205P - Advancing pre-clinical functional tests with immune-responsive Precision Cut Bladder Tumor Slices (PCTS)

Background

Most current pre-clinical models lack reliability in predicting effects of immunotherapeutic drugs intended for treatment of advanced cancer diseases. The key problem is that they don’t reflect the complexity of the tumor microenvironment. Patient-derived tumor models, like precision cut tissue slices, present an opportunity to test the effect of drugs on both tumor cells and cells in the tumor microenvironment.

Methods

We have established an ex vivo bladder tumor model using Precision Cut Bladder Tumor Slices (PCTS). PCTS maintain the original cellular composition and tissue architecture, making them conducive to the testing of various therapies. Upon treatment with immunogenic agents, cytostatic drugs, and therapeutic antibodies, response signatures were analyzed using H&E staining, high-plex flow cytometry, and multiplex immunoassay (Luminex) of secreted cyto- and chemokines. Slices were generated with a vibratome and cultivated for two days to ensure stable tissue viability.

Results

Cellular composition and treatment responses were evaluated based on expression of tumor markers (EpCam and Nectin-4), presence of immune cells (e.g. CD45, CD3, CD19, CD11c), and activation markers (e.g. CD137, CD69). Spatial information was obtained with H&E stainings enabling insights into structural changes. Analysis of supernatants revealed dose-dependent changes in secretion of relevant cytokines and chemokines like Granzyme B, CXCL10, and MIP3a. Additionally, the results clearly reflect patient heterogeneity.

Conclusions

The PCTS model represents a promising approach to 1.) evaluate the efficacy of novel drug candidates on cells in the tumor microenvironment and 2.) screen different treatments and their combinations to achieve the best possible therapy response.

Legal entity responsible for the study

The authors.

Funding

Co-funding from the European Union's Horizon 2020 Framework Programme for Research and Innovation under grant agreement 847583, Cancera Foundation, Mats Paulsson Foundation, Inga-Britt och Arne Lundbergs Forskningsstiftelse, The Royal Physiographic Society in Lund, John och Augusta Perssons Stiftelse, Stiftelse Tornspiran, and Crafoord Foundation.

Disclosure

All authors have declared no conflicts of interest.