Professor Kevin Harrington and Dr Tim Pencavel
This is an example of a translational research project, looking at ways to transfer results from the laboratory into a clinical trial in patients in a Phase 1 Trial. They are developing a system for treating limb sarcomas using Isolated Limb Perfusion (ILP) as well as oncolyic virotherapy (anti-cancer viruses)
ILP is used for sarcomas that can’t be removed by surgery because of their size or because they are close to vital structures such as blood vessels or nerves. During ILP the main blood vessels to the limb are identified and connected to a bypass machine to create a circuit. Fluid consisting of blood and an artificial plasma like fluid is then passed round this circuit. Chemotherapy can be added to the fluid, along with a naturally occurring human protein called tumour necrosis factor-alpha - TNFa - which makes the tumour blood vessels leaky. This means the amount of chemotherapy getting into the tumour through leaky blood vessel walls is higher than is usually possible, meaning treatment is more effective.
Oncolytic viruses infect tumour cells and replicate in them to a much greater extent than in normal cells. As part of their life cycle oncolytic viruses can lyse or burst tumour cells causing cell death. Once this bursting has occurred the immune system recognises not only the virus particles but components of the tumour cells. This leads to the immune system being able to destroy cancer cells that have not been exposed to the virus.
On the basis of results from several studies these viruses are now tested in humans with advanced cancer. However, then the viruses are put into human circulation much of their potency is lost because low numbers of viral particles reach the tumour, having been sieved out by the liver and spleen or held up by the immune system.
ILP with added TNFa may be the way to ensure that more anti cancer viruses reach the tumour, hence improving treatment.
They are doing a series of animal studies to test the effects of ILP combined with oncolytic virotherpy (anti cancer viruses) against sarcomas. They will measure how effective this is against the primary tumour and see how the treatment might be able to tackle sarcoma that has spread to other sites in the body.
They are hoping to use the results to move on to designing a Phase 1 trial.
- Pencavel, T. D. et al. (2010) Locoregional intravascular viral therapy of cancer: precision guidance for Paris’s arrow? Gene Therapy, 17(8). Read more: https://europepmc.org/abstract/med/20445580
- Pencavel, T. D. et al (2015) Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolonges survival in a rat model of advanced extremity sarcoma. International Journal of Cancer, 136(4). Read more: https://www.ncbi.nlm.nih.gov/pubmed/24978211
- Wilkinson, M. J et al. (2016) Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma. International Journal of Cancer, 139(6). Read more: https://www.ncbi.nlm.nih.gov/pubmed/27116656
- Wilkinson, M. J. et al. (2016) Oncolytic vaccinia combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis. Oncotarget, 7(49). Read more: http://europepmc.org/abstract/med/27783991
- Smith, H. G. et al. (2019) PD-1 blockade following isolated limb perfusion with vaccinia virus prevents local and distant relapse of soft-tissue sarcoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. Read more: https://www.ncbi.nlm.nih.gov/pubmed/30885937?dopt=Abstract
- Wilkinson, M. J. et al. The addition of oncolytic vaccinia virus to standard isolated limb perfusion chemotherapeutics delays tumour growth in a rat model of aggressive extremity sarcoma. Poster presented at the European Cancer Congress. September, 2013. Amsterdam, Netherlands.
Presentation & Workshops
- Pencavel, T., Seth, R., Hayes, A., and Harrington, K. Development of an in vivo model of isolated limb perfusion for oncolytic viral therapy in advanced extremity sarcoma and melanoma. Presentation given at the Imperial College London Surgical Symposium. 2009. London, UK.
- Pencavel, T., Seth, R., Hayes, A., and Harrington, K. Isolated Limb Perfusion and Viral Therapy: Precision Guidance for Paris’s Arrow? Presentation given at the British Sarcoma Group Annual Conference. May, 2010. London, UK.
- Pencavel, T., Seth, R., Hayes, A., and Harrington, K. Oncolytic virotherapy in an in vivo model of Isolated Limb Perfusion for advanced extremity sarcoma. Presentation given at the Imperial College London Surgical Symposium. 2010. London, UK.
- Pencavel, T., Seth, R., Hayes, A., and Harrington, K. Oncolytic virotherapy in an in vivo model of Isolated Limb Perfusion for advanced extremity sarcoma. Presentation given at the Society of Academic and Research Surgeons Annual meeting. January, 2011. Dublin, Ireland.
- Pencavel, T., et al. Administration of Oncolytic Vaccinia Virus GLV1h68 by Isolated Limb Perfusion to an Immunocompetent Rat Model of Advanced Extremity Sarcoma. Presentation given at the European Multidisciplinary Cancer Congress. September, 2011. Stockholm, Sweden.
- Wilkinson, M. J. Treatment with oncolytic viruses with TNF/elphalan isolated limb perfusion for extremity sarcoma and melanoma – preclinical models and clinical trials. Presentation given at the Sarkomen Conference, Beromum Expert Meeting. March, 2012. Berlin, Germany.
- Wilkinson, M. J. et al. Isolated limb perfusion with melphalan, tumour necrosis factor-alpha - α and oncolytic vaccinia virus delays tumour growth and prolongs survival in a rat model of locally advanced extremity sarcoma. Presentation given at the 7th International meeting on Replicating Oncolytic Virus Therapeutics. June, 2013. Quebec, Canada.
- Wilkinson, M. J. et al. Pre-clinical evaluation of oncolytic virotherapy delivered by isolated limb perfusion, alone and in combination with chemotherapy, radiotherapy and surgical resection. Presentation given at The British Association of Surgical Oncologists Conference (BASO). October, 2015. London, UK.
- Viral therapy could boost limb-saving cancer treatment. Media coverage produced by The Institute of Cancer Research, London. Read more: https://www.icr.ac.uk/news-archive/viral-therapy-could-boost-limb-saving...
- Pencavel, T., Seth, R., Hayes, A., and Harrington, K. were awarded 2nd prize for their presentation at the Imperial College London Surgical Symposium. 2009.
- Wilkinson, M. J. et al. were awarded the winners of the Ronald Raven Prize for their presentation given at the 2015 BASO.