Periodic Reporting for period 1 - PAVE (A nanovaccine Approach for the treatment of Pancreatic Cancer)
Período documentado: 2019-10-01 hasta 2021-09-30
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in men and women and still fatal in over 90% of patients. It is characterised by its extremely aggressive nature where it is also responsible for the
highest mortal ity rate compared to other major cancers, resulting in excess of 250,000 deaths worldwide per annum.
Current state-of-art therapies for advanced PDAC including chemo- and/or radiotherapy, despite extensive efforts, have met with only l imited success. Surgery is only appl icable for those with early stages of the disease, or to relieve symptoms, if the cancer is blocking the bile duct or the bowel . There are two major reasons for the resistance of PDAC to conventional therapy. Firstly, PDAC has a very defining hal lmark, where an abundance of stromal content is present in the tumour microenvironment to form a physical and biochemical barrier. Secondly, during progression of the disease, the body's immune system is hijacked to support the prol iferation of the cancer.
New approaches, such as immunotherapy, are therefore needed where it has already shown promise in overcoming many aspects of this resistance. Immunotherapy has the potential to treat minimal residual disease after pancreatic
resection (surgery) as wel l as for metastatic and non-resectable PDAC. Our objective for this project is to bring together a multidisciplinary and intersectoral group to develop novel vaccine approaches, including use of multiple
immunomodulating components.
highest mortal ity rate compared to other major cancers, resulting in excess of 250,000 deaths worldwide per annum.
Current state-of-art therapies for advanced PDAC including chemo- and/or radiotherapy, despite extensive efforts, have met with only l imited success. Surgery is only appl icable for those with early stages of the disease, or to relieve symptoms, if the cancer is blocking the bile duct or the bowel . There are two major reasons for the resistance of PDAC to conventional therapy. Firstly, PDAC has a very defining hal lmark, where an abundance of stromal content is present in the tumour microenvironment to form a physical and biochemical barrier. Secondly, during progression of the disease, the body's immune system is hijacked to support the prol iferation of the cancer.
New approaches, such as immunotherapy, are therefore needed where it has already shown promise in overcoming many aspects of this resistance. Immunotherapy has the potential to treat minimal residual disease after pancreatic
resection (surgery) as wel l as for metastatic and non-resectable PDAC. Our objective for this project is to bring together a multidisciplinary and intersectoral group to develop novel vaccine approaches, including use of multiple
immunomodulating components.
We have set up through the work of ESR8, a number of assays to measure IL-1β and IL-18 and early indications show that both may possess different roles in PDAC inflammation. As IL-1 and IL-18 are main inflammatory mediators processed by inflammasomes, it still remains unclear though how the host immune system integrates IL-1 and IL-18 signals. However, these early results provide an interesting angle to tackling this question. The work of ESR10 looked at different carriers for carrying immunomodulatory reagents. Chitosan nanoparticles (NPs) are commonly used as drug carriers since they have good biocompatibility, biodegradability and loading capacity and in the studies carried out by ESR10, we have seen that peptide vaccines loaded onto chitosan NPs were able to stimulate an immune response in mice. Studies initiated by ESR12 has focused upon exosomes, where assays have been set up to isolated and characterise miRNA markers from exosomes derived both from pancreatic cancer cell lines as well as from liquid biopsy samples in patients. Exosomes are membrane vesicles of endocytic origin ranging in size from 30-150 nm. They are secreted by both normal and cancerous cells into the extracellular space and into the blood circulation. These circulating extracellular vesicles are emerging as key players in intercellular communication between cancer cells and their microenvironment via horizontal transfer of information of their cargos. We have set up assays to looking at miR-21, miR-205, miR-210, miR-492, miR-1247, miR-196a, miR-196b, miR-744, miR-2, miR-210, miR-221, miR-7 and miR-451a. These are candidate miRNAs from body fluid, which we intend to investigate further as prognostic and predictive markers for pancreatic cancer. PDAC is one of the most lethal types of cancer, with a low 5-year survival rate. This is mainly caused by a late diagnosis. Considering the limitations of traditional biopsies, there is an urgent need for new tumour biomarkers. Liquid biopsy samples in the PAVE project will provide us with a set of important non-invasive clinical tools for early detection, for prognosis, and for the monitoring of responses of primary tumour and metastatic diseases to treatments. By taking multiple or serial biopsies, we could overcome the limitations of traditional biopsies by real time monitoring. ESR12 has already designed an assay using an aptamer-based ELISA protocol but in the meantime, aptamers for those miRNAs are currently being selected.
Early progress in PAVE has been made looking at chronic inflammation in the tumour microenvironment of PDAC. Inflammasomes are an important innate immune pathway critical for the production of active IL-1β and interleukin 18, as well as the induction of pyroptosis. However, their role in tumour progression remains elusive but moreover, we have found contradictory results indicating that inflammasomes can both promote and suppress tumour development depending on types of tumours, specific inflammasomes involved, and downstream effector molecules. The complexity of the role of inflammasomes opens up new opportunities and challenges to understand how to manipulate inflammasome pathways in the treatment of PDAC. IL-1β and IL-18 are potent inflammatory cytokines that trigger various signaling pathways, including NF-κB, MAPK, and PI3K pathways. They are members of the IL-1 family of cytokines produced by macrophages and other cells during an immune response.