PhD defence S.P. (Sai) Lau

Summary:

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death and its incidence is rising. Conventional treatment methods are not capable of inducing long-term survival. The 5-year overall survival of PDAC is 8.5%.

In this thesis, we aim to explore new immunotherapeutic options for PDAC. We explored the use of dendritic cell (DC) vaccination as it has been demonstrated that DCs are limited and DC-mediated T-cell priming is impaired during pancreatic carcinogenesis. We first investigated the efficacy of allogeneic-lysate DC vaccination in a poorly immunogenic murine model of PDAC to acquire preclinical support of our rationale. The finding of T-cell driven cross-reactive tumor-specific responses substantiated the application of DC vaccination in the REACtiVe trials. We targeted patients with resected disease in the REACtiVe-1 trail and demonstrated that DC vaccination was safe and treatment-induced tumor-specific T-cell responses could be found. We also investigated if modulation of the tumor microenvironment may improve T-cell immunity as the majority of patients present with unresectable pancreatic disease. In our murine model, clinically effective antitumor responses could be found when DC therapy was combined with an anti-CD40 agonist. We therefore initiated the REACtiVe-2 trail; here we explore the safety and efficacy of DC/anti-CD40 combination therapy for patients with metastatic pancreatic disease.  This trial is currently running. Furthermore, a heat-inactivated mycobacterium combined with stereotactic body radiotherapy was safe and induced transient lymphodepletion and signs of immune activation in patients with locally advanced pancreatic cancer (LAPC-2 trail).