Adoptive cellular immunotherapy (ACT) involving the genetic modification of T cells with antigen-specific chimeric single-chain receptors (CAR) represents an effective strategy for the generation of an unlimited number of tumor-specific T cells for the treatment of cancer. This therapy has shown recent success for the treatment of haematological malignancies such as ALL and CLL and was recently FDA approved for pediatric ALL. This presentation will cover the early origins of CAR T cell development in preclinical mouse models in the laboratory leading to the first ever CAR T cell Phase I trial undertaken at the Peter MacCallum Cancer Centre in Australia using CAR T cells directed against the Lewis Y carbohydrate antigen in patients with Acute Myeloid Leukaemia1. More recent studies have focused on developing new genetic modification strategies and combination approaches for enhancing the effect of CAR T cell therapy particularly for treatment of solid cancers. These strategies are designed to overcome current problems associated with CAR T cell therapy that include immunosuppressive mechanisms utilized by tumors to suppress immune clearance and thus facilitate tumor cell survival and the low frequency of transferred cells trafficking to the tumor site. Strikingly, our data demonstrates that dual blockade of adenosine and PD-1 suppressive pathways or the administration of immune agonist antibodies can potently enhance CAR T-cell responses in mice and this has significant implications for potentially improving therapeutic outcomes of ACT for patients in the future.