Details

Autor(en) / Beteiligte

• Fong, Lawrence
• Hotson, Andrew
• Powderly, John D
• Sznol, Mario
• Heist, Rebecca S
• Choueiri, Toni K
• George, Saby
• Hughes, Brett G M
• Hellmann, Matthew D
• Shepard, Dale R
• Rini, Brian I
• Kummar, Shivaani
• Weise, Amy M
• Riese, Matthew J
• Markman, Ben
• Emens, Leisha A
• Mahadevan, Daruka
• Luke, Jason J
• Laport, Ginna
• Brody, Joshua D
• Hernandez-Aya, Leonel
• Bonomi, Philip
• Goldman, Jonathan W
• Berim, Lyudmyla
• Renouf, Daniel J
• Goodwin, Rachel A
• Munneke, Brian
• Ho, Po Y
• Hsieh, Jessica
• McCaffery, Ian
• Kwei, Long
• Willingham, Stephen B
• Miller, Richard A

Titel

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

Ist Teil von

• Cancer discovery, 2020-01, Vol.10 (1), p.40-53

Ort / Verlag

United States

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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. . .