Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer

被引:239
作者
Fong, Lawrence [1 ]
Hotson, Andrew [2 ]
Powderly, John D. [3 ]
Sznol, Mario [4 ]
Heist, Rebecca S. [5 ]
Choueiri, Toni K. [6 ]
George, Saby [7 ]
Hughes, Brett G. M. [8 ,9 ]
Hellmann, Matthew D. [10 ]
Shepard, Dale R. [11 ]
Rini, Brian I. [11 ]
Kummar, Shivaani [12 ]
Weise, Amy M. [13 ]
Riese, Matthew J. [14 ]
Markman, Ben [15 ]
Emens, Leisha A. [16 ]
Mahadevan, Daruka [17 ]
Luke, Jason J. [18 ]
Laport, Ginna [2 ]
Brody, Joshua D. [19 ]
Hernandez-Aya, Leonel [20 ]
Bonomi, Philip [21 ]
Goldman, Jonathan W. [22 ]
Berim, Lyudmyla [23 ]
Renouf, Daniel J. [24 ]
Goodwin, Rachel A. [25 ]
Munneke, Brian [2 ]
Ho, Po Y. [2 ]
Hsieh, Jessica [2 ]
McCaffery, Ian [2 ]
Kwei, Long [2 ]
Willingham, Stephen B. [2 ]
Miller, Richard A. [2 ,25 ]
机构
[1] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA
[2] Corvus Pharmaceut, 863 Mitten Rd,Suite 102, Burlingame, CA 94010 USA
[3] Carolina Biooncol Inst, Huntersville, NC USA
[4] Yale Univ, Canc Ctr, New Haven, CT USA
[5] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA
[6] Dana Farber Canc Inst, Boston, MA USA
[7] Roswell Pk Canc Inst, Buffalo, NY USA
[8] Royal Brisbane Hosp, Brisbane, Qld, Australia
[9] Univ Queensland, Brisbane, Qld, Australia
[10] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA
[11] Cleveland Clin Fdn, Cleveland, OH USA
[12] Stanford Univ, Sch Med, Stanford, CA USA
[13] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA
[14] Med Coll Wisconsin, Wauwatosa, WI USA
[15] Monash Hlth & Monash Univ, Clayton, Vic, Australia
[16] UPMC Hillman Canc Ctr, Pittsburgh, PA USA
[17] Univ Arizona, Canc Ctr, Tucson, AZ USA
[18] Univ Chicago, Med Ctr Care & Discovery, Chicago, IL 60637 USA
[19] Icahn Sch Med Mt Sinai, New York, NY 10029 USA
[20] Washington Univ, Siteman Canc Ctr, St Louis, MO 63110 USA
[21] Rush Univ, Med Ctr, Chicago, IL 60612 USA
[22] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA
[23] Univ Nebraska Med Ctr, Omaha, NE USA
[24] BC Canc Vancouver, Vancouver, BC, Canada
[25] Ottawa Hosp Canc Ctr, Ottawa, ON, Canada
关键词
MEDIATED INHIBITION; CYTOKINE PRODUCTION; CYTOTOXIC ACTIVITY; HYPOXIA; CD73; INFLAMMATION; RESISTANCE; SUPPRESSES; GENERATION;
D O I
10.1158/2159-8290.CD-19-0980
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:40 / 53
页数:14
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