Using organotypic tumour slices to optimise 5T4 CAR-T cell therapy for pancreatic ductal adenocarcinoma

Cancer stem cells (CSCs) can drive tumorigenesis as founder elements or through malignant cells that gain stem cell traits. CSCs are defined as slowly replicating cells, where bulk tumour growth arises from non-CSCs. Therapeutic strategies target fast-replicating cells in bulk tumour, as more quiescent CSCs avoid targeting and contribute to recurrence and metastatic spread by repopulating the non-CSC compartment. Although challenging, targeting CSCs is critical in the search for curative cancer treatments. The oncofetal tumor-associated antigen 5T4 (TBGP) has been identified as a CSC marker in several malignancies. OXB have developed immunotherapies targeting 5T4 including a Vaccinia-based vaccine (Trovax) and 5T4-directed chimeric antigen receptor T-cells (CAR-T) (OXB-302) with positive responses in clinical trials.

Although promising, Vaccine and CAR-T cell therapies are less effective in solid tumours due to inefficient tumour targeting, the immunosuppressive microenvironment; and tumour heterogeneity/plasticity. These factors are particularly prevalent in pancreatic ductal adenocarcinoma (PDAC) - a malignancy with poor prognosis and limited treatment options. Live patient-derived tumour slices are a valuable tool for investigating these factors as they mimic the tumour in vivo. Within the slices the native immune cells, stromal architecture and tumour cell antigenic heterogeneity are maintained.

Thus, we propose to analyse the OXB-302 anti-5T4 CAR-T cell therapy in PDAC patient-derived tumour slices. CAR-T cells are generated from autologous patient blood to allow analysis in a physiologically representative scenario. In vitro analysis will compliment this work to understand the challenges facing CAR-T cells when targeting solid tumours. Analysis of supernatants generated from the culture of tumour slices can provide novel targets and will lead to the administration of combination therapies to augment CAR-T function.