Adoptive cellular immunotherapy (ACT) involving genetic modification of T cells with antigen-specific chimeric single-chain receptors (CAR) has been highly successful in treating B cell malignancies particularly ALL. We have successfully completed a Phase I clinical trial using CAR T cells directed against the Lewis Y antigen in patients with Acute Myeloid Leukaemia; the therapy was well tolerated and the transferred cells persisted long term and trafficked to the site of disease1. However, for effective treatment of solid cancers by ACT, a major problem is the immunosuppressive mechanisms utilized by tumors to suppress immune clearance. One such pathway that has largely been ignored is the generation of adenosine by CD73 expressed on tumor cells. In this study, we investigated whether blockade of this pathway could enhance ACT using CAR T cells. Blockade of the A2A adenosine receptor with the small molecule antagonist SCH58621 enhanced the ability of CAR T cells targeting Her-2 to produce cytokines when cocultured with Her-2+ tumors. Moreover, CAR T cells generated from A2A-/- mice demonstrated enhanced activity against Her-2+ tumors compared with wildtype CAR T cells, highlighting a role for A2A mediated suppression in vivo. Interestingly, we found that although combined CAR T therapy and A2A blockade only moderately reduced the growth of established Her-2+ tumors, the addition of anti-PD-1 mAb in the treatment regimen resulted in a striking increase in efficacy. In conclusion, this study demonstrates that simultaneous blockade of adenosine and PD-1 can potently enhance CAR T-cell action, with potentially significant implications for future trials of CAR T cell therapy in solid malignancies.