The incidence of hepatocellular carcinoma (HCC) in the UK has increased more than four-fold since 1990, and worldwide HCC is the second biggest cause of cancer-specific mortality. Very few patients achieve long-term survival, due to late diagnosis and a lack of effective therapies. Encouraging results are now emerging using immune checkpoint modulators (ICMs) that amplify T-cell activity. However, efficacy remains low and ICM-induced high-grade hepatotoxicity can be problematic.
Our published and ongoing work indicates that oncolytic reovirus, an immunotherapeutic wild-type virus, sensitises HCC to subsequent immune checkpoint-modulating therapies, through selective replication in tumour and expression of interferons, thereby providing a complementary and potentially safe combination immunotherapy strategy.
For patients with abnormal liver reserves, the potential to reverse hepatic immune tolerance, or to increase hepatotoxicity by immune cell-mediated elimination of hepatitis B/C virus (HBV/HCV)-infected non-malignant hepatocytes must be considered. In addition, HBV/HCV infections can suppress interferons thereby reducing OV-mediated immunotherapy.
• To rationally establish combinations and schedules of reovirus and immune checkpoint modulators for HCC, based on safety and efficacy.
• To define the immunological mechanisms of reovirus-ICM therapy.
• To assess the effects of HBV/HCV-induced immunosuppression on reovirus-ICM therapy, and whether optimal HBV/HCV inhibition improves safety and efficacy.
You will be supervised by a team of laboratory experts in the fields of cancer immunotherapy and virology. Dr Adel Samson is a dual-trained medical oncologist and translational scientist, specialising in oncolytic virus-based immunotherapies. Professor Adrian Whitehouse is a renowned oncogenic virologist and virus-host interactions expert. Dr Clive McKimmie is an immunologist and expert in virus-induced immune cell chemokinesis. https://medhealth.leeds.ac.uk/profile/1670/overview http://www.fbs.leeds.ac.uk/staff/Whitehouse_A/ https://medhealth.leeds.ac.uk/profile/900/1744/dr_clive_stewart_mckimmie
Experimental Approach and Techniques
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 of the temporal expression dynamics of a panel of co-inhibitory and co-stimulatory checkpoint receptors and their ligands on tissue-resident helper/cytotoxic T-cells NK cells, and antigen presenting cells, following pulsed reovirus stimulation. On this basis, checkpoint receptors that are specifically/preferentially upregulated in HCC samples, in comparison to non-malignant liver samples, will be taken forward.
3. Assessment of the mechanisms of reovirus-induced receptor/ligand upregulation.
4. Functional assessment of NK and T-cell mediated killing of HCC cells, alongside safety assessment using non-malignant hepatocytes.
5. Cell line models of infectious and subgenomic HBV/HCV in BSL 2-3 tissue culture facilities, to determine the effects of HBV and HCV on the efficacy and safety of immunotherapy.
6. In vivo experiments using the most promising immunotherapeutic combinations in immunocompetent models of HCC.
This project will establish the next generation of combination immunotherapies for the treatment of HCC. Your work will also indicate the need to include optimal HBV/HCV inhibition, as a generic component of HCC immunotherapy regimens, particularly those with an interferon-based mechanism of action. We anticipate that successful completion of this project will directly inform phase 1 trials, testing a new generation of potentially effective and safe combination immunotherapies for patients with HCC.
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/
1. Samson A, Scott K, Taggart D, West E, Wilson E, Nuovo G, Thomson S, Corns R, Mathew R, Fuller M, Kottke T, Thompson J, Ilett E, Cockle J, Van Hille P, Sivakumar G, Polson E, Turnbull S, Appleton E, Migneco G, Rose A, Coffey M, Beirne D, Collinson F, Ralph C, Anthoney A, Twelves C, Furness A, Quezada S, Wurdak H, Errington-Mais F, Pandha H, Harrington K, Selby P, Vile R, Griffin S, Stead L, Short S, Melcher A " Intravenous Delivery of Oncolytic Reovirus to Brain Tumor Patients Immunologically Primes for Subsequent Checkpoint Blockade." Science Translational Medicine. 03 Jan 2018. Vol. 10, Issue 422, eaam7577. DOI: 10.1126/scitranslmed.aam7577
2. Samson A, Bentham B, Scott K, Nuovo G, Bloy A, Appleton E, Adair, RA. Dave R, Peckham-Cooper A, Toogood G, Nagamori S, Coffey M, Vile R, Harrington K, Selby P, Errington-Mais F, Melcher AA, Griffin SDC. "Oncolytic Reovirus as Combined Anti-Viral and Anti-Tumor Agent for the Treatment of Liver Cancer." Gut doi:10.1136/gutjnl-2016-312009