Translational groups

Project title: Translational group for drug repurposing and target identification in difficult-to-treat cancers

Main applicant: Dr. Raquel Blazquez (University Hospital Regensburg)

Participating locations: FAU Erlangen-Nuremberg, Julius-Maximilians-Universität Würzburg

The BZKF-TLG-PRe-Drug (Preclinical drug repurposing and target identifi-cation in hard-to-treat cancers) translation group aims to establish a platform for drug repurposing and target identification within the BZKF that enables the rapid translation of approved drugs into phase I clinical trials. To this end, the BZKF-TLG-PRe-Drug is working on a preclinical pilot study for triple negative breast cancer (TNBC) and lung adenocarcinoma (LUAC) to identify ferroptosis-inducing drugs (PRe-Ferro 001). Compared to traditional approaches to drug development, drug repurposing significantly reduces the cost and, more importantly, the time required to bring a drug into the clinic. In addition, these drugs have been medically and chemically optimized and have well-characterized pharmacokinetics. For this reason, the group is focusing on FDA-approved agents that can be repurposed for cancer treatment and the mechanism of action of ferroptosis induction, a newly described form of cell death that is particularly effective in highly plastic (mesenchymal) and therapeutically challenging tumor cells. In a preliminary study, we identified artesunate, an anti-malaria drug, as a potent ferroptosis inducer. The aim is to develop a predictive marker signature and validate it in preclinical samples. The expression of selected predictive markers will be evaluated in a series of TNBC and LUAC samples in collaboration with pathologists from the BZKF network Molecular Tumor Board and Early Clinical Trial Unit (MTB/ECTU) and the BZKF working group "Biobank" and will be used to develop a classifier for ferroptosis sensitivity.

Project title: Investigation of the combined effect of inhibitors of the MIA molecule

and immune checkpoint inhibitors for the treatment of malignant melanoma

Lead applicant: Prof. Dr. rer. nat. Anja Katrin Bosserhoff (FAU Erlangen-Nuremberg)

Melanoma is a highly malignant tumor that originates from pigment cells. The most dangerous aspect of this tumor is its ability to metastasize early. The melanoma cells can manipulate the immune system via important checkpoints in such a way that they evade attacks by the immune system. To switch off this mechanism, so-called (immune) checkpoint inhibitors are used for melanoma therapy. However, their effect is usually not permanent, as the tumor cells develop resistance mechanisms, and they are sometimes associated with considerable side effects. The protein MIA is produced in large quantities by melanoma cells, but not by normal pigment cells. The release of MIA enables the tumor cell to detach itself from its surroundings, thereby migrating into other tissues and forming metastases there. In addition, by binding to certain surface molecules on immune cells, MIA suppresses the immune system and thus a natural immune response against the tumor. MIA also appears to be a promising therapeutic target. The group has succeeded in uncovering the molecular mechanism of MIA's effect on melanoma cells and, based on this, in developing substances that can be used to effectively inhibit MIA. Preclinical models have shown that the application of these new substances can induce a significant reduction in metastasis and an almost complete reversal of immunosuppression. The aim of this project is to investigate whether the response to immune checkpoint inhibitors can be improved by the combined administration of MIA inhibitors. In this way, the basis for a novel, effective and tolerable therapy for the treatment of melanoma patients is to be created and its clinical application then further advanced at the BZKF.

Project title: CAR T Control - Understanding and Addressing Toxicities of CAR T-Cell Therapy

Applicant: Prof. Dr. Marion Subklewe (LMU Hospital Munich)

Participating sites: University Hospital Erlangen

Members: PD Dr. med. Kai Rejeski, PD Dr. Fabian Müller, Prof. Dr. Frederik Graw, Prof. Dr. Louisa von Baumgarten, Prof. Dr. Nathalie Albert

Chimeric antigen receptor T-cell therapy (CAR-T) has significantly changed the therapeutic landscape of advanced B-cell neoplasia and is now also being tested for the treatment of solid tumors and autoimmune diseases. Unfortunately, CAR-T associated side effects, which often go hand in hand with treatment response, are often long-lasting and can lead to significant limitations in quality of life. As part of the BZKF Cellular Immunotherapies Lighthouse, structures for the prospective collection of clinically annotated patient samples (n>200 CAR patients) have already been established and are now being used highly efficiently for associated translational support projects. The pathophysiological relationships of the most important side effects of modern T-cell based immunotherapies are being explored. In the group's comprehensive work program, serological and imaging biomarkers of neurotoxicity are analyzed and interactions between systemic inflammation and hematopoiesis are investigated. In addition, the group focuses on long-term changes in the immune system and their consequences for adaptive immunity. Machine learning is used to predict toxicity and therapy response. The knowledge gained will deepen our pathophysiological understanding of the particular side effects and enable risk-adapted interventions for CAR T-cell therapies and other cell therapies.

Project title: TANGO - Unravel the power of microbial meTabolites As a Novel precision oncoloGy approachin CAR T cell treated patients

Applicant: Prof. Dr. Hendrik Poeck (University Hospital Regensburg)

Participating sites: University Hospital Erlangen, LMU Klinikum München, TUM Klinikum München, University Hospital Würzburg

The composition of microorganisms in humans (the so-called microbiome) is crucial for a large number of physiological processes. Cancer immunotherapies such as CAR T-cell therapy are significantly modulated by the microbiome. This enables the development of novel microbiome-addressing interventions to overcome previous limitations of adaptive cell therapies. In two work packages, the TANGO initiative will investigate the microbial metabolome of patients with regard to its association with the efficacy and side effects of CAR T-cell therapy in collaboration with five sites associated in the BZKF and other Bavarian and European networks. Subsequently, the findings will be translated in reverse into established preclinical models in order to make the findings mechanistically tangible. We will use mixtures of pure metabolites and stool from donors based on their "metabolite profile" (Precision Fecal Microbiome Transplantation, or "Precision FMT"). The findings will in turn form the basis for a multicenter "Precision FMT" study within the NCT/BZKF/DKTK network for CAR T-cell patients with biomarker-detected "intestinal dysbiosis". The recent establishment of an accredited FMT laboratory in Regensburg for the production of such a precision FMT product is a unique prerequisite for this project.