Adoptive cellular therapy (ACT) with T cells engineered to express a CAR that specifically recognizes tumor associated antigen has shown great clinical promise with objective responses being reported in patients with haematological cancers. However, responses against solid cancers has been more modest to date. A major problem inhibiting ACT is the immunosuppressive mechanisms utilized by tumors to suppress immune clearance and thus facilitate tumor cell survival. One of these immunosuppressive pathways which has largely been ignored is the generation of adenosine by CD73 expressed on tumor cells. Blockade of adenosine 2A (A2A) receptors has been shown by us, and others, to enhance the cytokine production and cytotoxicity of CD8+ T cells and lead to greater anti-tumor immune responses. In this study, we investigated whether A2A blockade may enhance the efficacy of CAR T cell therapy. We demonstrated that blocking the A2A receptor with the small molecule antagonist SCH58621 could enhance the ability of chimeric antigen receptor (CAR) transduced T cells targeting the Her-2 antigen to produce cytokines when cocultured with Her-2+ tumors. Moreover, experiments using CAR T cells generated from A2A-/- mice further confirmed the suppressive role of the A2A receptor in this system. We also demonstrated that CAR T cells upregulate expression of the A2A receptor following activation through the CAR, providing a rationale to block this pathway in vivo. In adoptive transfer experiments utilizing Her-2 transgenic mice, we found that A2A-/- CAR T cells have enhanced activity against Her-2+ tumors in terms of primary tumor growth and survival compared with wildtype CAR T cells, highlighting a role for A2A mediated suppression in vivo. In subsequent transfer experiments, we found that combined therapy involving CAR T cells and A2A blockade with SCH58261 led to significantly enhanced survival of mice bearing established Her-2+ tumors and that the addition of anti-PD-1 mAb resulted in a striking increase in anti-tumor efficacy. Importantly, increased antitumor effects in this model were not associated with any autoimmune pathology in normal tissue expressing the Her-2 antigen. This study shows that specifically blocking tumor induced immunosuppression can potently enhance CAR T-cell therapy and this has significant implications for potentially improving therapeutic outcomes of CAR T cell therapy for patients.