Overview
Despite years of intensive research, cancer has poor patient outcomes largely due to late-stage diagnosis, limited treatment options, and lack of biomarkers for early detection. Kinase inhibitors and immunotherapies, such as checkpoint inhibitors, that enhance an effective immune response have demonstrated robust anti-tumour efficacy in patients. However, the efficacy of such therapies varies, and, in some cases, may trigger life-threatening adverse events. For example, in one trial up to 80% of patients develop serious liver injury, which required cessation of therapy. With the increasingly widespread use of kinase inhibitor-cancer immunotherapy combinations, the cases of adverse events have become a prevalent and costly burden for the NHS, and this will continue to increase, representing a major barrier to delivering effective therapies to cancer patients.
About this opportunity
In this PhD we will focus on the following hypothesis: for kinase-checkpoint inhibitor adverse events, kinase-antigens are presented by HLA proteins to activate pathogenic T-cells and checkpoint inhibitors remove the immune breaks to enhance susceptibility in patients. To address this hypothesis multi-omics approaches will be used. Liver cells will be cultured with kinase inhibitors and binding to cellular proteins will be characterised using global proteomic analysis. Drug-modified peptides naturally presented by HLA molecules will be assessed using established immunopeptidomics methods. Drug immunogenicity towards the ligands identified in the omics studies will then be assessed using blood from patients exposed to the drug combinations with adverse events. Immunogenicity will be assessed through bespoke assays including CyTOF and single cell sequencing. Finally, we will model kinase inhibitor-checkpoint inhibitor T-cell responses using healthy donor cells. These experiments will explore the impact of the pharmacology of different checkpoint inhibitors (e.g., anti PD-1, anti PD-L1, anti CTLA-4) on the strength of the drug-specific T-cell response.
Why this is important: Immune-mediated adverse events are a leading cause of drug withdrawals and increases mortality, and healthcare costs in patients with cancer. This studentship will allow us to make an impact clinically, by translating laboratory finding into patient care. Specifically, data generated will help clinicians optimise treatment strategy and enable safe ICI resumption after liver injury resolution, improving patient quality of life and life expectancy.
The student will be based in the immunopharmacology group led by Prof Naisbitt (https://www.liverpool.ac.uk/people/dean-naisbitt, X: @ImmunoPharm) and Dr Meng (https://www.liverpool.ac.uk/people/xiaoli-meng, X: @xl_meng) at the Pharmacology department, University of Liverpool. The student will receive training in a wide variety of techniques including proteomics and advanced primary cell culturing. Under the supervision of Dr Catherine Betts (AstraZeneca) the student will gain valuable experience in Immunology and safety science in an industry setting. An industrial placement at AstraZeneca will provide the student with opportunity to gain hands-on experience within real-world Pharma. Furthermore, this multi-disciplinary training will give the student a broad range of skills allowing a wide choice of career options post PhD, both within and outside of academia.
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, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
Further reading
1. Sun L, Huai P, Wang Z, Zhao Q, Lin Y, Liu T, Xue X, Ao S, You J, Sun Y, Mi Z, Gardner J, Thomson PJ, Naisbitt DJ, Meng X, Liu J, Liu H, Zhang F.TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity.
Signal Transduct Target Ther. 2025 Jun 21;10(1):196.
2. Sun L, Zhao Q, Ao S, Liu T, Wang Z, You J, Mi Z, Sun Y, Xue X, Ogese MO, Gardner J, Meng X, Naisbitt DJ, Liu H, Zhang F.Feedback regulation of VISTA and Treg by TNF-α controls T cell responses in drug allergy.
Allergy. 2025 May;80(5):1400-1416. doi: 10.1111/all.16393.
3. Whitaker P, Gibson A, Farrell J, Gillgrass L, Meng X, Peckham D, Naisbitt DJ. Prospective Piperacillin Lymphocyte Transformation Testing in Patients With Cystic Fibrosis Receiving Regular and Desensitization Courses of Piperacillin-Tazobactam.
J Allergy Clin Immunol Pract. 2025 Mar;13(3):594-609.e8. doi: 10.1016/j.jaip.2024.12.003.
4. Gardner J, Abrams ST, Toh CH, Parker AL, Lovatt C, Nicolson PLR, Watson SP, Grice S, Hering L, Pirmohamed M, Naisbitt DJ. Identification of cross reactive T cell responses in adenovirus based COVID 19 vaccines.
NPJ Vaccines. 2024 Jun 5;9(1):99. doi: 10.1038/s41541-024-00895-z.
5. Thomson P, Fragkas N, Kafu LM, Aithal GP, Lucena MI, Terracciano L, Meng X, Pirmohamed M, Brees D, Kullak-Ublick GA, Odermatt A, Hammond T, Kammüller M, Naisbitt DJ. Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-desmethyl naproxen metabolite but not the acyl glucuronide.
Allergy. 2024 Jan;79(1):200-214. doi: 10.1111/all.15830.
6. Ogese MO, Lister A, Farrell L, Gardner J, Kafu L, Ali SE, Gibson A, Hillegas A, Meng X, Pirmohamed M, Williams GS, Sakatis MZ, Naisbitt DJ. A blinded in vitro analysis of the intrinsic immunogenicity of hepatotoxic drugs: implications for preclinical risk assessment.
Toxicol Sci. 2023 Dec 21;197(1):38-52. doi: 10.1093/toxsci/kfad101.