CRC Transregio 221|Projects

Project A01

 

Deciphering the role of HLA-DO in immune responses after allogeneic stem cell transplantation.  

Site: Erlangen  
Principal Investigator: Dr. rer. nat. Hannah Reimann, PD Dr. Dr. med. Anita Kremer, Ph.D.

Summary Project A01

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.

 

Contact to Principal Investigator

Dr. rer. nat. Hannah Reimann

Universitätsklinikum Erlangen

Medizinische Klinik 5

Hartmannstraße 14

91052 Erlangen

T: 09131 85-36287

hannah.reimann(at)uk-erlangen.de

PD Dr. Dr. med. Anita Kremer, Ph.D.

Universitätsklinikum Erlangen

Medizinische Klinik 5

Ulmenweg 18

91054 Erlangen

T: 09131 85-43183

anita.kremer(at)uk-erlangen.de

Project A02

 

Efficacy and safety of HLA-DPB1-specific T cell receptors as mediators of graft-versus-leukemia effect.

Site: Regensburg
Principal Investigators: Prof. Dr. med. Simone Thomas, Prof. Dr. med. Wolfgang Herr

Summary Project A02

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.

 

Contact to Principal Investigators

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

wolfgang.herr(at)ukr.de

simone.thomas(at)ukr.de

 

Project A03

 

Advanced CAR T cell engineering to augment the graft-versus-leukemia effect of allogeneic HSCT

Site: Würzburg
Principal Investigators: Prof. Dr. med. Michael Hudecek, Prof. Dr. med. Hermann Einsele

Summary Project A03

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.

 

Contact to Principal Investigators

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

hudecek_m(at)ukw.de

einsele_h(at)ukw.de

Project A04

 

Novel tri-specific T-cell activating antibodies for personalized graft-versus-leukemia therapy

Site: Würzburg
Principal Investigators: Dr. med. Thomas Bumm, Dr. rer. nat. Zeinab Mokhtari, Prof. Dr. med. Gernot Stuhler

Summary Project A04

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.

 

Contact to Principal Investigators

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

bumm_t(at)ukw.de

T: +49 931 201-44051

Stuhler_g(at)ukw.de

 

Mokhtari_z(at)ukw.de 

Project A06

 

Metabolic stress related immune alterations with impact on graft-versus-leukemia effect in allogeneic stem cell transplantation.

Site: Erlangen
Principal Investigators: Prof. Dr. med. Dimitrios Mougiakakos, Prof. Dr. med. Andreas Mackensen

Summary Project A06

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.

 

Contact to Principal Investigators

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

dimitrios.mougiakakos(at)uk-erlangen.de

andreas.mackensen(at)uk-erlangen.de

Project A07

 

Enhancing graft-versus-leukemia responses by donor-derived CAR-modified CD8+ T memory stem cells

Site: Regensburg
Principal Investigator: Dr. med. Dennis Harrer, Prof. Dr. med. Luca Gattinoni

Summary Project A07

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.

Contact to Principal Investigators

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

dennis.harrer(at)ukr.de

luca.gattinoni(at)ukr.de

 

Project A08

 

Timed targeting of cGAS / STING to improve tissue-regeneration and anti-tumor responses following allo-HSCT

Site: Regensburg
Principal investigator(s): Prof. Dr. med. Hendrik Poeck, Dr. rer. nat. Christian Schmidl, PhD

Summary Project A08

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.

Contact to Principal Investigators

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

hendrik.poeck(at)ukr.de

christian.schmidl(at)ukr.de