Chimeric antigen receptor (CAR) T cells have been highly successful in treating haematological malignancies including ALL and CLL. However, treatment of solid tumours using CAR T cells has been largely unsuccessful to date, partly due to tumour-immunosuppressive mechanisms including expression of PDL-1 and adenosine production. PDL-1 and adenosine inhibit T cells through interaction with PD-1 and A_2A receptors (A_2ARs) respectively. Recent studies in our laboratory have shown that combining CAR T cells with either anti-PD-1¹ and/or A_2AR antagonists² significantly enhances CAR T cell responses.

 In these studies, we observed that CAR activation resulted in increased expression of both PD-1 and A_2AR, resulting in suppression of both murine and human CAR T cell function. In two syngeneic Her2⁺ self-antigen tumour models we found that either genetic, pharmacological or antibody targeting of PD-1 or the A_2AR significantly increased CAR T cell efficacy, particularly when combined together. This resulted in enhanced control of tumour growth and significantly enhanced survival of mice. Mechanistically, this was associated with increased cytokine production of CD8⁺ CAR T cells and increased activation of both CD8⁺ and CD4⁺ CAR T cells. The increased production of IFNγ by CAR T cells following A_2AR blockade was shown to be critical for the enhanced anti-tumour efficacy. We confirmed these findings using CAR T cells generated from melanoma patients cocultured with the patient's own tumour cells. In this setting A_2AR blockade was shown to enhance human CAR T cell function.

Recently the combination of CAR T cells and anti-PD-1 has been evaluated in phase I clinical trials³. Given that A_2AR antagonists are currently entering phase I trials in oncology, this approach also has high translational potential to enhance CAR T cell efficacy in several cancer types.