Faculty Collaboration Database

Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer. Cancer Discov 2020 Jan;10(1):40-53

Date

11/17/2019

Pubmed ID

31732494

Pubmed Central ID

PMC6954326

DOI

10.1158/2159-8290.CD-19-0980

Scopus ID

2-s2.0-85077761754 (requires institutional sign-in at Scopus site)   204 Citations

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.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.

Author List

Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri TK, George S, Hughes BGM, Hellmann MD, Shepard DR, Rini BI, Kummar S, Weise AM, Riese MJ, Markman B, Emens LA, Mahadevan D, Luke JJ, Laport G, Brody JD, Hernandez-Aya L, Bonomi P, Goldman JW, Berim L, Renouf DJ, Goodwin RA, Munneke B, Ho PY, Hsieh J, McCaffery I, Kwei L, Willingham SB, Miller RA

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Carcinoma, Renal Cell
Drug Resistance, Neoplasm
Female
Follow-Up Studies
Furans
Humans
Kidney Neoplasms
Male
Middle Aged
Neoplasm Recurrence, Local
Prognosis
Pyridines
Pyrimidines
Receptor, Adenosine A2A
Salvage Therapy
Survival Rate