CRC Transregio 221|Projects

Project A01

 

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

Site: Erlangen  
Principal Investigator: Priv.-Doz. Dr. med. Anita Kremer

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

Priv.-Doz. Dr. med. Anita Kremer

University Hospital Erlangen

Department of Medicine 5

Ulmenweg 18

91054 Erlangen

T: +49 9131 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: Priv.-Doz. 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

Priv.-Doz. Dr. med. Simone Thomas

Prof. Dr. med. Wolfgang Herr

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: +49 941 944-5142

T: +49 941 944-5501

simone.thomas(at)ukr.de

wolfgang.herr(at)ukr.de

Project A03

 

CAR-engineered T cells that augment the graft-versus-leukemia effect of allogeneic HSCT.

Site: Würzburg
Principal Investigators: 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

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 bi-molecular T-cell activating antibodies for personalized graft-versus-leukemia therapy.

Site: Würzburg
Principal Investigators: Dr. med. Thomas Bumm, Prof. Dr. med. Ralf Bargou

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

Prof. Dr. med. Ralf Bargou

University Hospital Würzburg

University Hospital Würzburg

Department of Medicine 2

Department of Medicine 2

Versbacher Straße 5

Comprehensive Cancer Center Mainfranken

97078 Würzburg

Josef-Schneider-Straße 6

T: +49 931 201-44402

97080 Würzburg

bumm_t(at)ukw.de

+49 931 201-35156

 

bargou_r(at)ukw.de

Project A05

 

Targeting novel immune check points in multiple myeloma and acute myeloid leukemia to improve allogeneic hematopoietic stem cell transplantation.

Site: Regensburg
Principal Investigator: Prof. Dr. med. Philipp Beckhove

Summary Project A05

Within this CRC/TR subproject we will identify novel immune check point molecules (ICM) expressed by acute myeloid leukemia and multiple myeloma cells as well as by tumor-associated macrophages using a proprietary genome wide siRNA based screening approach. We will use established cell culture systems, preclinical mouse models and genome and proteome analyses of human samples to (i) functionally delineate the mode of action of selected ICM in modulating GvL after adoptive T cell therapy and in patients undergoing allo-HSCT and DLI and (ii) to explore the role of ICM expressed on target organs of GvHD in determining the risk and severity of GvHD after allo-HSCT.

 

Contact to Principal Investigator

Prof. Dr. med. Philipp Beckhove

University Hospital Regensburg

RCI Regensburg Center for Interventional Immunology

Franz-Josef-Strauß-Allee 11

93053 Regensburg

T: +49 941 944-5330

beckhove(at)rcii.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