MRC DiMeN Doctoral Training Partnership: Towards Mitigating Severe Neurotoxicity in T-cell Immunotherapy

 Why this project matters:

• ICANS has emerged alongside the success of CAR-T cells and T-cell engagers (TCEs) in oncology and is increasingly relevant as these platforms expand into autoimmune indications. Clinical reports link ICANS to systemic cytokine release, endothelial activation, and BBB leakage, yet mechanisms remain unresolved due to limitations in animal and conventional in vitro models.
• You will leverage a robust, human-relevant iPSC-derived BBB model to define how TCEs such as blinatumomab perturb barrier function, and you will test clinically relevant NRF2 pathway activators as a protective strategy with direct translational implications for drug safety.

Project aims and approach:

• Aim 1: Quantify TCE-induced BBB disruption using iPSC-derived brain endothelial cells co-cultured with PBMCs; measure endothelial activation, cytokine release profiles, and barrier integrity.
• Aim 2: Increase model complexity to evaluate immune cell adhesion, permeability, and tight junction tightness.
• Aim 3: Evaluate NRF2 activation as BBB protection; perform transcriptomic and metabolomic profiling to map NRF2-dependent pathways and broader mechanisms of BBB compromise.

Training environment and iCASE placement:

• You will be based in a vibrant University of Liverpool research group specializing in iPSC-derived brain endothelial cells, embedded in multiple BBB-focused projects funded by bodies such as NC3Rs and UCB Pharma, with active international collaborations and cohort-wide training through the DiMeN DTP.
• A placement at AstraZeneca’s Discovery Centre (Cambridge) will deliver a proof-of-concept study on cytokine release and BBB disruption using advanced imaging and multiplex cytokine platforms, strengthening the translational and industrial impact of your work.

Impact: Join the DiMeN DTP to shape how we predict and prevent neurotoxicity in immuno-oncology and autoimmune therapy area. Your findings could inform safer therapy design, guide clinical risk management, and deliver real benefits to patients. Additionally, this training equips graduates for careers across the pharmaceutical industry (with emphasis on drug safety and pharmacovigilance), academia (research and teaching), and regulatory sciences (including regulatory affairs, benefit–risk assessment).

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/