@article{9f34a3b4b06d4835bdf588e648e9c307,
title = "Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer",
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 I 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 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.",
author = "Lawrence Fong and Andrew Hotson and Powderly, {John D.} and Mario Sznol and Heist, {Rebecca S.} and Choueiri, {Toni K.} and Saby George and Hughes, {Brett G.M.} and Hellmann, {Matthew D.} and Shepard, {Dale R.} and Rini, {Brian I.} and Shivaani Kummar and Weise, {Amy M.} and Riese, {Matthew J.} and Ben Markman and Emens, {Leisha A.} and Daruka Mahadevan and Luke, {Jason J.} and Ginna Laport and Brody, {Joshua D.} and Leonel Hernandez-Aya and Philip Bonomi and Goldman, {Jonathan W.} and Lyudmyla Berim and Renouf, {Daniel J.} and Goodwin, {Rachel A.} and Brian Munneke and Ho, {Po Y.} and Jessica Hsieh and Ian McCaffery and Long Kwei and Willingham, {Stephen B.} and Miller, {Richard A.}",
note = "Funding Information: We thank Jennifer Law, Raj Phadtare, Chris Clark, Gabriel Luciano, and other members of the Corvus clinical operations team, Cindy Wilson and Janet Koe for regulatory support and project management, Chunyan Gu for assistance with biosample management, Erik Evensen and J. Ireland for bioinformatic support, Ben Jones, Jingrong Xu, Felicia Flicker, and Liang Liu for drug supply and DMPK support, Katherine Woodworth and Brandon Deze-wiecki for administrative and facilities support, Leiv Lea and the Corvus finance team for budgetary oversight, and Erik Verner and Zhihong Li for thoughtful discussions. Genentech provided atezolizumab for this trial. Clinical trial and associated biomarker research funded by Corvus Pharmaceuticals. L. Fong is supported by NIHR01CA223484 and U01CA233100. Funding Information: We thank Jennifer Law, Raj Phadtare, Chris Clark, Gabriel Luciano, and other members of the Corvus clinical operations team, Cindy Wilson and Janet Koe for regulatory support and project management, Chunyan Gu for assistance with biosample management, Erik Evensen and J. Ireland for bioinformatic support, Ben Jones, Jingrong Xu, Felicia Flicker, and Liang Liu for drug supply and DMPK support, Katherine Woodworth and Brandon Dezewiecki for administrative and facilities support, Leiv Lea and the Corvus finance team for budgetary oversight, and Erik Verner and Zhihong Li for thoughtful discussions. Genentech provided atezolizumab for this trial. Clinical trial and associated biomarker research funded by Corvus Pharmaceuticals. L. Fong is supported by NIH R01CA223484 and U01CA233100. Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2020",
month = jan,
doi = "10.1158/2159-8290.CD-19-0980",
language = "English",
volume = "10",
pages = "40--53",
journal = "Cancer discovery",
issn = "2159-8274",
number = "1",
}