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.
Cancer discovery. 2019 Nov 15 [Epub ahead of print]
Lawrence Fong, Andrew Hotson, John Powderly, Mario Sznol, Rebecca S Heist, Toni K Choueiri, Saby George, Brett Gm Hughes, Matthew D Hellmann, Dale R Shepard, Brian I Rini, Shivaani Kummar, Amy M Weise, Matthew J Riese, Ben Markman, Leisha A Emens, Daruka Mahadevan, Jason J Luke, Ginna Laport, Joshua D Brody, Leonel Hernandez-Aya, Philip Bonomi, Jonathan W Goldman, Lyudmyla Berim, Daniel J Renouf, Rachel A Goodwin, Brian Munneke, Po Y Ho, Jessica Hsieh, Ian McCaffery, Long Kwei, Stephen B Willingham, Richard A Miller
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco ., Research, Corvus Pharmaceuticals., Cancer Therapy & Research, Carolina BioOncology Institute., Smilow Cancer Center, Yale School of Medicine., Cancer Center, Massachusetts General Hospital., Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School., Cell Stress Biology, Roswell Park Cancer Institute., Cancer Care Services, The Prince Charles Hospital, University of Queensland., Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center., Department of Hematology and Medical Oncology, Cleveland Clinic., Cleveland Clinic., Division of Oncology, Stanford University School of Medicine., Oncology, Karmanos Cancer Institute., MedicinDivision of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin., Oncology, Monash Medical Centre., Medicine, UPMC Hillman Cancer Center., Department of Medicine, University of Arizona Cancer Center., Department of Medicine, University of Pittsburgh Medical Center and Hillman Cancer Center., Corvus Pharmaceuticals., Hematology & Oncology, Icahn School of Medicine at Mount Sinai., Washington University Medical Center., Section of Medical Oncology, Rush University Medical Center., David Geffen School of Medicine at UCLA., University of Nebraska Medical Center., Medical Oncology, BC Cancer., Cancer Centre, Ottawa Hospital., Oncology Translational Research, Janssen Research and Development LLC.