Sage, E; (2013) Cell Therapy for the Treatnent of Malignant Pleural Mesothelioma. Doctoral thesis , UCL (University College London).

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Abstract

Malignant pleural mesothelioma (MPM) is a devastating malignancy of the pleural lining. It presents insidiously and at the time of presentation the disease is often diffusely spread throughout the chest cavity. There are few effective therapies available, the average survival is 9-12 months from diagnosis and 5-year survival rates are only 2%. Novel therapies are desperately needed. There is increasing interest in combined gene and cell therapy approaches and for a malignant disease this is particularly appealing. Mesenchymal stem cells (MSCs) are known to home to tumours and are readily transduced with viral vectors making them ideal cells for delivering targeted therapy. TNF-related apoptosis inducing ligand (TRAIL) is an exciting anti-cancer therapy as it selectively causes apoptosis in cancer cells without affecting healthy cells. This makes the combination of MSCs carrying TRAIL (MSCTRAIL) a viable prospect for the targeted treatment of MPM. Lentiviral vectors expressing TRAIL were used to transduce human bone marrow-derived MSCs (MSCTRAIL) which induced apoptosis and cell death in multiple human MPM cell lines. MPM cells were transduced with a luciferase-expressing lentiviral vector (MPMLuc) and were used to establish a murine model of MPM allowing me to track tumour growth in vivo using bioluminescent imaging. Systemic delivery of MSCTRAIL to MPM tumours resulted in a significant reduction in tumour growth but topical delivery was not effective. Using dual bioluminescent and fluorescent imaging I showed that MSCs home to tumours when delivered both systemically and topically but that they engraft in greater numbers following systemic delivery. Combining chemotherapy with MSCTRAIL showed promising effects in vitro but was not effective in reducing tumour burden in vivo. In summary, human bone marrow derived MSCs were shown to localise to areas of MPM and when modified to express TRAIL and delivered systemically they significantly reduced tumour burden.

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