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.
- T Pencavel and K J Harrington et al. Locoregional intravascular viral therapy of cancer: precision guidance for Paris’s arrow? Gene Therapy. 2010. 1-12.
- T Pencavel and K J Harrington et al. Isolated limb perfusion with melphalan, tumour necrosis factoralpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma. International Journal of Cancer. 2014.
- Wilkinson MJ et al. 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. 15 September 2016. 139(6):1414-22.
- Wilkinson MJ et al. Oncolytic vaccinia combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis. Oncotarget. 22 October 2016.
- Wilkinson MJ 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. European Cancer Congress. September 2013. Amsterdam.
- Pencavel T, Seth R, Hayes A, Harrington K. Development of an in vivo model of isolated limb perfusion for oncolytic viral therapy in advanced extremity sarcoma and melanoma. Imperial College Surgical Symposium, 2009. London. (Awarded 2nd Prize).
- Pencavel T, Seth R, Hayes A, Harrington K. Isolated Limb Perfusion and Viral Therapy: Precision Guidance for Paris’s Arrow? British Sarcoma Group Annual Conference, 2010. London.
- Pencavel T, Seth R, Hayes AJ, Harrington KJ. Oncolytic virotherapy in an in vivo model of Isolated Limb Perfusion for advanced extremity sarcoma. Imperial College Surgical Symposium, 2010. London.
- Pencavel T, Seth R, Hayes AJ, Harrington KJ. Oncolytic Virotherapy in an In Vivo model of Isolated Limb Perfusion for advanced extremity sarcoma. Society of Academic and Research Surgeons Annual Meeting, January 2011. Dublin.
- Pencavel T, Seth R, Khan AA, Mansfield D, Hayes AJ, Harrington KJ. Administration of Oncolytic Vaccinia Virus GLV1h68 by Isolated Limb Perfusion to an Immunocompetent Rat Model of Advanced Extremity Sarcoma. European Multidisciplinary Cancer Congress, September 2011. Stockholm.
- Wilkinson MJ et al. Treatment with oncolytic viruses with TNF/melphalan isolated limb perfusion for extremity sarcoma and melanoma – preclinical models and clinical trials. Sarkomen Conference, Beromun Expert Meeting, March 2012. Berlin.
- Wilkinson MJ, Pencavel T, Khan AA, Mansfield DC, Kyula J, RoulstoneV, Yu YA, Szalay AA, Hayes AJ, Harrington KJ. 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. 7th International Meeting on Replicating Oncolytic Virus Therapeutics. June 2013. Quebec City, Canada.
- Wilkinson MJ, Smith HG, Pencavel TD, Mansfield DC, Kyula-Currie J, Khan AA, McEntee G, Roulstone V, Hayes AJ, Harrington KJ. Pre-clinical evaluation of oncolytic virotherapy delivered by isolated limb perfusion, alone and in combination with chemotherapy, radiotherapy and surgical resection. The British Association of Surgical Oncologists Conference. October 2015. London, UK - Winner of Ronald Raven Prize.
- Viral therapy could boost limb-saving cancer treatment. The Institute of Cancer Research London Media Release. 22 July 2014.