Induction of the graft-versus-leukemia (GvL) effect in the absence of graft-versus-host disease (GvHD) by CD4+ T-cells directed against DM-sensitive antigens will be tested in murine models of allogeneic bone marrow transplantation both in a minor and a major mismatch setting. Using H2-O (murine HLA-DO) knock-out and transgenic mice as well as wild type mice as recipient strains will allow us to determine the role of the tissue-specific expression of H2-O for induction of GvL effect and GvHD. In addition, we aim to unravel regulation of HLA-DO expression in human cells. Finally, we will test effects of HLA-DO regulators on GvL effect and GvHD.
Dr. rer. nat. Hannah Reimann |
Universitätsklinikum Erlangen |
Medizinische Klinik 5 |
Hartmannstraße 14 |
91052 Erlangen |
T: 09131 85-36287 |
PD Dr. Dr. med. Anita Kremer, Ph.D. |
Universitätsklinikum Erlangen |
Medizinische Klinik 5 |
Ulmenweg 18 |
91054 Erlangen |
T: 09131 85-43183 |
HLA-DPB1 mismatch antigens occur in allogeneic HSCT from unrelated donors and represent powerful leukemia rejections antigens, which can be efficiently targeted by T cells that have been genetically reprogrammed with allo-HLA-DPB1 specific T-cell receptors (TCR-DP). In this project we will develop an approach that allows for efficient and safe TCR-DP gene therapy in allogeneic HSCT. Special emphasis will be placed on the prevention of treatment-induced HLA-DP-specific alloreactivity to non-hematopoietic tissues (e.g. by „ON-Switch“ TCR or TCR-RNA transfer) and on the development of a novel humanized mouse model that enables the pre-clinical testing of this approach.
Prof. Dr. med. Simone Thomas | Prof. Dr. med. Wolfgang Herr |
LIT - Leibniz Institute for Immunotherapy (former RCI) | University Hospital Regensburg |
University Hospital Regensburg | Department of Internal Medicine III |
Department of Internal Medicine III | Franz-Josef-Strauß-Allee 11 |
Franz-Josef-Strauß-Allee 11 | 93053 Regensburg |
93053 Regensburg | T: +49 941 944-5501 |
T: +49 941 944-5142 | |
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In this project, we apply the chimeric antigen receptor (CAR) technology to augment the GvL effect of HSCT. CARs are synthetic designer receptors that redirect the specificity of T cells to recognize malignant cells. We will pursue two novel CAR targets, i.e. FLT3 in acute myeloid leukemia and SLAMF7 in multiple myeloma, and apply cutting-edge strategies to increase their efficacy (e.g. through metabolic arming) and safety (e.g. with enhanced suicide genes). To avoid GvHD, we will generate CMV-specific (endogenous TCR) CAR-T cells and employ novel in vivo models to evaluate their ability to concomitantly battle against leukemia/myeloma and CMV infection.
Prof. Dr. med. Michael Hudecek | Prof. Dr. med. Hermann Einsele |
University Hospital Würzburg | University Hospital Würzburg |
Department of Medicine III | Department of Medicine III |
Oberdürrbacher Straße 6 | Oberdürrbacher Straße 6 |
97080 Würzburg | 97080 Würzburg |
T: +49 931 201-71091 | T: +49 931 201-40001 |
We aim to develop novel bi-molecular hemibody constructs that address antigen combinations instead of single target molecules for high precision immunotherapy in the context of allogeneic HSCT. In a first step, we opt to improve the biochemical properties of the constructs focusing on stability, solubility and producibility. In a second step, we will establish humanized NSG mouse models to investigate pharmacokinetics and the specific requisites of dual antigen targeting, mimicking the clinical situation of leukemia patients undergoing allogeneic HSCT.
Dr. med. Thomas Bumm | Dr. rer. nat. Zeinab Mokhtari | Prof. Dr. med. Gernot Suhler |
University Hospital Würzburg | University Hospital Würzburg | University Hospital Würzburg |
Department of Medicine II | Department of Medicine II | Department of Medicine II |
Oberdürrbacher Straße 6 | IZKF Research Laboratory for Experimental Hematopoietic Cell Transplantation | Versbacher Straße 5 |
97080 Würzburg | Zinklesweg 10 | 97080 Würzburg |
T: +49 931 201-44977 | 97078 Würzburg | T: +49 931 201-44423 |
T: +49 931 201-44051 | ||
| Mokhtari_z(at)ukw.de |
We hypothesize that oxidative stress confers immunological “hits” that predispose for leukemia relapse. The reconstituting donor immune system, which is fundamental for the GvL effect, is negatively impacted by oxidative stress. Our project addresses the importance of redox-balance after allo-HSCT. We will assess oxidative stress and its impact on immune reconstitution and function in allo-HSCT patients. We will test interventions for improving the T-cells’ anti-oxidative capacities together with other key functional properties. Our goal is to identify novel redox biomarkers predicting relapse risk that will allow us the rational design of targeted redox modulation for relapse prevention.
Prof. Dr. med. Dimitrios Mougiakakos | Prof. Dr. med. Andreas Mackensen |
University Hospital Erlangen | University Hospital Erlangen |
Department of Medicine 5 | Department of Medicine 5 |
Ulmenweg 18 | Ulmenweg 18 |
91054 Erlangen | 91054 Erlangen |
T: +49 9131 85-43172 | T: +49 9131 85-35954 |
Relapse after alloHSCT is frequently associated with poor survival in patients with advanced B-cell malignancies. In order to investigate curative options for those patients, we are conducting in collaboration with the US National Cancer Institute (NCI) a first in human trial employing donor-derived CD19-CAR TSCMcells. In this project, we plan to perform a comprehensive and detailed immunomonitoring comparing TSCM-enriched CAR T cell products to conventional donor-derived CAR T cells from a prior NCI study conducted on a similar subset of patients. In particular, we will investigate potential benefits of the TSCM cell platform in terms of CAR T cell expansion, long-term persistence, CAR T cell functionality, safety profile and alloreactivity. Finally, by using retroviral insertion and TCR clonotype analyses, we will assess the differentiation trajectory of CD19-CAR and untransduced TSCMcells to determine how CAR signaling affect their self-renewal and multipotency.
Dr. med. Dennis Harrer | Prof. Dr. med. Luca Gattinoni |
Universitätsklinikum Regensburg | LIT - Leibniz Institute for Immunotherapy (former RCI) |
Klinik und Poliklinik für Innere Medizin III | c/o Universitätsklinikum Regensburg |
Franz-Josef-Strauß-Allee 11 | Franz-Josef-Strauß-Allee 11 |
93053 Regensburg | 93053 Regensburg |
T: +49 941 944-15557 | T: +49 941 944-38131 |
The impact of selective and timed activation or inhibition of the type I interferon inducing cGAS / STING pathway during the course of allo-HSCT and its influence on the GvL effect as well as donor T cell activation and differentiation remains unknown. Using selective receptor ligands and inhibitors, and a combination of advanced in vivo models of leukemia and lymphoma, allogeneic transplantation models, and next-generation sequencing approaches, we aim to unravel the consequences of timed cGAS/STING activation / inhibition during allo-HSCT.
Prof. Dr. med. Hendrik Poeck | Dr. rer. nat. Christian Schmidl |
University Hospital Regensburg | LIT - Leibniz Institute for Immunotherapy (former RCI) |
Department of Internal Medicine III | c/o Universitätsklinikum Regensburg |
Franz-Josef-Strauß-Allee 11 | Franz-Josef-Strauß-Allee 11 |
93053 Regensburg | 93053 Regensburg |
T: +49 941 944-5542 | T: +49 941 944-18176 |