- Email: email@example.com
- Thesis title: Harnessing T cells to target brain metastases
- Supervisors: Dr Mihaela Lorger, Dr Robert Salmond, Professor Julia Newton-Bishop
In 2016, I graduated with a BSc in Biomedical Sciences, during my third year, I completed a 12-month placement at LGC Ltd; a Contract Research Organisation in Cambridgeshire focused on providing project-based contract work to pharmaceutical and biotechnology companies to support both pre-clinical and clinical studies. I then went to the London Institute of Medical Sciences (LMS), Imperial College London for a summer placement, where I worked in the Genes and Metabolism group on a project using a Drosophila insulin-resistant model, to investigate the correlation between obesity and the progression of tumours.
In 2017, I completed an MSc in Cancer Immunology and Biotechnology, where I investigated the impact of hypoxia on endothelial cell quiescence. I then worked as a research associate at F-star Therapeutics in Cambridge. My primary role was to develop bespoke immunoassays to support preclinical drug development for F-star's Modular Antibody Technology™ to rapidly develop a large panel of tetravalent bispecific antibodies to improve the treatment of cancer.
In 2019, I moved to Leeds to begin my PhD under the supervision of Dr Mihaela Lorger, Dr Robert Salmond and Professor Julia Newton-Bishop. The project will investigate ways to improve T cell homing towards brain metastases in the context of immune checkpoint inhibition.
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 represents 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 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. The group have 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, the group identified a 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.
- Does the over-expression of key CR(s) in murine CD8+ T cells enhance T cell migration towards corresponding chemokines in vitro and their trafficking to BrM in vivo?
- Does 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?
- Does 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?
- MSc Cancer Immunology and Biotechnology
- BSc Biomedical Science