Photodynamic Therapy and Ionizing Radiation – A Combined Approach for Effective Treatment of Bladder Carcinoma.
Final Report Abstract
Focal therapies such as photodynamic therapy (PDT) and ionizing radiation (IR) are promising options for minimal-invasive treatment of bladder cancer (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 was intended to investigate first the benefits of PDT with the near-infrared photosensitizer THPTS in combination with IR for the effective treatment of BCa. In vitro experiments were performed in human BCa organoids showing an inverse bladder-like structure. Treatment with IR+PDT showed tumor-selective cytotoxicity with synergistic effects in BCa organoids. Thereby, IR+PDT led to multimodal tumor cell death (e.g. via apoptosis, necroptosis, ferroptosis) depending on the cellular context. Migration of cocultured T cells into the environment of treated organoids illustrates the immunogenic potential of IR+PDT. Safety and effectiveness of local PDT+IR (single-/triple-time; vs. monotherapy and untreated controls) was studied in the orthotopic F344 Fischer rat BCa model. Kaplan-Meier analysis was followed by histological examination of rat bladders with determination of viable tumor count, the maximum basal diameter and the evaluation of the tumor regression grading. The in vivo trials indicated the need for multiple applications of PDT and/or IR. Triple PDT led to a doubling of median survival compared to untreated controls. In the triple-time IR+PDT group as well as the IR group, the termination criteria were not reached during the experimental period. The superiority of the combination therapy was subsequently demonstrated in the histological analysis. It could be demonstrated that only the triple IR+PDT led to a treatment response in all tumors. The radiation-induced damages to the urinary bladder wall were low with fractionated treatment. 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. A comparative analysis of immunomodulation in vivo was not expedient due to the frequently achieved complete tumor regression in the trial groups. The analyses of the local and systemic immune response will be continued in a further officially approved cohort with a defined termination date.
Publications
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Synergistic effects of ionizing radiation (IR) and photodynamic therapy (PDT) in human bladder cancer organoids, 74th Congress of the German Society of Urology (DGU), 21th – 24th September 2022, Hamburg, Germany
A. Reinhold, A. Glasow, I. Patties, A. Weimann, S. Nürnberger, J. Neuhaus & M. Berndt-Paetz
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Cell Line-Based Human Bladder Organoids with Bladder-like Self-Organization—A New Standardized Approach in Bladder Cancer Research. Biomedicines, 11(11), 2958.
Berndt-Paetz, Mandy; Han, Shanfu; Weimann, Annett; Reinhold, Annabell; Nürnberger, Sandra & Neuhaus, Jochen
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Ionizing radiation (IR) and photodynamic therapy (PDT) led to necroptosis- and ferroptosis-induced cytotoxicity and immune cell invasion in human bladder cancer organoids, 75th Congress of the German Society of Urology (DGU), 20th – 23th September 2023, Leipzig, Germany
A. Reinhold, A. Glasow, S. Nürnberger, J. Neuhaus & M. Berndt-Paetz
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Ionizing radiation (IR) and photodynamic therapy (PDT) led to prolonged survival and tumor reduction in an orthotopic rat bladder cancer model, 76th Congress of the German Society of Urology (DGU), 25th – 28th September 2023, Leipzig, Germany
S. Nürnberger, A. Glasow, S. Gonsior, E. Pączek-Hippe, J. Neuhaus & M. Berndt-Paetz
