Research > Focus B > Work Packages B01
Summary
Based on work in the first funding period, we will specifically study mechanisms of resistance to therapies employing glioma-specific T cells. A focus will be on strategies to enhance T cell homing and to overcome T cell dysfunction in the glioblastoma microenvironment. Furthermore, the analysis of post-treatment human glioma tissue from clinical trials and defined transgenic T cells recognizing glioma antigens allows testing hypotheses on determinants of metabolic, genetic, and exogenous factors defining T cell states in the glioblastoma microenvironment.
Task 1
Identify molecular determinants of genotype-dependent T cell exhaustion in the glioma microenvironment
Steps / Workflow
- Define relevance of mutational load via CV in hypermutated GBM
- Define antigens and TCR Molecular and functional profiles of tumor-associated immune cell subsets
Task 2
Understand the metabolic, genetic and epigenetic determinants of T cell dysfunction preventing response to immune checkpoint inhibition
Steps / Workflow
- Define genetic determinants of T cell dysfunction and discover epigenetic biomarkers of response to ICI.
- Investigate spatial distribution of reactive T cells Metabolic profiling of T cell dysfunction with MALDI
- Novel imaging of metabolites
Task 3
Validate the osteopontin-CD29 pathway on activated T cells as a key and therapeutically targetable signalling event promoting T cell exhaustion in the glioma microenvironment
Steps / Workflow
- Evaluation of CD29 blocking antibodies to prevent T cell exhaustion in experimental glioma
- Generation of genetic models targeting CD29 on T cells and myeloid OPN
- Profiling T cells function of CD29 deficient adoptively transferred TCR-transgenic T cells
Task 4
Develop genetic engineering strategies to improve homing and resilience of T cell receptor transgenic T cells for adoptive transfer
Steps / Workflow
- Evaluation of genetic engineering techniques and adoptive transfer of CXCL13 overexpressing TCR transgenic T cells
- Flow cytometry + scRNA Seq. + Histology + MRI monitoring Evaluation of improved T cell homing and its therapeutic effect + transcriptomic features of modified T cells
Previous Funding period
PRINCIPLE INVESTIGATORS
BUNSE, THERESA, NEE SCHUMACHER, DR. RER. NAT.
Post Doc
Heidelberg University, Mannheim Medical Faculty, University Hospital Mannheim, Department of Neurology, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
PLATTEN, MICHAEL, PROF. DR. MED.
Chairman/Head
Heidelberg University, Mannheim Medical Faculty, Mannheim University Hospital (UMM), Department of Neurology & DKFZ, Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany