Improving the spread of oncolytic viruses through solid tumors

It was hypothesised that genetic modification of viruses to encode for an extracellular matrix degrading enzyme would improve virus spread through solid tumours. Initially, the effect of extracellular matrix degrading enzymes on adenovirus infection was investigated in 3-dimensional spheroid cell cultures. Hyaluronidase demonstrated good enhancement of adenovirus infection with limited toxicity and was therefore investigated further. The oncolytic adenovirus, vKH6, was modified to encode the sperm-associated hyaluronidase SP AMi, however no hyaluronidase activity was detectable from infected cells. A replication-deficient adenovirus encoding SP AMi was also engineered and found to produce hyaluronidase activity. A vaccinia virus with attenuating deletions of thymidine kinase and vaccinia growth factor was engineered and was demonstrated to produce detectable levels of SPAMi activity. The efficacy of this virus was tested in an immunocompetent murine model however no enhancement of tumour inhibition was detected.EThOS - Electronic Theses Online ServiceGBUnited Kingdo