Paving the way for immunotherapy in pancreatic cancer by unravelling its tumour microenvironment and exploring a novel combination immunotherapy consisting of a CD40 agonist and interleukin-15

Pancreatic Ductal Adenocarcinoma (PDAC) has the worst 5-year survival of all cancers nowadays and is projected to become the 2nd leading cause of cancer-related death by the end of this decade. Despite hopeful breakthroughs in new treatment options for other cancer types, no improvement has been made for pancreatic cancer patients. The unique tumour microenvironment (TME) of PDAC is held responsible for the great amount of therapy resistance towards current and novel treatment schemes. More specifically, a profound desmoplastic reaction, orchestrated by activated pancreatic stellate cells (PSC), causes shielding of the tumour and an extremely high intra-tumoural pressure. This leads to a virtually impenetrable tumour resulting in this dismal prognosis for PDAC patients. Therefore, new treatment options targeting not only the tumour but also this particular TME are urgently needed. Hence, this thesis focusses on the development of new combination strategies to address the highly unmet medical need. Recently, immunotherapy has booked unseen successes in the treatment of patients with malignant melanoma, non-small-cell lung cancer and kidney cancer. More specifically, activating T cells by using so-called immune checkpoint inhibitors like PD-(L)1 and CTLA-4 unlocked an unseen potential for treatment of cancer. The Nobel Prize 2018 for this discovery underlines the significance of this finding. However, despite their success, these checkpoint inhibitors failed to improve survival in PDAC patients. Therefore, I focussed in this thesis on the potential of Natural Killer (NK) cells to attack both tumour and its TME. As professional cancer killing cells, they are prime candidates for battling cancer. From the plethora of cytokines that could stimulate NK cells, Interleukin(IL)-15 is deemed to be one of the most attractive, evidenced by its third place on the cancer immunotherapy trials network (CITN) priority list of immunotherapy agents. Hence, I sought to investigate the potential of IL-15 stimulated NK cells to kill not only PDAC cancer cells (PCC) but especially also the stromal PSC. Here, I demonstrated that NK cells are capable of killing both cell types and this to a significantly greater extent after IL-15 stimulation. This contact-dependent killing was partially regulated by the NKG2D receptor but the full mechanism still has to be further clarified. I confirmed these results in an ex vivo assay using human tumour-derived PSC and autologous NK cells, underlining the potential of IL-15 for future PDAC treatments. Next, I investigated the potential of combining IL-15 with a CD40 agonist for the treatment of cancer. The latter has the specific capacity to prime the immune system and has already proven anti-cancer and anti-stromal effects in PDAC. Using two different mouse models of PDAC, I showed that when these agents are combined, they invigorate each other resulting in profound anti-tumour responses and significantly prolonged survival with the majority of mice becoming tumour-free in both models. In-depth research revealed that this combination of immunotherapeutic agents resulted in increased numbers of both NK cells and CD8 T cells and a reduction of regulatory T cells in the tumour. In summary, this thesis provides evidence for inclusion of NK cell targeting therapies in the treatment of PDAC. In particular, IL-15 shows great potential to accomplish improved treatment outcome. I provided a solid foundation for initiation of an early phase clinical trial investigating IL-15 combined with a CD40 agonist.

Publication year:2020

Keywords:Doctoral thesis

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