MRC DiMeN Doctoral Training Partnership: Harnessing T cells to target brain metastases
Dr Mihaela Lorger
Dr R Salmond
Prof J Newton-Bishop
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
An MRC-funded PhD student position is available to explore how T cells can be harnessed to enhance the efficacy of immune checkpoint inhibitors in melanoma brain metastases. The project will be based within the Brain metastasis research group at the University of Leeds in the UK, led by Dr. Mihaela Lorger (please visit https://medicinehealth.leeds.ac.uk/medicine/staff/548/dr-mihaela-lorger for more information), and the student will be co-supervised by Dr. Robert Salmond (https://medicinehealth.leeds.ac.uk/medicine/staff/733/dr-robert-salmond) and Prof. Julia Newton-Bishop (https://medicinehealth.leeds.ac.uk/medicine/staff/648/professor-julia-newton-
bishop). This multidisciplinary supervisory team brings together expertise in brain tumour research, immunology, and clinical melanoma research.
PD-1 and CTLA-4 are immune-inhibitory receptors (immune checkpoints) expressed mainly on T cells. Their inhibition with function-blocking antibodies enhances anti-tumour T cell responses, and results in promising therapeutic efficacy in different cancers, including melanoma. However, ~40% of melanoma patients fail to show long-term responses to the combined PD-1/CTLA-4 blockade, requiring further enhancement of the therapeutic efficacy. In addition, approximately 60% of melanoma patients develop brain metastases (BrM), which are associated with a particularly poor prognosis. The incidence of BrM in the clinic is increasing given longer survival and as they are difficult to treat, BrM represent an unmet clinical need. With PD-1 and CTLA-4 blockade becoming the frontline therapy in metastatic melanoma, it is urgent to develop strategies for an enhanced efficacy of this therapy in BrM. Notably, recent clinical trials suggest a superior intracranial activity of combined PD-1/CTLA-4 blockade in melanoma BrM as compared to the respective monotherapies.
We have recently developed an in vivo model in which the clinically observed intracranial activity of immune checkpoint inhibitors can be recapitulated (Taggart et al., 2018, PNAS). Using this model, we identified chemokine receptor (CR)-dependent trafficking of CD8+ T cells to brain metastases (BrM) as one of the key factors required for the intracranial activity of combined anti-PD-1 plus anti-CTLA-4 therapy. We hypothesize that stable overexpression of the key CRs in T cells can potentiate their homing to BrM, and thereby enhance the intracranial efficacy of PD-1/CTLA-4 blockade. To test this, the project will first determine whether the over-expression of key CR(s) in murine CD8+ T cells enhances T cell migration towards corresponding chemokines in vitro and their trafficking to BrM in vivo. Secondly, the study will investigate whether PD-1/CTLA-4 blockade enhances the migration of human blood-derived CD8+ T cells towards chemokines of interest, and whether there is patient-to-patient variability in CR expression. Lastly, the efficacy of adoptive T cell therapy using CR-overexpressing T cells in combination with PD-1/CTLA-4 blockade will be tested in our in vivo models of brain metastases.
The student will receive training in cell culture of murine and primary human cells, handling of lentiviral vectors and generation of stable cell lines, cell migration assay, multi-colour flow cytometry, and different in vivo techniques required for work with brain metastases models, including surgery to initiate tumours, administration of drugs, bioluminescence imaging for monitoring of tumour growth, adoptive T cell transfer, as well as tissue isolation and processing.
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:
Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Stipend at national UKRI standard rate
Research training and support grant (RTSG)
Studentships commence: 1st October 2019.
To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: https://goo.gl/8YfJf8