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Development of an absolute quantitation method for genetically modified cell therapy

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  • Full or part time
    Dr S Papa
    Dr J Sosabowski
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This 4-year PhD studentship is offered by the Cancer Research UK City of London Centre

T cells have a critical role in the normal immune response, recognising and killing infected cells. CAR T cell therapy is a type of immunotherapy which uses T cells isolated from cancer patients. The cells are modified in the laboratory to make them express chimeric antigen receptors (CARs) on their surface which recognise antigens on the surface of cancer cells. The modified T cells, now known as CAR T cells, are then multiplied and infused back into the patient where they target and kill cancer cells expressing the target antigen. CAR T cell therapy is being used successfully for the treatment of some haematological malignancies, however, solid tumours have proved much more difficult to treat in this way. If we can track and quantify T cells in vivo we can speed up our understanding of T cell therapeutics: promoting the successes, and moving on from the failures, with greater efficiency.

We have successfully co-expressed a reporter gene, the human sodium iodide symporter (hNIS), with a chimeric antigen receptor (CAR) specific for prostate specific membrane antigen (PSMA) [1]. This construct is expressed via retroviral transduction in T cells. The hNIS functions to concentrate the imaging reporter 99mTc pertechnetate in the transduced cells. In an established xenograft model we have used SPECT/CT imaging to show spatial accumulation of CAR T cells in tumours and the temporal relationship between accumulation of CAR T cells and rejection of established tumours. This construct can be adapted to incorporate any CAR (thus the system can be used for other cancer targets) and is fully clinically translatable.

To make this approach quantitative we need to thoroughly explore the relationships between host, reporter gene and tracer. This challenge will be addressed through collaboration between physical science, computational biology/mathematics and cancer immune-biology. Using one of the most advanced preclinical imaging systems currently available, we will use dual isotope PET/SPECT/CT imaging and pharmacokinetic modelling to understand the relationship between the numbers of T-cells reaching the target tissue and levels of CAR expression needed to effect a response. We will do this using two newly developed PET radiotracers, F-18-tetrafluoroborohydrate which has already been tested in clinical subjects [2] and F-18-fluorosulphate [3]. Dual isotope imaging capability allows us to inject cells that have been directly labelled using SPECT tracers and also track these cells with PET hNIS reporter probes and vice versa. As well as in vivo targeting, we will use the superior spatial resolution and sensitivity of the preclinical system to assess penetrance, expansion/contraction of cell numbers and persistence of T-cells non-invasively through imaging. This has the potential to speed up our understanding of T cell behaviour in pre-clinical models of disease. Researchers adopting this approach will be able to track T cell migration, expansion and death without the use of invasive techniques. This will help the understanding of dosing, response, reasons for treatment failure, as well as the evolution of toxicity and assessment of combination therapies.

Suitable candidates for this project would be pharmacology/biology or chemistry/biochemistry graduates. Tissue culture expertise and evidence of strong mathematical abilities would be advantageous.

Potential research placements
1. Training on in vivo imaging equipment to collect data for kinetic modelling and monitoring treatment response. Dr Jane Sosabowski, QMUL.
2. Training on PET tracers. Prof Phil Blower, School of Biomedical Engineering and Imaging Sciences, King’s College London.
3. Training in kinetic modelling and parametric imaging. Dr Joel Dunn, School of Biomedical Engineering and Imaging Sciences, King’s College London.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the CRUK CoL Centre PhD Programme in September 2019 and will register for their PhD at their primary supervisor’s university.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 19 MARCH 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.


Funding Notes

Successful candidates will receive a £21,000 tax-free student stipend (living allowance) per year for 4 years plus payment of university tuition fees. Non-EU candidates are not eligible to apply.

References

1. Emami-Shahri N et al. Clinically Compliant Spatial and Temporal Imaging of Chimeric Antigen Receptor T-cells. Nat Commun. 2018; Mar 14;9(1):1081. doi: 10.1038/s41467-018-03524-1.
2. O'Doherty J et al. 18F-Tetrafluoroborate, a PET Probe for Imaging Sodium/Iodide Symporter Expression: Whole-Body Biodistribution, Safety, and Radiation Dosimetry in Thyroid Cancer Patients. J Nucl Med. 2017; Oct;58(10):1666-1671. doi: 10.2967/jnumed.117.192252.
3. Khoshnevisan A et al. 18F-Fluorosulfate for PET Imaging of the Sodium-Iodide Symporter: Synthesis and Biologic Evaluation In Vitro and In Vivo. J Nucl Med. 2017; Jan;58(1):156-161. doi: 10.2967/jnumed.116.177519.



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