Photodynamic Therapy and Ionizing Radiation – A Combined Approach for Effective Treatment of Bladder Carcinoma.

• Applicant: Dr. Mandy Berndt-Paetz
• Subject Area: Reproductive Medicine, Urology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448260160

The development of new organ-sparing treatment methods for bladder cancer (BCa) is a hot issue of urological research. Focal therapies such as photodynamic therapy (PDT) and ionizing radiation (IR) are promising options for minimal-invasive treatment of BCa. PDT and IR mediate tumor destruction with release of specific tumor molecules which can prime the immune system for further destruction of persistent tumor cells, concurrent metastatic disease and may also reduce tumor recurrence. The project is intended to investigate first the benefits of a focal PDT+IR combination therapy for multimodal treatment of BCa. For PDT we will use the novel photosensitizer Tetrahydroporphyrin-Tetratosylat (therapeutic depth ≥ 15 mm) which resulted in a significant reduction of muscle-invasive tumors after single-time application in our preliminary in vivo study. The safety and efficacy of local PDT+IR (single-time/triple; vs. monotherapy and control treatment) will be explored in an orthotopic Fischer rat BCa model. Aim is providing evidence of increased survival time after treatment by Kaplan-Meier analysis and determining reduced tumor size (tumor volume and invasiveness) in serial bladder tissue sections. In addition, analyses of immune stimulation by quantification of local immune cell recruitment (cytotoxic T cells, T helper cells, M1 macrophages) after treatment will be performed by immunohistochemistry in bladder sections. To determine whether an adjuvant immunotherapy would be beneficial following PDT+IR, immune cell - tumor cell - interactions (e.g. via PD-1/PD-L1) will be studied by in situ proximity ligation assay and 3D confocal laserscanning microscopy. In human organotypical BCa spheroids, which can serve as models for invasive BCa, we will study cell death mode and released tumor molecules by flow cytometry. Further on, immune cell invasion into organoids after addition of monocytes and T cells will be studied by live cell imaging under different treatment conditions. The development of a novel PDT+IR combination therapy could provide a gentle, effective and resistance-independent treatment option for BCa. Immune priming by PDT+IR could contribute to long-term success of therapy (reduced tumor recurrences and metastases) or may be enhanced by adjuvant immunotherapy.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Annegret Glasow; Professor Dr. Jochen Neuhaus