Project ID CM-HD2023_42

ThemeCM-HD

Co Supervisor 1A Department of Infectious DiseasesWebsite

Co Supervisor 1B School of Cancer and Pharmaceutical SciencesWebsite

Role of extracellular vesicles in the outcome of CAR T cell therapy in cancer

The importance of cell-to-cell communication mediated by extracellular vesicles (EV) is gaining increasing attention. In patients with cancer, Tumour-derived EV can be readily detected, these can contain micro and other RNAs in addition to various chemokines and enzymes which can influence the immune response. Thus, EV have the potential to negatively impact T cell-driven anti-tumour responses. On the other hand, chimeric antigen receptor (CAR) T cell-derived EV have shown potent anti-tumour activity. These findings suggest that EV can play a role in the success or failure of CAR T cell therapy.

Dr Schurich is an expert in the regulation of T cell function and Dr Benjamin is a leading haematologist and expert in CAR T cell therapy for blood cancers

We have an established collaboration with all necessary research infrastructure and ethics in place, allowing us to study longitudinal samples from patients before and post CAR T cell infusion.

As a PhD student leading this highly translational project you will:
1. Profile CAR-T patient-derived EV (identifying both tumour and T cell derived EV) to determine the suitability of EV as early biomarkers for cancer progression or regression
2. Assess the impact of these EV on human T cell phenotype and function
3. Study the nucleic acid and protein cargo of EV to identify mechanisms which allow EV to impact T cell function.

This approach could allow us to stratify patients by using EV-biomarkers to obtain a clearer understanding of each specific cancer and its immune suppressive potential and furthermore uncover novel molecular targets for intervention.

One representative publication from each co-supervisor:

• Muliaditan T, Halim L, Whilding LM, Draper B, Achkova DY, Kausar F, Glover M, Bechman N, Arulappu A, Sanchez J, Flaherty KR, Obajdin J, Grigoriadis K, Antoine P, Larcombe-Young D, Hull CM, Buus R, Gordon P, Grigoriadis A, Davies DM, Schurich A, Maher J. Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors. Cell Reports Medicine 2021; 2: 100457. [PMID: 35028604 DOI: 10.1016/j.xcrm.2021.100457]

• Benjamin R, Graham C, Yallop D, et al (2020) Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. The Lancet 396 (10266) 1885-1894