Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer, with a median survival time of <11 months. While incidences of PDAC continues to rise, treatment options remain limited and largely ineffective. The complex genomic, microenvironmental and immunophenotypic heterogeneity of PDAC tumours presents as a major obstacle in the assessment and development of novel therapeutic interventions. Immunotherapies aim to treat cancer through the activation and enhancement of anti-tumour immunity and have shown great success in the treatment of haematological cancers. However, they are limited in their ability to reach solid tumours such as PDAC. The discouraging success rate of immunotherapies in solid tumours may be due, at least in part, to the lack of representative preclinical models. Current preclinical models are heavily reliant on murine immune compartments or reconstitution with an allogeneic human immune system (HIS), and thus do not represent the immunophenotypic variations between patients.

In this dissertation I outlined the development of a novel preclinical model of human pancreatic cancer (hPC) that incorporated patient derived organoids (PDOs) with autologous splenic mononuclear cell (SPMC)-derived HIS mice. I first assessed the immunophenotypic profile of lymphocytes, primary tumour tissue and adjacent tissue from patients with PDAC, intraductal tubular papillary neoplasm (ITPN) and ampullary carcinoma (AMP). I then outlined the derivation of PDAC, ITPN and AMP PDOs, and in vitro retention of parental morphology and key biomarkers. PDAC and ITPN PDOs were then implanted orthotopically into NSG-dKO mice to assess tumour establishment, recapitulation of parental tumour histology and gene expression. Mice bearing hPC PDO grafts were then humanised with either autologous or allogeneic SPMCs (hu-PDOs) for the assessment of graft survival, tumour immune infiltration, inflammation and upregulation of antigen presentation, pancreatic cancer, and immune pathways. Lastly, I treated autologous hu-PDOs with PD-1 blockade alone or in combination with CTLA-4 blockade to assess treatment linked inflammation, immune-mediated tumour killing and differential gene expression. Treatment response to immune checkpoint inhibition was further assessed with complementary in vitro autologous and allogeneic hPC PDO + SPMC derived T cell co-cultures.

hPC PDOs in this study were established with a high level of success and formed in vivo grafts that were representative of the primary tumour. hPC PDO grafts appeared susceptible to both autologous and allogeneic immune attack, showing increased inflammation and graft rejection post allogeneic immune reconstitution. The autologous hu-PDO model showed increased immune-mediated tumour clearance in response to combined anti-PD-1 + anti-CTLA-4. Patient specific treatment responses to PD-1 blockade alone were observed in autologous hu-PDOs and appeared to correspond with in vitro co-cultures. Overall, the work presented within this dissertation demonstrates a novel in vivo model that is highly applicable to the field of immuno-oncology and shows promise in the modelling of individual treatment response to immunotherapies.