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Adenosine A2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer. Cancer discovery Fong, L., Hotson, A., Powderly, J., Sznol, M., Heist, R. S., Choueiri, T. K., George, S., Hughes, B. G., Hellmann, M. D., Shepard, D. R., Rini, B. I., Kummar, S., Weise, A. M., Riese, M. J., Markman, B., Emens, L. A., Mahadevan, D., Luke, J. J., Laport, G., Brody, J. D., Hernandez-Aya, L., Bonomi, P., Goldman, J. W., Berim, L., Renouf, D. J., Goodwin, R. A., Munneke, B., Ho, P. Y., Hsieh, J., McCaffery, I., Kwei, L., Willingham, S. B., Miller, R. A. 2019

Abstract

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase 1 clinical trial with a small molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 renal cell cancer (RCC) patients, we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-(L)1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treament can also broaden the circulating T cell repertoire. Clinical responses are associated with an adenosine-regulated gene expression signature in pre-treatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-(L)1 that restricts anti-tumor immunity.

View details for DOI 10.1158/2159-8290.CD-19-0980

View details for PubMedID 31732494