Targeting the CD40 Ligand/Receptor System for Treatment of Hepatocellular Carcinoma
3rd Supervisor: Dr Peter Searle, CRUK Institute of Cancer Studies
4th Supervisor: Professor Daniel Palmer, CRUK Institute of Cancer studies and College of Medicine and Dentistry
Hepatocellular carcinoma (HCC) is a major cause or morbidity and mortality worldwide. Most are already at an advanced stage at diagnosis, when current treatments offer very limited survival benefit. New, more effective treatments are urgently required. CD40 is a member of the TNF (tumour necrosis factor)-receptor family that is expressed on cells of the immune system including dendritic cells (DC), and is also upregulated on a number of epithelial tumours including HCC. Engagement of CD40 by CD40 ligand (CD40L - also known as CD154) is emerging as a potent signal for maturation or licensing of DC, enabling them to activate antigen-specific, cytotoxic T lymphocytes. On carcinoma cells, CD40L can promote cell death, alone or in synergy with some chemotherapeutic agents. Our preliminary studies have indicated that a modified version of CD40L that is resistant to proteolytic cleavage from the cell surface is a more potent activator of cell death pathways (non-cleavable, ncCD40L). This project will investigate both the immunological and cytotoxic actions of CD40 agonists, including recombinant soluble ligands, monoclonal antibodies, the natural membrane-expressed CD40L and ncCD40L. Adenovirus vectors will be used to express the CD40L/ncCD40L, and the potential benefit of a tumour-selective, replicating (“oncolytic”) vector will be investigated. The project will make extensive use of primary human clinical samples of HCC and non-malignant liver, to validate the findings and potentially provide justification for subsequent clinical trials of CD40L-based gene/immunotherapy in patients with HCC.
This PhD project aims to test and extend the hypothesis that CD40L delivered via adenovirus vectors could be an effective therapy for HCC. This study forms part of a wider ongoing programme of work involving collaborations between D. Adams, S.C. Afford, P. Johnson, D. Palmer, P. Searle and LS Young investigating dendritic cell-based immunotherapy and the potential of TNF/TNF-receptor family members as therapeutic targets for the treatment of liver cancers.
Specific questions to be addressed in this project:
1. Determine the frequency, level and distribution of CD40 and CD40L expression on a panel of HCC by immunocytochemistry of tissue arrays
2. Confirm /compare the effects of different CD40 agonists (rsCD40L, mAb, adenovirus-expressed CD40L and ncCD40L) on cell survival and cell death pathways using a panel of HCC cell lines. This will be extended to primary HCC cells prepared from freshly resected tumours, and in comparison with the effects on normal/non-malignant liver cells
3. Investigate the tumour selectivity and efficacy of CD40L expression via replication-competent/oncolytic adenovirus, in comparison with standard replication-defective vectors
4. Investigate the relative effectiveness of the different CD40 agonists for activation of dendritic cells, and their consequent potential to enhance anti-tumour immune responses
This studentship is open to self-funded students only. Current home/EU tuition fees are £3,996 per annum. Current overseas tuition fees are £16,230 per annum.