Exosomes in oncolytic virotherapy
Nominating Supervisor: Prof Len Seymour
Second Supervisor: Dr Kerry Fisher
Oncolytic viruses promise new opportunities for targeted cancer therapy, but spread of viruses through solid tumour masses is often limited. Sometimes this is thought to reflect stress responses within the tumour tissue. This D.Phil. project will explore the possibility of using exosomes produced from virus-infected cells to ‘condition’ other cells within the tumour microenvironment. It will focus initially on characterising exosomes produced from virus infected tumour cells to determine which virus components are packaged into exosomes most efficiently. The work will use type 5 adenovirus because most tools are available for that agent aiming to engineer viruses to promote spread of chosen proteins to nearby cells. We will also assess hypothesis that microRNA are incorporated randomly into exosomes, and that the highest expression can lead to most efficient packaging. Successful development of this exosome-targeting system would enable design of oncolytic viruses that are capable of preparing nearby cells for virus infection, and preventing stress-related inhibition of spread.
Main outputs of the studentship: Characterise mechanisms for viral agents to exploit natural (or virus-induced) exosome pathways to distribute effector molecules or therapeutics around the tumour microenvironment. In this way we aim to condition uninfected cells to encourage better virus spread under conditions of cellular stress/hypoxia, and to allow therapeutic proteins to penetrate beyond the limits of virus spread and thereby increase their effectiveness.
The student would join a dynamic research group (approx. 15 personnel) with a good friendly and engaging culture. There will be extensive molecular biological and virological training, coupled with strong immunological focus. We encourage applications from ambitious students with an interest in understanding molecular mechanisms and exploiting them for therapeutic benefit.
Freedman, J., Muntzer, A., Duffy, M., Lei, J., Bryant, R., Verrill, C., Lambert, A., Miller, P., Seymour, L. and Fisher, K., Multimodal oncolytic virus encoding a bispecific antibody that retargets endogenous T cells to attack tumour-associated fibroblasts, thereby combining direct cytotoxicity with active reversal of local immunosuppression, Cancer Research (published online November 18th 2018) DOI: 10.1158/0008-5472.CAN-18-1750
Dyer, A., Schoeps, B., Frost, S. Jakeman, P., Scott, E., Freedman, J. Seymour, L.W., Antagonism of glycolysis and reductive carboxylation of glutamine potentiates activity of oncolytic adenoviruses in cancer cells, Cancer Research published online November 28th DOI: 10.1158/0008-5472.CAN-18-1326
Lei J, Jacobus EJ, Taverner WK, Fisher KD, Hemmi S, West K, Slater L, Lilley F, Brown A, Champion B, Duffy MR, Seymour LW. Expression of human CD46 and trans-complementation by murine adenovirus 1 fails to allow productive infection by a group B oncolytic adenovirus in murine cancer cells. J Immunother Cancer. 2018 Jun 13;6(1):55