The MINT Clinician Scientist Program Participants

Investigation of immune evasion mechanisms of cancer cells have led to the clinical use of immune checkpoint inhibitors (ICIs) against PD-1 and PD-L1 in urothelial bladder cancer (UBC). However, one major problem is that only 20% of ICI-treated patients respond to the therapy. To improve patient´s selection, and to protect non-responder of unnecessary treatment, a thorough investigation of immune-cancer cell interactions in the UBC immunological tumor microenvironment (TME) is urgently needed to understand the complexity. In my project, I will investigate tissue from ICI-treated UBC patient cohorts to identify cell-cell-interactions of the UBC TME to understand its spatial composition and how this is related to therapy response. In my project, I will use state-of-the-art spatial technologies, including CO-Detection by indEXing (CODEX) to build a spatially resolved single-cell map of UBC patients treated with immunotherapy. Deciphering the tissue architecture of treated UBC will detect advanced immunophenotypes which will better stratify UBC patients and will improve immunotherapy responses.

The metabolic syndrome (MS) is a cluster of risk factors and can lead to multiple vascular complications. Most of the patients with MS suffer from insulin resistance (IR), which can contribute to the development of proteinuric chronic kidney disease (CKD). Disturbance of sodium homeostasis resulting in sodium retention and hypertension is common in MS. To get a better pathophysiologic understanding a novel model of insulin resistance and proteinuric kidney disease will be established. Furthermore in-depth investigations in proteolytic ENaC activation and its impact on sodium homeostasis in the setting of proteinuric CKD and IR are planned as well as studies on the role of aldosterone in proteolytic ENaC activation and diuretic resistance. As a goal there should be a better understanding of pathophysiologic processes increasing the vascular burden of MS.

A significant share of degenerative ataxias is caused by pathogenic variants coding for ion channels. Next generation sequencing (NGS) techniques have expanded the number of known pathogenic variants as well as variants of unknown significance in these genes, including CACNA1A, KCNC3 and KCND3, among others. Since comprehensive longitudinal natural history studies are still missing in these patient cohorts, my project aims to study the clinical course and phenotypic spectrum in these conditions. Electrophysiological studies of mutant channels offer a promising opportunity of studying the functional consequences of variants in these genes, allowing to assess the pathogenicity of gene variants. Further, studying the effects of small molecules (such as 4-aminopyridine) on mutated ataxia channels may inform future therapeutic trials in patients and pave the way for personalized medicine.

In this project my team develops RNA-modulators for T-cell immunotherapies. Specifically, we focus on donor lymphocytes - a T-cell-therapy given to hematopoietic stem cell recipients in order to prevent or to treat leukemia relapse. Donor lymphocytes, however, often induce severe graft-versus-host effects. Graft-versus-host effect is mechanistically very similar to the therapeutic graft-versus-leukemia effect. In this project we use a precision immunosuppression concept and apply various mixtures of chemically modified siRNAs and mesenchymal stem cell derived extracellular vesicles to T cells with the aims to (1) prevent graft-versus-host effects while preserving graft-versus-leukemia effects, and (2) induce longer lifespan of therapeutic donor lymphocytes. We use fully chemically modified siRNAs similar to approved siRNA drugs - warranting high translation potential to this project. We aim to set the stage for further clinical development of RNA-based ex vivo treatments of donor lymphocytes - making this T-cell-immunotherapy safer and more efficient for all patients.

In drug-resistant focal epilepsy, identifying small epileptogenic lesions by magnetic resonance imaging (MRI) is crucial because it enables epilepsy surgery – a treatment that can significantly reduce seizure activity and improve overall outcomes. The goal of this research project is to improve the detection of such lesions, in particular focal cortical dysplasias, by using ultra-high field 9.4T MRI, which provides higher-resolution images than standard clinical 3T MRI. This project is a collaboration between the Department of Neurology and Epileptology (Prof. Holger Lerche) and Prof. Esther Kühn’s group “Translational Imaging of Cortical Microstructure” at the Hertie-Institute for Clinical Brain Research. We will apply specialized acquisition and post-processing techniques to characterize known lesions in detail at the ultra-high field strength. Subsequently, we aim to develop a pipeline for the automated detection of epileptogenic lesions using 9.4T MRI data.

Regardless of established risk factors, approximately 10% of children with embryonal rhabdomyosarcoma of the bladder and prostate develop local tumor recurrence after bladder-preserving resection and brachytherapy. It stands to reason that this group of patients would benefit from extended therapy. In this project, funded by the MINT-Clinician Scientist program, tissue and plasma samples from 54 patients treated in our department for embryonal rhabdomyosarcoma of the bladder and prostate will be analyzed and compared between patients with and without local tumor recurrence. The following potential molecular risk factors will be investigated in 4 projects: Molecular resection status, DNA methylation profile and transcriptome, immunological tumor microenvironment and molecular composition of extracellular vesicles. Identification of molecular risk factors for embryonal rhabdomyosarcoma of the bladder and prostate could enable optimization of preoperative treatment planning, adjustment of postoperative brachytherapy and, if necessary, personalized adjuvant systemic therapy.

In my project I would like to establish cadavers from human body donors as an aseptic resource to isolate vital nerve and muscle cells from the intestine in the intermittent life phase. My project will also provide important knowledge by comparing existing and new intestinal resections from children, adults and the deceased over the course of the project using modern immunofluorescence histology and ultrastructural analysis.

The last decades have seen an unprecedented leap in our understanding of cancer biology. At the same time, outcomes for many patients with leukemia and other malignancies remain poor. In this translational research project, I will explore the mechanisms of treatment failure in acute myeloid leukemia (AML) by focusing on the interaction of leukemic stem cells (LSCs) with the tumor immune microenvironment (TIME). 

LSCs are the major cause of relapse and treatment failure in AML due to their resistance to chemotherapy and antitumor immunity. To effectively eliminate LSCs, we need to discover their specific vulnerabilities. Here, I will use cutting-edge methods to identify and characterize LSCs at the single cell level and visualize their spatial interaction with other cells in the TIME. This will help to find new markers and molecular mechanisms of treatment resistance and pave the way for precision medicine approaches in AML.

Immune thrombocytopenia (ITP) is a condition in which antibodies to platelet antigens destroy platelets, resulting in a low platelet count. Interestingly, bleeding in ITP patients often does not correspond to the platelet count. Furthermore, recent evidence suggests that ITP patients are at increased risk of thrombosis despite low platelet counts. A better understanding of hemostatic regulation in ITP patients is critical to prevent bleeding complications and avoid treatment failure or thrombosis. The platelet phenotype in patients with ITP remains poorly understood. Procoagulant platelets are a distinct platelet subpopulation that act as a scaffold to support the assembly of prothrombinase and tenase complexes, leading to thrombin burst, fibrin formation and aggregation. In this project, we will investigate the mechanisms involved in the modulation of the platelet phenotype, particularly the formation of procoagulant platelets, in ITP patients and its potential impact on clinical outcomes such as bleeding and thrombosis.

Myocarditis, a frequent cause of sudden cardiac death, is defined as inflammation of myocardium, typically resulting from cardiotropic viral infection. The pathogenesis of viral myocarditis includes both the direct damage mediated by viral replication and the indirect injury induced by the host immune responses. Clinical diagnosis of myocarditis relies on a combination of clinical features, laboratory analyses and imaging findings. However, a definitive diagnosis is based on endomyocardial biopsy, which is not routinely employed due to concerns of complications.

The aim of the project is to develop a novel and clinically translatable imaging strategy, which can non-invasively and quantitatively visualize both the innate and adaptive immunity dynamically. This approach has the potential to facilitate the diagnosis by serving as a non-invasive imaging ‘Biopsy’ in detecting myocarditis lesions and improve the management of myocarditis patients by providing new insights of the disease and discovering reliable prognostic markers for worse outcomes.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated prothrombotic disorder leading to life-threatening thromboembolic events despite low platelet counts. HIT is caused by antibodies of the immunoglobulin G subclass that recognize complexes of the endogenous protein platelet factor 4 (PF4) and heparin. These immune complexes harbor the potential to activate platelets and multicellular effector mechanisms that drive a prothrombotic condition in patients. Despite platelets are main actors in HIT, a greater understanding regarding the contribution of different antibody-induced platelet subpopulations in this complex coagulation disorder is missing. Hence, this project aims to investigate the relevance of procoagulant PLTs, a PLT subpopulation that is increasingly identified to harbor dramatic prothrombotic potential, in a prospective clinical study. Additionally, the crosstalk of antibody-induced procoagulant PLTs with different leukocyte subsets will be investigated via the of ex and in vivo models. Findings of these studies will help to identify new mechanisms and therapeutic targets to treat the prothrombotic condition typically observed in HIT patients.