Fu, Hongchang; (2025) Next generation ex vivo patient-derived tumour explant model for immunotherapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Over the past decade, immunotherapy has become a new pillar of cancer treatment. Despite the success of some therapeutic agents, most patients do not benefit. This can be attributed to several factors. Clinically, there is a lack of effective therapeutic targets. Pre-clinically, there is a lack of models that accurately recapitulate the patient tumour microenvironment (TME). This discrepancy highlights the urgent need for models that can close this gap. The patient-derived tumour explant model (PDE) offers a preclinical model that mimics the patient tumour microenvironment. Studies have used this model to predict the clinical response to standard-of-care immunotherapies. However, as it preserves an intact patient TME, its use for dissecting the immune- and tumour intrinsic mechanisms remains largely underexplored. In this thesis, I investigated the potential of PDE for the pharmacological modulation of tumour cell-intrinsic pathways, the nonsense-mediated decay pathway with SMG1 inhibitors, leading to anti-tumour immunogenicity, where such an elevated response is tumour-specific and not in normal-adjacent tissue. Furthermore, the PDE model was further explored to modulate immune-cell-intrinsic mechanisms. Three biological pathways were targeted with novel therapeutic agents, focusing on T cells, macrophages, and dysfunctional dendritic cells, respectively. Among these targets, the anti-OSM antibody was successfully proven to reduce the percentage of dysfunctional CD8+ T cells, paving the way for preclinical possibilities in combination therapies alongside standard-of-care immunotherapies. Meanwhile, technical innovations were developed to tackle some of the challenges in the PDE field. These efforts aimed to enhance viability and support the perfusion of external cells by vascularising PDEs with genetically engineered HUVECs and microfluidics. In summary, this thesis provides a comprehensive overview of the field. These findings and innovations highlight PDE as a promising next-generation preclinical model for cancer immunotherapy.

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