UCL Application of Synthetic Biology to T-Cell Engineering

BBSRC Project Post-doc Position: UCL Application of Synthetic Biology to T-cell Engineering The Project: The administration of genetically modified immune effector cells (T-cells) is a promising new form of cancer therapy. For instance, we have shown that administration of T-cells engineered to recognize a cancer antigen can result in clinical responses in children with neuroblastoma1. T-cells have been engineered with a wide variety of disparate transgenes to alter their function for therapeutic effect: Typically, transgenes have altered the T-cell’s specificity to a surface antigen (Chimeric Antigen Receptors, CAR), or to an epitope of an intracellular antigen (native T-cell receptor transfer). More recently, we and others have introduced transgenes which alter a T-cell’s behaviour, for instance suicide genes, homing receptors and cytokines, or knocked out expression of single genes. To date however, the work has largely involved a single genetic modification. We propose to increase the level of genetic alteration to yield not only a single effect but to allow re-programming of T-cells with new more complex cellular behaviours for therapeutic application, with a particular focus on cancer. We plan to achieve this by application of synthetic biology principles to T-cell engineering, namely to develop a library of well-characterized inter-connectable components performing logic and input/output functions. These components will be generated with a view to build systems composed of combinations of these components. In this way we hope to develop therapeutics with heavily engineered cells which should exceed the complexity and refinement possible with traditional therapeutics such as small molecules or therapeutic proteins. The Facilities: The project is shared between the UCL Cancer Institute and the Bloomsbury site of the London Centre for Nanotechnology (both buildings 5 minutes’ walk from each other). The UCL Cancer Institute is a consolidation of Cancer research across the campus into one new state-of-the-art facility consolidating cancer research across the campus. The Institute covers an internal floor area of 8,832m2 and will eventually house 300 scientists. It houses CABI (Centre for Advanced Biological Imaging) in its basement. It fosters links between basic cancer researchers across Biomedicine, and with the clinical activities of our partner Hospitals (University College London Hospitals including Queen Square, Great Ormond Street Hospital for Children and the Royal Free Hospital). The London Centre for Nanotechnology (LCN) is a UK-based multidisciplinary enterprise operating at the forefront of science and technology. Its purpose is to solve global problems in information processing, healthcare, energy and environment through the application of nanoscience and nanotechnology. Founded in 2003, the LCN is a joint venture between University College London and Imperial College London. The LCN occupies a purpose-built eight storey facility in Gordon Street, Bloomsbury (opened in 2006). The Centre’s experimental research is supported by leading edge modelling, visualisation and theory through its access to state-of-the-art clean-room, characterisation, fabrication, manipulation and design laboratories. The Centre has a unique operating model that accesses and focusses the combined skills of both universities across several key departments; Chemistry, Physics, Materials, Medicine, Electrical and Electronic Engineering, Mechanical Engineering, Chemical Engineering, Biochemical Engineering and Earth Sciences. The supervisors and candidate: The project will be co-supervised by Dr Martin Pule (UCL Cancer Institute), and Prof. Gabriel Aeppli (LCN). Dr Pule is a clinician-scientist with an active T-cell engineering programme including clinical studies with engineered T-cells. He has been active in the T-cell engineering field since 2001 and has described the first clinical study describing efficacy with CAR engineered T-cells. Prof. Gabriel Aeppli is the Quain Professor of Physics and director of the London Centre for Nanotechnology. The candidate can come from any scientific discipline. We anticipate that most candidates will have a background wholly in biology, engineering or physical sciences - this should not preclude application. A key characteristic of the applicant is the desire to cross the boundary between biology and engineering. Please direct any questions to Martin Pule ([email protected]) http://www.ucl.ac.uk/cancer http://www.london-nano.com/ .

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