Background:
Tumour ablative procedures, such as microwave ablation and cryoablation, offer localised tumour control for hepatocellular carcinoma (HCC) but are limited by damage to the surrounding cirrhotic background liver. Histotripsy is a new non-invasive and highly targeted tumour ablation procedure under development by Histosonics, which stands to improve local tumour control whilst allowing patients with frail liver function to benefit from tumour ablation. Furthermore, understanding the immune response to histotripsy in HCC would enable targeted immunotherapy regimens to be developed to prevent the emergence of subsequent tumours, whilst protecting the frail background liver.
Objectives:
1. To characterise tumour immunology post-histotripsy in comparison to microwave- and cryoablation.
2. To design novel immunotherapy regimens post-ablation in HCC to induce robust and long-lasting anti-cancer immunity, whilst limiting side-effects to the frail background liver.
Experimental Approach:
The project will include the following experimental themes.
1. Tissue culture of primary HCC and non-malignant liver samples derived from patients undergoing hepatic surgery.
2. Flow cytometry assessment and plasma cytokine quantification of the temporal expression dynamics of immune checkpoint molecules on helper/cytotoxic T-cells, NK cells and antigen presenting cells, post-microwave-/cryo-ablation or histotripsy in HCC patients.
3. Assessment of the mechanisms of innate and adaptive immune anti-tumour effects post-histotripsy, by RNAseq, TCRseq and functional immune assays.
4. Optimisation of histotripsy-immunotherapy combinations and schedules in an in vitro T-cell priming model to test anti-cancer efficacy and background liver safety in non-malignant hepatocytes.
5. In vivo models of combination immunotherapy with tumour ablation in a bilateral flank syngeneic model of HCC.
6. Rational design of an early-phase clinical trial of combination immunotherapy with histotripsy in HCC.
Impact:
The Hope4Liver study is the first application of histotripsy in the UK. This project is the first to characterise the immunological sequelae of histotripsy, in comparison to conventional microwave- and cryoablation techniques. Successful completion of this project will directly define and refine a combination immunotherapy-histotripsy study in HCC. This therefore stands to be a practice-changing PhD project, defining and refining future tumour ablation-immunotherapy treatment regimens for patients with HCC and wider tumour types.
Training Environment:
The successful student will receive training in a broad range of skills from a translational Clinician Scientist specialising in tumour immunology and immunotherapies (Samson), a T-cell biologist with extensive expertise in basic science and pre-clinical animal models (Salmond), and an interventional radiologist with expertise in tumour ablation therapies (Wah). All three supervisors contribute to student teaching and training by lecturing undergraduate and postgraduate science trainees, attending/chairing postgraduate platform events and by acting as internal/external examiners for PhD students.
https://medicinehealth.leeds.ac.uk/medicine/staff/735/dr-adel-samson
https://medicinehealth.leeds.ac.uk/medicine/staff/733/dr-robert-salmond
https://scholar.google.com/citations?user=FuiWScoAAAAJ&hl=en
The supervisors, along with colleagues, hold weekly floor-wide ‘research in progress’ meetings, providing an opportunity for students to improve their work, gain new ideas from their own and other student’s talks or to practice ahead of conference speaking. Dr Samson also holds a weekly journal club in his group and regularly teaches students. All these training opportunities will be open to the DiMeN DTP student.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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