Fong et al. evaluated the safety and efficacy of the adenosine 2A receptor inhibitor ciforadenant alone or in combination with anti-PD-L1 in a phase Ib trial in patients with treatment-refractory renal cell cancer. Ciforadenant was well tolerated. Median PFS was 4.1 months as monotherapy and 5.8 months in combination with anti-PD-L1. Estimated OS was 69% at 16 months for monotherapy and 90% at 25 months for combination therapy. CD8+ T cell infiltration was associated with better disease control, and treatment expanded the TCR repertoire. An adenosine-related gene signature was observed in infiltrating monocytic cells and correlated with response.
Contributed by Shishir Pant
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.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p.
Author Info: (1) UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California. Lawrence.Fong@ucsf.edu rmiller@corvuspharma.com. (2) Corvus Pharmaceuticals, Burlingame, Califo
Author Info: (1) UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California. Lawrence.Fong@ucsf.edu rmiller@corvuspharma.com. (2) Corvus Pharmaceuticals, Burlingame, California. (3) Carolina BioOncology Institute, Huntersville, North Carolina. (4) Yale University Cancer Center, Yale University, New Haven, Connecticut. (5) Massachusetts General Hospital, Harvard University, Boston, Massachusetts. (6) Dana- Farber Cancer Institute, Boston, Massachusetts. (7) Roswell Park Cancer Institute, Buffalo, New York. (8) Royal Brisbane Hospital and University of Queensland, Herston, Brisbane, Queensland, Australia. (9) Memorial Sloan Kettering Cancer Center, New York, New York. (10) Cleveland Clinic Foundation, Cleveland, Ohio. (11) Cleveland Clinic Foundation, Cleveland, Ohio. (12) Stanford University School of Medicine, Stanford, California. (13) Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. (14) Medical College of Wisconsin, Wauwatosa, Wisconsin. (15) Monash Health and Monash University, Melbourne, Clayton, Victoria, Australia. (16) UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. (17) University of Arizona Cancer Center, Tucson, Arizona. (18) University of Chicago Medical Center for Care and Discovery, Chicago, Illinois. (19) Corvus Pharmaceuticals, Burlingame, California. (20) Icahn School of Medicine at Mount Sinai, New York, New York. (21) Washington University Siteman Cancer Center, St Louis, Missouri. (22) Rush University Medical Center, Chicago, Illinois. (23) Ronald Reagan UCLA Medical Center, Los Angeles, California. (24) University of Nebraska Medical Center, Omaha, Nebraska. (25) BC Cancer - Vancouver, Vancouver, British Columbia, Canada. (26) The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada. (27) Corvus Pharmaceuticals, Burlingame, California. (28) Corvus Pharmaceuticals, Burlingame, California. (29) Corvus Pharmaceuticals, Burlingame, California. (30) Corvus Pharmaceuticals, Burlingame, California. (31) Corvus Pharmaceuticals, Burlingame, California. (32) Corvus Pharmaceuticals, Burlingame, California. (33) Corvus Pharmaceuticals, Burlingame, California. Lawrence.Fong@ucsf.edu rmiller@corvuspharma.com.
