EXocrine Pancreatic Insufficiency and Enzyme Replacement Therapy in Pancreatic Cancer Patients: Impact on Fecal Microbiome, Nutritional Status, Quality of Life, and Survival (EXPERT Study)

This clinical-translational project aims to investigate the impact of exocrine pancreatic insufficiency (EPI), pancreatic enzyme replacement therapy (PERT), sarcopenia, and fecal microbiome dynamics on the quality of life and survival of patients with metastatic, unresectable pancreatic adenocarcinoma (PDAC) in UICC stage IV. The ultimate goal is to provide data that can inform and enhance current German clinical guidelines for the diagnosis and management of this specific patient group. The project comprises three key components:

1.Retrospective Data Collection: 

This component analyses patient records from University Hospital Ulm to determine the prevalence of EPI and the use of PERT in patients with unresectable PDAC, establishing baseline data on current management practices and outcomes.

2. Survey Study: 

A nationwide survey of German physicians and PDAC patients to evaluate the current care landscape for PDAC with EPI. This survey will provide insights into clinical practices, challenges, and patient experiences.

3. Prospective Multicenter Cohort Study: 

This study examines the effects of EPI and PERT on quality of life, nutritional status, fecal microbiome, and survival in PDAC patients. The plan includes evaluating quality of life, collecting biomaterials (blood and stool), and assessing sarcopenia through clinical and radiological methods at various time points. Involving multiple centres, the study aims to generate robust data on the clinical benefits of PERT and other factors influencing quality of life and survival in unresectable PDAC.
 

Establishment of Urothelial Carcinoma Assembloids for Investigating Immune Checkpoint Inhibitor and Antibody-Drug Conjugate-Mediated Therapy Response

Urothelial carcinoma is the second most prevalent malignancy of the urogenital system. The prognosis for patients with locally advanced or metastatic urothelial carcinoma remains poor. While cisplatin and gemcitabine have been the standard first-line therapy for metastatic urothelial carcinoma for over 20 years, recent results from a Phase III clinical trial have demonstrated a significant improvement in progression-free survival with a combination of the antibody-drug conjugate (ADC) enfortumab vedotin and the PD-1 checkpoint inhibitor pembrolizumab, prompting a paradigm shift in first-line treatment. 

Despite improved survival rates, not all patients respond to these novel therapeutic combinations. To date, no in vitro test system has been established for therapeutics with complex molecular mechanisms, such as immune checkpoint inhibitors (ICI) or ADC. However, multicellular assembloids could serve as predictive models for individual therapeutic response. Following the successful implementation and application of urothelial carcinoma organoids for pharmacotyping with chemotherapeutics in our clinic, we now aim to develop a multicellular assembloid model system to enable the in vitro testing of therapeutics such as ICI and ADC.

Initially, T cells derived from healthy donors will be co-cultured with urothelial carcinoma organoids from our organoid biobank at varying ratios. After optimizing culture conditions and determining the ideal T cell-to-organoid ratios, potential alterations in T cell phenotypes and activation states will be investigated. Additionally, the expression of immune checkpoints on immune and tumor cells (PD-1/PD-L1, CTLA-4) will be assessed.

Subsequently, ADC and/or ICI treatments will be applied to the multicellular assembloid model system. Cytotoxicity analyses will be conducted using flow cytometry and immunohistology, and dose-response curves will be generated. Organoids will then be classified into resistant, intermediate or sensitive groups using the Jenks natural breaks method.

In the final step, the in vitro therapy response to the tested treatments will be compared with the actual clinical result of patients to assess the validity of the in vitro test model as a predictive tool for therapeutic efficacy.