T cells genetically modified with a Chimeric Antigen Receptor(CAR) to target malignant cells is a novel approach with proven success in human trials. CART cell therapy reprograms a patient’s own immune T cells needed to recognize and kill tumour cells. CART cell therapy targeting CD19 is a potentially a curative treatment for leukaemia and lymphomas. Currently used methods of CAR gene transfer to T cells mostly based on viral vectors are complicated by the time and expense involved in the elaborate protocols required for their implementation. Non-viral transposon technologies offer an alternative gene delivery system to viral vectors for CAR T cell production. We have engineered novel CARs targeting CD19 (CAR19) using the non-viral, piggyBac (PB) transposon/transposase system that, compared to viral vectors, is comparatively inexpensive and simple to use, has no infectious potential, and has a similar integration profile. The PB transposon also has a large cargo capacity of ≥200 kb that enables delivery of multiple transgenes simultaneously, a feature likely to be important in future generations of CART cells. PB transposon-based CAR19T cells have demonstrated strong efficacy against leukaemia cells in a pre-clinical patient derived xenograft (PDX) mouse models. Using 4-1BB co-stimulation, as opposed to CD28, led to greater potency and persistence of CART cells and provided protection against B-ALL re-challenge even at diminishing doses out to 150 days post-infusion. These pre-clinical data provided the basis for testing PB transposon-based CAR19T cells in clinical trials. A phase I/II multicenter clinical trial of PB-transposon-based CAR19T cells in B cell malignancies has now opened. Sofar, T cells engineered to express PB transposon-CARs have demonstrated strong efficacy against leukaemia in 5 patients with previously incurable leukaemia and lymphoma. Importantly, non-viral genome modification methods such as PB have the potential to increase the number of hospitals capable of implementing therapies by decreasing both the vector cost and complexity of the procedure and further improve patient access to CART cell therapies.