Cancer immunotherapies have revolutionized the treatment options for patients with advanced stage disease. However, only a subset of patients experiences (durable) response. Reasons for therapy failure can be tumor intrinsic, or due to alterations within the immune system.

Our group aims to understand the alterations of the immune system better, which contribute to treatment response and failure, especially in the context of T cell-based cancer immunotherapies like immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cell therapies.

By collaborations with several Departments and Institutes within the University Medical Center Mainz (Department of Hematology and Medical Oncology, University Cancer Center (UCT), Department of Dermatology, Institute of Immunology, Institute of Pathology) and with the Institute of Molecular Biology (IMB) Mainz, we aim to perform highly translational as well as latest state of the art translational research.

Project 1: Modifying macrophage polarization to improve cancer immunotherapies

The tumor microenvironment (TME) contains several immunosuppressive factors, which dampen the anti-tumor reactivity of cytotoxic T cells and therefore the efficiency of T cell-based cancer immunotherapies like immune checkpoint blockade (ICB). One of these suppressive factors are tumor-associated macrophages (TAM). Macrophages can generally polarize towards a pro-inflammatory (M1-like) or anti-inflammatory (M2-like) phenotype, with the latter supporting tumor growth. 

Within this DFG-funded research project, and in collaboration with Toszka Bohn from the Institute of Immunology, we aim to characterize macrophages in melanoma tumor samples, and to analyze their correlation with response to immunotherapies. Further, we are analyzing characteristics of peripheral blood monocytes in melanoma patients, which can potentially serve as biomarkers for therapy response. To identify targets involved in macrophage polarization, we will additionally perform a CRISPR knockout screen in macrophages.

Understanding and modifying macrophage polarization within the TME can help to develop personalized immunotherapies in the future, by supporting the immune cell-mediated tumor clearance.

Project 2: Characterization of age-related functional alterations in healthy T cells that are essential for efficient CAR T cell products

T cells are one of the most important immune cell subsets in cancer immunotherapies, and they can efficiently clear cancer cells, as successfully demonstrated in cellular therapies like in chimeric antigen receptor (CAR) T cell therapies. At least since the application of this therapy as standard of care for some hematologic malignancies, defining and modifying T cell fitness, and thus the efficacy of this treatment, is a major research focus in this field. 

It is well established, that chronological and biological age of humans do not necessarily correlate. Therefore, we study aging of T cells as a specific factor influencing their fitness status. Firstly, we are addressing this research question in healthy donors. We produce CD19 CAR T cells, and analyze them for CAR T cell functionality and aging aspects. Furthermore, we are studying their transcriptome for differential gene expression between fit and unfit CAR T cells, to identify targets or gene expression signatures potentially determining CAR T cell therapy response. Subsequently, we will validate our findings in a CAR T cell-treated patient cohort. 

With our results, we aim to contribute to an individualized therapy decision making in the growing field of (cellular) cancer immunotherapies, and to modulate (CAR) T cell fitness to improve treatment response rates.