Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

PA Beavis; MA Henderson; L Giuffrida; JK Mills; K Sek; RS Cross; AJ Davenport; LB John; S Mardiana; CY Slaney; RW Johnstone; JA Trapani; J Stagg; S Loi; L Kats; D Gyorki; MH Kershaw; PK Darcy

Journal article

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

PA Beavis, MA Henderson, L Giuffrida, JK Mills, K Sek, RS Cross, AJ Davenport, LB John, S Mardiana, CY Slaney, RW Johnstone, JA Trapani, J Stagg, S Loi, L Kats, D Gyorki, MH Kershaw, PK Darcy

Journal of Clinical Investigation | AMER SOC CLINICAL INVESTIGATION INC | Published : 2017

DOI: 10.1172/JCI89455

Abstract

Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR a..

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University of Melbourne Researchers

Paul Beavis Author

Ryan Cross Author

Clare Slaney Author

Ricky Johnstone Author

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Grants

Awarded by Cancer Council Victoria

Funding Acknowledgements

The authors acknowledge the assistance of the Animal Facility technicians at the Peter MacCallum Cancer Centre. This work was funded by Project and Program grants from the National Health and Medical Research Council (NHMRC; APP1062580, APP1122444), a Cancer Council Victoria Project Grant (APP1084420), and a grant from the Peter MacCallum Cancer Centre Foundation. PAB and CYS are supported by National Breast Cancer Foundation Fellowships (ID nos. PF-14-008 and ECF-16-005). PKD and MHK are supported by NHMRC Senior Research Fellowships (APP1041828 and APP1058388, respectively). RWJ is supported by a Senior Principal Research Fellowship from the NHMRC.