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08 July 2013
Scientists from Cardiff University have made a significant advance in their ability to target skin cancer.Researchers at the School of Medicine are part of a team that has developed an artificially enhanced molecule called a T-cell receptor, derived from a white blood cell that targets and kills melanoma cells.Working in collaboration with an Oxford-based biotechnology company (Immunocore), scientists at the University were able to solve the molecular structure of the enhanced T-cell receptor, bound to a fragment from a melanoma cell.The T-cell receptor was engineered to bind to cancerous cells with a 30,000-fold improved affinity using technology developed by partners, Immunocore. Molecular visualisation using X-rays (the technique used to solve the structure of DNA) enabled them to understand how this molecule targets melanoma cells with high specificity and affinity.Dr David Cole of the Institute of Infection and Immunology at Cardiff University’s School of Medicine said: "We wanted to visualise these novel molecules at the molecular level to better understand how they work. We hope that these experiments will provide the information we need to safely improve these T-cell receptors to target cancer and other types of human diseases."Professor Andrew Sewell, also from the Institute of Infection and Immunology, added: "The ability to see how such molecules work is of paramount importance to modern medicine and drug design. They are far too small to see in detail even with the most advanced light microscopes, so it is essential to have access to Diamond Light Source, the UK's cutting edge national synchrotron facility, to look at these molecules using X-rays."The scientists involved in developing this therapy are using molecular techniques to test its safety and improve it further. Their findings are published in the Journal of Biological Chemistry.The structure of the T-cell receptor has important implications for cancer therapy design. With the new ability to visualise white blood cells’ interaction with cancer cells, scientists can begin to design more targeted therapies.Last year the same team of researchers used a similar therapy to target HIV and shrink tumours. The latest findings indicate a growing number of possibilities for T-cell receptors in developing new medicines.
Similar molecules to the T-cell receptor, called antibodies - found on the surface of other immune cells, called B-cells - now account for almost half of new medicines. T-cell receptors may yet eclipse the phenomenal success of B-cells because of their ability to identify disease-related targets originating from inside cells that are hidden from most antibodies. This ability offers exciting new possibilities for developing disease specific therapies.
Professor Vincent Piguet, Institute of Infection and Immunity Director at Cardiff University, said:
"It’s great to see the link from basic immunology to a potentially translational (therapeutic in this case) application from this research. I hope the Dr Cole, Prof Sewell and Dr Rizkallah research team will continue to address important immunological questions in the future."Dr Ian Lewis, Associate Director of Research at the Welsh Cancer Charity Tenovus, said;
"We are extremely proud to be associated with this research that seeks to improve the treatment of malignant melanoma, one of the most aggressive and increasingly common cancers in the UK.
"We are pleased our funding has helped support the PhD student within the group whose work was an instrumental part of this project. Each year, Tenovus invests over £500,000 supporting early career scientists in Wales who are working on some of the most innovative and cutting edge cancer research in the UK.
"This project is a great example of how this funding is being translated into new treatments for some of the most common and deadly cancers."
Professor Dave Stuart, Life Science Director at Diamond Light Source, commented:
"This pioneering research is an example of the enormous potential and ingenuity of structure-based targeted therapeutic proteins. The development of engineered T-cell receptors is still at an early stage but this indicates not only considerable potential for cancer treatments but suggests that there may be significant implications for a host of other diseases.
"The UK is at the forefront of targeted drug and therapeutic protein design such as this thanks to cutting-edge research capabilities and highly advanced technology at facilities such as Diamond. We're proud that Diamond has contributed to this innovative research."
The project was funded by Tenovus Foundation, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC) and Diamond Light Source.The research was conducted by Dr David Cole, Professor Andrew Sewell, Dr Pierre Rizkallah and Dr Florian Madura in collaboration with Immunocore Ltd./Ends
Images of T-Cell Receptors below can be issued on request:Figure 1.tiff shows the high affinity TCR reagent (blue and cyan) binding to the fragment from the melanoma skin cancer cell (yellow and red balls and grey).
Figure 2.tiff shows the atomic interactions between the high affinity TCR reagent (cyan) binding to the fragment from the melanoma skin cancer cell (yellow) that allow it to specifically target skin cancer cells.
Figure 3.tiff shows the high affinity TCR reagent (red, green, blue, cyan, magenta, orange) binding to the fragment from the melanoma skin cancer cell (grey).
School of MedicineInstitute of Infection and Immunology
Tomas Llewelyn BarrettPublic Relations Cardiff University Tel: 029 20 875 596 Mobile: 07950792532E-mail: BarrettTL1@cardiff.ac.uk
Cardiff University is recognised in independent government assessments as one of Britain’s leading teaching and research universities and is a member of the Russell Group of the UK’s most research intensive universities. Among its academic staff are two Nobel Laureates, including the winner of the 2007 Nobel Prize for Medicine, University Chancellor Professor Sir Martin Evans. Founded by Royal Charter in 1883, today the University combines impressive modern facilities and a dynamic approach to teaching and research. The University’s breadth of expertise encompasses: the College of Humanities and Social Sciences; the College of Biomedical and Life Sciences; and the College of Physical Sciences, along with a longstanding commitment to lifelong learning. Cardiff's three flagship Research Institutes are offering radical new approaches to neurosciences and mental health, cancer stem cells and sustainable places.
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