Hepatocellular carcinoma (HCC) is a cancer of unmet need, with 12% five-year survival across all stages, due to late diagnosis and inadequate non-personalised therapies. Promising results are being obtained with immune checkpoint blockade (ICB), although only a minority of HCC patients currently benefit. The challenge is to predict immunotherapy-resistant tumours and to sensitise them to ICB, whilst maintaining the health and immune-tolerance of the abnormal background liver.
Initial evidence indicates that the response to ICB monotherapy is poor in tumours with a low neoepitope load (a low number of tumour-specific mutated peptides that are recognised by T-cell receptors). Our preliminary research indicates that co-vaccination using heteroclitic peptides (modified peptides that elicit a T-cell response against closely related wild-type tumour epitopes) may sensitise tumours to ICB.
1) To define the T-cell response to ICB in HCC tumours, taking into account the tumour neoepitope load.
2) For tumours with a low neoepitope load, to design and test the efficacy and toxicity of heteroclitic peptides in combination with ICB.
You will develop a truly interdisciplinary set of skills, in the fields of cancer immunotherapy, functional immunology, high-tech OMICS approaches and optionally in virology techniques. Dr Adel Samson is a CRUK Clinician Scientist, trained in medical oncology and specialising in translational oncolytic virus-based immunotherapies. Professor Reuben Tooze is a renowned expert in pathology and data analytics. https://medicinehealth.leeds.ac.uk/medicine/staff/735/dr-adel-samson#journal_article_div https://medicinehealth.leeds.ac.uk/medicine/staff/825/professor-reuben-tooze#presentation_conference_workshop_etc__div
The primary and secondary supervisors hold weekly meetings and partake in floor-wide ‘research in progress’ meetings, providing an opportunity for the student to improve their work, gain new ideas and to practice ahead of conference speaking. Dr Adel Samson also maintains extensive collaborations with industry partners, enabling the student to be involved in the steps towards clinical translation of the project findings.
The primary supervisor enjoys ready access to liver surgical samples through established ethical agreements. Leeds is one of the largest HCC surgical centres in the UK (>60 HCC resections/year) Forty tumour samples will be collected in years 1 and 2, enabling ample statistical power.
1) Prediction of the expressed tumour neoepitope load by whole-exome-sequencing, RNAseq and an online epitope prediction algorithm.
2) Defining the relationship between ICB therapy and the tumour neoepitope load, by building on long-standing expertise in human in-vitro T-cell priming assays, using peripheral blood immune cells and freshly resected HCC samples.
3) For tumours with a low predicted neoepitope load, synthesis of heteroclitic peptides for in-vitro T-cell priming.
4) Testing the efficacy and toxicity of combination ICB plus heteroclitic peptide therapy in an immunocompetent orthotopic model of HCC.
Current combination immunotherapy trials for patients with HCC have little scientific rationale and are non-personalised. This project will enable prediction of ICB resistance and the development of a novel T-cell therapy, based on the tumour neoepitope load. This project will provide the scientific rationale to commence clinical testing of next-generation immunotherapies in HCC. We anticipate that successful completion of this project will directly inform early phase clinical trials.
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 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 can be found on our website: http://www.dimen.org.uk/