Redirecting T cells with a Chimeric Antigen Receptor against ROR1 to target Chronic Lymphocytic Leukaemia. (360G-Wellcome-101658_Z_13_Z)

Our overriding aim is to demonstrate the safety & efficacy of adoptive immunotherapy for patients with chronic lymphocytic leukaemia (CLL) with T cells engineered to express chimeric antigen receptors (CAR) targeting the tumour associated antigen ROR1. CARs comprise an extracellular single-chain antibody fragment coupled with intracellular signalling domains sufficient for cytotoxicity, independent of MHC, when bound to their cognate antigen. This approach is necessary as CLL remains incurable i n the vast majority of patients. The key goals of this proposal are designed to establish the preclinical feasibility of our strategy with the intention of generating data to support a future clinical trial in poor prognosis CLL patients: 1. Demonstrate cytotoxicity of ROR1CAR-T cells against ROR1 expressing cells in a xenograft model. 2. Assess off target toxicity by analysing interaction of ROR1CAR-T cells with primary human tissues representing vital organs and undertaking safety assessm ent in a syngeneic mouse model. 3. Develop a good manufacturing practice compliant protocol which allows generation of sufficient numbers of human ROR1CAR-T cells for future clinical use whilst minimising manipulation and maximising efficacy. We would use the results of this project to gain regulatory approval for a future trial aimed at benefiting patients.