Assessing anti-tumour immunity and adoptive T cell therapies in solid tumours

Abstract

Adoptive T cell therapies have achieved tremendous progress in haematological malignancies and represent an emerging modality for solid tumours with limited treatment options. This thesis aims to improve their translation in pancreatic and appendiceal cancers. In pancreatic cancer, mesothelin (MSLN)-targeting chimeric antigen receptor (CAR) T cells have shown limited efficacy, and the antigen remains poorly characterised. In a cohort of 74 patients examined by immunohistochemistry (IHC), high MSLN expression (H-score ð€€ƒ 62) was significantly associated with improved relapse-free survival (p = 0.021). Analysis of transcriptomic datasets found that MSLN-high tumours exhibited an immunosuppressive microenvironment with reduced CD8 T cell abundance, supported by IHC in a small validation cohort (n = 10). In appendiceal cancer, adoptive T cell therapies have not been explored, and CAR T cell and tumour infiltrating lymphocyte (TIL) therapies were assessed for the first time. MSLN and mucin-1 (MUC1) were detected in three of four patient-derived organoids by flow cytometry and transcriptomic analyses. Two anti-MSLN CAR T cell products, SS1 and P4 CAR T cells, demonstrated effective killing of antigen-positive organoid-derived monolayer cells in impedance-based cytotoxicity assays. TIL expansion ð€€„ð€€ƒ 15 million cells) was achieved from 73% (8/11) of surgical specimens, yielding highly enriched CD3+ populations (>95%) with upregulated functional responses to superantigen stimulation, but consistent tumour-specific activity was not observed in co-cultures with matched, dissociated organoids. Overall, this thesis identifies a barrier limiting the efficacy of MSLN-targeting CAR T cells in pancreatic cancer and demonstrates the potential of CAR T cell and TIL approaches in appendiceal cancer, offering crucial insights to guide the development of more effective adoptive T cell therapies in these malignancies of significant unmet need