Deep conditioning using CRISPR edited T cells

T cells modified to express chimeric antigen receptors (CAR) have been successfully applied to treat B cell malignancies and are now being made more widely available as the first licenced products become available. The application of similar strategies against acute myeloid leukaemia have been challenging, in particular in infants and young children. Mortality is anticipated to be >70% for children who relapse after a first allogeneic transplant in high risk AML, and this reflects a failure to eliminate residual disease with chemotherapy or by anti-leukaemia transplant effects. We propose applying CRISPR base editing tools to generate ‘off the shelf’ T cells expressing CARs against different antigens and aim to secure deep molecular remission during pre-transplant conditioning in children who otherwise face a dismal prognosis. This application seeks to complete preclinical stage investigations of targeted base-conversion by cytidine deamination to disrupt critical genes required to overcome HLA-barriers and allow expression of CARs specific for shared T and myeloid lineage antigens. We propose translational advancement and rapid deployment into a Phase 1 trial in UK and Germany of the most effective available reagents to address unmet clinical need, while continuing development work on additional target antigens and improved editing tools.