Development Fund

Acute myeloid leukaemia (AML) in children remains a significant unmet, with high prevalence of specific gene fusions. We hypothesize that these fusion-proteins could be well presented by proteasome-generated spliced peptides, and recognised by CD8+ T cells. Their cytotoxicity could be used to attach AML by developing novel immunotherapies. The project will verify this hypothesis by applying a multidisciplinary strategy, which ranges from bioinformatics to clinics though biochemistry, molecular and cellular immunology.

The project is funded on the unique expertise of the applicants, who are located at King’s College London, University College London and Queen Mary University of London, and with the support of the Francis Crick Institute

One bottleneck in developing this combination therapy further is that many factors, which are central to its successful delivery, remain poorly understood. This is because the laboratory models that researchers have been using, do not adequately mimic the complexity of the human body. Consequently, it is now necessary to improve these models and use new techniques to obtain more and better research data from them. Here, we will pilot new analysis workflows, which will allow us to apply for more funding to develop this therapy combination.

TBC

We have developed a novel therapeutic concept in which CAR-T cells are rendered more proliferative and endowed with greater cytolytic activity when exposed to B-ALL blasts that have been pre-treated with a metabolic stressing agent that starves cells of arginine. With the support of the CRUK City of London Centre Award we will now analyse the molecular determinants of this phenomena using single cell proteomics via CyTOF, then expand to an in vivo testing platform to identify its potential pre-clinical benefit. Finally, we will test the portability of this effect to other tumour types to assess whether metabolic stress can be used more widely to enhance the anti-cancer effect of CAR-T.

Chimeric antigen receptor (CAR) T-cell immunotherapy represents a potentially powerful approach for treating neuroblastoma, however, immune suppressive macrophages in the microenvironment represent a potential barrier to robust clinical outcomes. This project will employ a screen of FDA-approved drugs to block the immune suppressive activity of macrophages on CAR T-cells. These drug candidates will be investigated using in vitro an in vivo models of neuroblastoma. As the drugs within the screen are FDA-approved, it will permit their rapid translation to the clinic for improving the efficacy of CAR T-cell immunotherapy in neuroblastoma.