]
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- 2017
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191. Refinement of the Definition of Permissible HLA-DPB1 Mismatches with Predicted Indirectly ReCognizable HLA-DPB1 Epitopes.
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Thus, Kirsten A., Ruizendaal, Mieke T.A., de Hoop, Talitha A., Borst, Eric, van Deutekom, Hanneke W.M., te Boome, Liane, Kuball, Jürgen, and Spierings, Eric
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HLA histocompatibility antigens , *EPITOPES , *PREDICTION models , *FEASIBILITY studies , *GRAFT versus host disease - Abstract
Hematopoietic stem cell transplantation with HLA-DPB1–mismatched donors leads to an increased risk of acute graft-versus-host disease (GVHD). Studies have indicated a prognostic value for classifying HLA-DPB1 mismatches based on T cell–epitope (TCE) groups. The aim of this study was to determine the contribution of indirect recognition of HLA-DP–derived epitopes, as determined with the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) method. We therefore conducted a retrospective single-center analysis on 80 patients transplanted with a 10/10 matched unrelated donor that was HLA-DPB1 mismatched. HLA-DPB1 mismatches that were classified as GVH nonpermissive by the TCE algorithm correlated to higher numbers of HLA class I as well as HLA class II presented PIRCHE (PIRCHE-I and -II) compared with permissive or host-versus-graft nonpermissive mismatches. Patients with acute GVHD grades II to IV presented significantly higher numbers of PIRCHE-I compared with patients without acute GVHD ( P < .05). Patients were divided into 2 groups based on the presence or absence of PIRCHE. Patients with PIRCHE-I or -II have an increased hazard of acute GVHD when compared with patients without PIRCHE-I or -II (hazard ratio [HR], 3.19; 95% confidence interval [CI], 1.10 to 9.19; P < .05; and HR, 4.07; 95% CI, .97 to 17.19; P = .06, respectively). Patients classified as having an HLA-DPB1 permissive mismatch by the TCE model had an increased risk of acute GVHD when comparing presence of PIRCHE-I with absence of PIRCHE-I (HR, 2.96; 95% CI, .84 to 10.39; P = .09). We therefore conclude that the data presented in this study describe an attractive and feasible possibility to better select permissible HLA-DPB1 mismatches by including both a direct and an indirect recognition model. [ABSTRACT FROM AUTHOR]
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- 2014
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192. 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
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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
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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.
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- 2018
193. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD
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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)
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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.
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- 2016
194. Immune monitoring in allogeneic hematopoietic stem cell transplant recipients: a survey from the EBMT-CTIWP
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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
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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
195. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
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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
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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.
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- 2018
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196. Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia.
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Barneh F, Koedijk JB, Wijnen NE, Meulendijks T, Ashtiani M, Dunnebach E, Dautzenberg N, Cornel AM, Krippner-Heidenreich A, Klein K, Zwaan MC, Kuball J, Nierkens S, Cloos J, Kaspers GJL, and Heidenreich O
- Abstract
Not available.
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- 2024
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197. Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.
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Garderet L, Gras L, Koster L, De Wreede L, Montserrat R, Vincent L, Fenk R, Karunanithi K, Deeren D, Kaufmann M, Kuball J, Ozdogu H, Cascon MJP, Passweg J, Rye A, Salmenniemi U, Snowden J, Hansen CT, Leleu X, Gastaud L, Sokolowska JD, Raj K, Beksac M, Schönland S, Hayden P, and McLornan D
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- Humans, Male, Female, Middle Aged, Retrospective Studies, Adult, Treatment Outcome, Aged, Glomerular Filtration Rate, Immunoglobulin Light Chains blood, Paraproteinemias therapy, Paraproteinemias mortality, Paraproteinemias diagnosis, Follow-Up Studies, Europe, Registries, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Transplantation, Autologous
- Abstract
There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the European Society for Blood and Bone Marrow transplantation registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 μmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100 mg/m2 in 23%, 140 mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pretransplant to 66% at day +100 post- ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median estimated glomerular filtration rate increased from 44 to 51 mL/min/1.73 m2. There was no further change between 3 and 12 months post-ASCT. No patient who was RRT-independent at ASCT became RRT dependent by day + 100 post-ASCT. Median follow- up post-ASCT was 84 months (interquartile range [IQR]: 46-122). At 6-years post ASCT, overall survival was 88% (95% confidence interval [CI]: 78-98) and PFS was 44% (95% CI: 28-60). The 2-year cumulative incidence of relapse and non-relapse mortality was 17% (95% CI: 6-27) and 2% (95% CI: 0-6), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI: 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favorable with low non-relapse mortality and good long-term overall survival.
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- 2024
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198. BEHAV3D: a 3D live imaging platform for comprehensive analysis of engineered T cell behavior and tumor response.
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Alieva M, Barrera Román M, de Blank S, Petcu D, Zeeman AL, Dautzenberg NMM, Cornel AM, van de Ven C, Pieters R, den Boer ML, Nierkens S, Calkoen FGJ, Clevers H, Kuball J, Sebestyén Z, Wehrens EJ, Dekkers JF, and Rios AC
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- Humans, Immunotherapy methods, Coculture Techniques methods, T-Lymphocytes immunology, Imaging, Three-Dimensional methods, Neoplasms immunology, Neoplasms pathology, Neoplasms therapy
- Abstract
Modeling immuno-oncology by using patient-derived material and immune cell co-cultures can advance our understanding of immune cell tumor targeting in a patient-specific manner, offering leads to improve cellular immunotherapy. However, fully exploiting these living cultures requires analysis of the dynamic cellular features modeled, for which protocols are currently limited. Here, we describe the application of BEHAV3D, a platform that implements multi-color live 3D imaging and computational tools for: (i) analyzing tumor death dynamics at both single-organoid or cell and population levels, (ii) classifying T cell behavior and (iii) producing data-informed 3D images and videos for visual inspection and further insight into obtained results. Together, this enables a refined assessment of how solid and liquid tumors respond to cellular immunotherapy, critically capturing both inter- and intratumoral heterogeneity in treatment response. In addition, BEHAV3D uncovers T cell behavior involved in tumor targeting, offering insight into their mode of action. Our pipeline thereby has strong implications for comparing, prioritizing and improving immunotherapy products by highlighting the behavioral differences between individual tumor donors, distinct T cell therapy concepts or subpopulations. The protocol describes critical wet lab steps, including co-culture preparations and fast 3D imaging with live cell dyes, a segmentation-based image processing tool to track individual organoids, tumor and immune cells and an analytical pipeline for behavioral profiling. This 1-week protocol, accessible to users with basic cell culture, imaging and programming expertise, can easily be adapted to any type of co-culture to visualize and exploit cell behavior, having far-reaching implications for the immuno-oncology field and beyond., (© 2024. Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF
199. Efficacy and safety of daratumumab in pure red cell aplasia after allogeneic transplantation: Dutch real-world data.
- Author
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Weverling F, Roeven M, Nijssen C, Broers AEC, Dovern E, van Rhenen A, Sluis GV, Hazenberg CLE, Balen PV, Kuipers MT, de Vooght KMK, Morsink L, Kuball J, Nur E, and de Witte MA
- Subjects
- Humans, Transplantation, Homologous, Antibodies, Monoclonal adverse effects, Red-Cell Aplasia, Pure drug therapy, Red-Cell Aplasia, Pure etiology
- Published
- 2024
- Full Text
- View/download PDF
200. Allogeneic hematopoietic cell transplantation for VEXAS syndrome: results of a multicenter study of the EBMT.
- Author
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Gurnari C, Koster L, Baaij L, Heiblig M, Yakoub-Agha I, Collin M, Passweg J, Bulabois CE, Khan A, Loschi M, Carnevale-Schianca F, Crisà E, Caravelli D, Kuball J, Saraceni F, Olivieri A, Rambaldi A, Kulasekararaj AG, Hayden PJ, Badoglio M, Onida F, Scheid C, Franceschini F, Mekinian A, Savic S, Voso MT, Drozd-Sokolowska J, Snowden JA, Raj K, Alexander T, Robin M, Greco R, and McLornan DP
- Subjects
- Transplantation, Homologous, Humans, Hematopoietic Stem Cell Transplantation methods, Myelodysplastic Syndromes, Skin Diseases, Genetic
- Published
- 2024
- Full Text
- View/download PDF
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