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.
Original language | English (US) |
---|---|
Pages (from-to) | 40-53 |
Number of pages | 14 |
Journal | Cancer Discovery |
Volume | 10 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2020 |
ASJC Scopus subject areas
- Oncology
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Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. / 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.
In: Cancer Discovery, Vol. 10, No. 1, 01.2020, p. 40-53.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer
AU - Fong, Lawrence
AU - Hotson, Andrew
AU - Powderly, John D.
AU - Sznol, Mario
AU - Heist, Rebecca S.
AU - Choueiri, Toni K.
AU - George, Saby
AU - Hughes, Brett G.M.
AU - Hellmann, Matthew D.
AU - Shepard, Dale R.
AU - Rini, Brian I.
AU - Kummar, Shivaani
AU - Weise, Amy M.
AU - Riese, Matthew J.
AU - Markman, Ben
AU - Emens, Leisha A.
AU - Mahadevan, Daruka
AU - Luke, Jason J.
AU - Laport, Ginna
AU - Brody, Joshua D.
AU - Hernandez-Aya, Leonel
AU - Bonomi, Philip
AU - Goldman, Jonathan W.
AU - Berim, Lyudmyla
AU - Renouf, Daniel J.
AU - Goodwin, Rachel A.
AU - Munneke, Brian
AU - Ho, Po Y.
AU - Hsieh, Jessica
AU - McCaffery, Ian
AU - Kwei, Long
AU - Willingham, Stephen B.
AU - Miller, Richard A.
N1 - Funding Information: L. Fong reports receiving commercial research grants from AbbVie, Bavarian Nordic, Bristol-Myers Squibb, Dendreon, Janssen, Merck, and Roche/Genentech and has ownership interest (including patents) in Atreca, Nutcracker, and Teneobio. A. Hotson is a scientist at Corvus Pharmaceuticals and has ownership interest (including patents) in the same. J.D. Powderly is a founder and president at Carolina BioOncol-ogy Institute, PLLC and BioCytics Inc., reports receiving commercial research grants from Bristol-Myers Squibb, Genentech, Corvus Pharmaceuticals, AbbVie, Sequenom, Top Alliance BioSciences, EMD Serono, AstraZeneca, InCyte, Arcus, FLX BioSciences, Alkermes, Tempest, and Curis, reports receiving other commercial research support from Precision Medicine and MT Group, has received speakers Funding Information: bureau honoraria from Bristol-Myers Squibb, Genentech, and Merck, and has ownership interest (including patents) in Iovance, BioCyt-ics Inc., and Carolina BioOncology Institute, PLLC. M. Sznol is a consultant at AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Merck US, and Omniox, and has ownership interest (including patents) in Adaptive Biotech. R.S. Heist is a consultant at Boehringer Ingelheim, Novartis, Apollomics, and Tarveda. T.K. Choueiri reports receiving a commercial research grant from Corvus Pharmaceuticals, has received other commercial research support from Bristol-Myers Squibb, Merck, Roche, Exelixis, Pfizer, and Novartis, and has ownership interest (including patents) in Tempest and PionyR. S. George is a consultant at Pfizer, Bristol-Myers Squibb, Bayer, Corvus Pharmaceuticals, EMD Serono, Sanofi, Exelixis, and Genentech. M.D. Hellmann is a consultant at Merck, AstraZeneca, Genentech/Roche, Bristol-Myers Squibb, Nektar, Syndax, Mirati, Shattuck Labs, Immu-nai, and Blueprint Medicines, reports receiving a commercial research grant from Bristol-Myers Squibb, and has ownership interest in a patent filed by Memorial Sloan Kettering (PCT/US2015/062208) for the use of tumor mutation burden for prediction of immunotherapy efficacy, which is licensed to Personal Genome Diagnostics, Immunai, and Shattuck Labs. B.I. Rini is a consultant at Corvus Pharmaceuticals, Pfizer, Merck, Roche, BMS, Arravive, 3D Medicines, and Surface Oncology and reports receiving commercial research grants from Corvus, Merck, Pfizer, Roche, Bristol-Myers Squibb, and AstraZeneca. S. Kummar is a member of the data safety monitoring committee at Corvus Pharmaceuticals. L.A. Emens is a member of the board of directors at the Society for Immunotherapy of Cancer, reports receiving commercial research grants from F. Hoffmann La Roche, Genentech, Aduro Biotech, AstraZeneca, Bristol-Myers Squibb, Corvus Pharmaceuticals, EMD Serono, HeritX, Incorporated, Maxcyte, and Merck, has ownership interest (including patents) in Aduro Biotech, and is a consultant/advisory board member for F. Hoffmann La Roche, Genentech, Roche, Syndax, Lilly, Peregrine, Pfizer, eTHeRNA, AbbVie, Bayer, Bristol-Myers Squibb, Gritstone, Medim-mune, Molecuvax, Macrogenics, and Replimmune. D. Mahadevan is IRC Chair at Pfizer and a data safety consultant at TG Therapeutics and has received speakers bureau honoraria from Guardant Health. J.J. Luke is a consultant at TTC Oncology, 7 Hills, Array, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Compugen, EMD Serono, IDEAYA, Immunocore, Incyte, Actym, Janssen, Merck, Mersana, Novartis, RefleXion, Vividion, Akrevia, Alphamab Oncology, Mavu, Pyxis, Springbank, Tempest, and AbbVie, reports receiving commercial research grants from Array, CheckMate, Evelo, and Palleon, and has ownership interest (including patents) in Actym, Alphamab Oncology, Mavu, Pyxis, and Tempest. G. Laport has ownership interest (including patents) in Corvus Pharmaceuticals. J.D. Brody reports receiving commercial research grants from Merck, Genentech, Acerta Pharma, Kite Pharma, Celgene, Celldex Therapeutics, Seattle Genetics, and Janssen. L. Hernandez-Aya is a consultant/advisory board member for Bristol-Myers Squibb and has received speakers bureau honoraria from Regeneron. P. Bonomi is a consultant/advisory board member for AstraZeneca, Biodesix, Merck, and Pfizer. J.W. Goldman is a consultant at AstraZeneca and Genentech, reports receiving commercial research grants from BMS, Genentech, and AstraZeneca, and has received speakers bureau honoraria from Merck. D.J. Renouf has received speakers bureau honoraria from Celgene, Roche, Servier, AstraZeneca, and Taiho. R.A. Goodwin is a consultant/advisory board member for Ipsen, Novartis, AAA, Amgen, and Tahio, reports receiving commercial research grants from Ipsen, Novartis, and Apo-biologix, and has received speakers bureau honoraria from Amgen. B. Munneke is a director of biostatistics at Corvus Pharmaceuticals and has ownership interest (including patents) in the same. P.Y. Ho is a senior research associate at Corvus Pharmaceuticals and has ownership interest (including patents) in the same. J. Hsieh is a research associate at Corvus Pharmaceuticals and has ownership interest (including patents) in the same. I. McCaffery is a VP, transla- tional sciences at Corvus Pharmaceuticals and has ownership interest (including patents) in the same. L. Kwei is a VP of biometrics and clinical operations at Corvus Pharmaceuticals Inc. S.B. Willingham is a senior scientist II at Corvus Pharmaceuticals and has ownership interest (including patents) in the same. R.A. Miller is CEO at, reports receiving a commercial research grant from, and has ownership interest (including patents) in Corvus Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors. Funding Information: We thank Jennifer Law, Raj Phadtare, Chris Clark, Gabriel Luciano, and other members of the Corvus clinical operations team, Cindy Wilson and Janet Koe for regulatory support and project management, Chunyan Gu for assistance with biosample management, Erik Evensen and J. Ireland for bioinformatic support, Ben Jones, Jingrong Xu, Felicia Flicker, and Liang Liu for drug supply and DMPK support, Katherine Woodworth and Brandon Deze-wiecki for administrative and facilities support, Leiv Lea and the Corvus finance team for budgetary oversight, and Erik Verner and Zhihong Li for thoughtful discussions. Genentech provided atezolizumab for this trial. Clinical trial and associated biomarker research funded by Corvus Pharmaceuticals. L. Fong is supported by NIHR01CA223484 and U01CA233100.
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077761754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077761754&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-19-0980
DO - 10.1158/2159-8290.CD-19-0980
M3 - Article
C2 - 31732494
AN - SCOPUS:85077761754
VL - 10
SP - 40
EP - 53
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 1
ER -