PMID- 35508656
OWN - NLM
STAT- MEDLINE
DCOM- 20220527
LR  - 20240210
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 605
IP  - 7911
DP  - 2022 May
TI  - Intermittent PI3Kdelta inhibition sustains anti-tumour immunity and curbs irAEs.
PG  - 741-746
LID - 10.1038/s41586-022-04685-2 [doi]
AB  - Phosphoinositide 3-kinase delta (PI3Kdelta) has a key role in lymphocytes, and inhibitors 
      that target this PI3K have been approved for treatment of B cell 
      malignancies(1-3). Although studies in mouse models of solid tumours have 
      demonstrated that PI3Kdelta inhibitors (PI3Kdeltai) can induce anti-tumour immunity(4,5), 
      its effect on solid tumours in humans remains unclear. Here we assessed the 
      effects of the PI3Kdeltai AMG319 in human patients with head and neck cancer in a 
      neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT 
      no. 2014-004388-20). PI3Kdelta inhibition decreased the number of tumour-infiltrating 
      regulatory T (T(reg)) cells and enhanced the cytotoxic potential of 
      tumour-infiltrating T cells. At the tested doses of AMG319, immune-related 
      adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of 
      patients treated with AMG319, suggestive of systemic effects on T(reg) cells. 
      Accordingly, in mouse models, PI3Kdeltai decreased the number of T(reg) cells 
      systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a 
      PI3Kdeltai-driven loss of tissue-resident colonic ST2 T(reg) cells, accompanied by 
      expansion of pathogenic T helper 17 (T(H)17) and type 17 CD8(+) T (T(C)17) cells, 
      which probably contributed to toxicity; this points towards a specific mode of 
      action for the emergence of irAEs. A modified treatment regimen with intermittent 
      dosing of PI3Kdeltai in mouse models led to a significant decrease in tumour growth 
      without inducing pathogenic T cells in colonic tissue, indicating that 
      alternative dosing regimens might limit toxicity.
CI  - (c) 2022. The Author(s).
FAU - Eschweiler, Simon
AU  - Eschweiler S
AUID- ORCID: 0000-0002-6379-8588
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Ramirez-Suastegui, Ciro
AU  - Ramirez-Suastegui C
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Li, Yingcong
AU  - Li Y
AUID- ORCID: 0000-0002-0746-0531
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
AD  - Division of Biological Sciences, University of California San Diego, La Jolla, 
      CA, USA.
FAU - King, Emma
AU  - King E
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
AD  - Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole, UK.
FAU - Chudley, Lindsey
AU  - Chudley L
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK.
FAU - Thomas, Jaya
AU  - Thomas J
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
FAU - Wood, Oliver
AU  - Wood O
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
FAU - von Witzleben, Adrian
AU  - von Witzleben A
AUID- ORCID: 0000-0001-6766-4758
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
AD  - Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical 
      Center, Ulm, Germany.
FAU - Jeffrey, Danielle
AU  - Jeffrey D
AUID- ORCID: 0000-0003-3193-3420
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
FAU - McCann, Katy
AU  - McCann K
AUID- ORCID: 0000-0003-4388-7265
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
FAU - Simon, Hayley
AU  - Simon H
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Mondal, Monalisa
AU  - Mondal M
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Wang, Alice
AU  - Wang A
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Dicker, Martina
AU  - Dicker M
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Lopez-Guadamillas, Elena
AU  - Lopez-Guadamillas E
AD  - UCL Cancer Institute, University College London, London, UK.
FAU - Chou, Ting-Fang
AU  - Chou TF
AUID- ORCID: 0000-0001-7095-3518
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Dobbs, Nicola A
AU  - Dobbs NA
AD  - Centre for Drug Development, Cancer Research UK, London, UK.
FAU - Essame, Louisa
AU  - Essame L
AD  - Centre for Drug Development, Cancer Research UK, London, UK.
FAU - Acton, Gary
AU  - Acton G
AD  - Centre for Drug Development, Cancer Research UK, London, UK.
FAU - Kelly, Fiona
AU  - Kelly F
AD  - Centre for Drug Development, Cancer Research UK, London, UK.
FAU - Halbert, Gavin
AU  - Halbert G
AD  - Cancer Research UK Formulation Unit, University of Strathclyde, Glasgow, UK.
FAU - Sacco, Joseph J
AU  - Sacco JJ
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK.
AD  - Clatterbridge Cancer Centre NHS Foundation Trust and Liverpool Cancer Research UK 
      Experimental Cancer Medicine Center Liverpool, Liverpool, UK.
FAU - Schache, Andrew Graeme
AU  - Schache AG
AUID- ORCID: 0000-0001-9466-6038
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK.
AD  - Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
FAU - Shaw, Richard
AU  - Shaw R
AUID- ORCID: 0000-0002-5157-4042
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK.
AD  - Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
FAU - McCaul, James Anthony
AU  - McCaul JA
AD  - Queen Elizabeth University Hospital, Glasgow, UK.
FAU - Paterson, Claire
AU  - Paterson C
AD  - Beatson West of Scotland Cancer Centre, Glasgow, UK.
FAU - Davies, Joseph H
AU  - Davies JH
AD  - Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole, UK.
FAU - Brennan, Peter A
AU  - Brennan PA
AD  - Queen Alexandra Hospital, Portsmouth, UK.
FAU - Singh, Rabindra P
AU  - Singh RP
AD  - Southampton University Hospitals NHS Foundation Trust, Southampton, UK.
FAU - Loadman, Paul M
AU  - Loadman PM
AUID- ORCID: 0000-0002-4259-8616
AD  - University of Bradford, Institute of Cancer Therapeutics, Bradford, UK.
FAU - Wilson, William
AU  - Wilson W
AD  - Cancer Research UK and UCL Cancer Trials Centre, London, UK.
FAU - Hackshaw, Allan
AU  - Hackshaw A
AUID- ORCID: 0000-0002-5570-5070
AD  - Cancer Research UK and UCL Cancer Trials Centre, London, UK.
FAU - Seumois, Gregory
AU  - Seumois G
AUID- ORCID: 0000-0002-8164-6852
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Okkenhaug, Klaus
AU  - Okkenhaug K
AUID- ORCID: 0000-0002-9432-4051
AD  - Department of Pathology, University of Cambridge, Cambridge, UK.
FAU - Thomas, Gareth J
AU  - Thomas GJ
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK.
FAU - Jones, Terry M
AU  - Jones TM
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK.
AD  - Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
FAU - Ay, Ferhat
AU  - Ay F
AUID- ORCID: 0000-0002-0708-6914
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Friberg, Greg
AU  - Friberg G
AD  - Amgen, Thousand Oaks, CA, USA.
FAU - Kronenberg, Mitchell
AU  - Kronenberg M
AUID- ORCID: 0000-0001-6318-6445
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA.
AD  - Division of Biological Sciences, University of California San Diego, La Jolla, 
      CA, USA.
FAU - Vanhaesebroeck, Bart
AU  - Vanhaesebroeck B
AUID- ORCID: 0000-0002-7074-3673
AD  - UCL Cancer Institute, University College London, London, UK.
FAU - Vijayanand, Pandurangan
AU  - Vijayanand P
AUID- ORCID: 0000-0001-7067-9723
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA. vijay@lji.org.
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK. vijay@lji.org.
AD  - Department of Medicine, University of California San Diego, La Jolla, CA, USA. 
      vijay@lji.org.
FAU - Ottensmeier, Christian H
AU  - Ottensmeier CH
AUID- ORCID: 0000-0003-3619-1657
AD  - La Jolla Institute for Immunology, La Jolla, CA, USA. 
      c.ottensmeier@liverpool.ac.uk.
AD  - CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, 
      Southampton, UK. c.ottensmeier@liverpool.ac.uk.
AD  - Liverpool Head and Neck Center and Institute of Systems, Molecular and 
      Integrative Biology, University of Liverpool, Liverpool, UK. 
      c.ottensmeier@liverpool.ac.uk.
AD  - Clatterbridge Cancer Centre NHS Foundation Trust and Liverpool Cancer Research UK 
      Experimental Cancer Medicine Center Liverpool, Liverpool, UK. 
      c.ottensmeier@liverpool.ac.uk.
LA  - eng
GR  - S10 OD025052/OD/NIH HHS/United States
GR  - S10 RR027366/RR/NCRR NIH HHS/United States
GR  - 25722/CRUK_/Cancer Research UK/United Kingdom
GR  - 28803/CRUK_/Cancer Research UK/United Kingdom
GR  - P01 DK046763/DK/NIDDK NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20220504
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinolines)
RN  - 19DG7G1U5Q (N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/therapeutic use
MH  - Animals
MH  - *Antineoplastic Agents/therapeutic use
MH  - Disease Models, Animal
MH  - *Head and Neck Neoplasms/drug therapy
MH  - Humans
MH  - Immunotherapy
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases
MH  - Quinolines/therapeutic use
MH  - T-Lymphocytes, Regulatory
PMC - PMC9132770
COIS- G.F. is an employee of Amgen Inc. B.V. is a consultant for iOnctura (Geneva, 
      Switzerland), Venthera (Palo Alto, US) and Olema Pharmaceuticals (San Francisco, 
      US) and has received speaker fees from Gilead (Foster City, US). K.O. has 
      received consultancy fees from iOnctura, Macomics, Gilead Sciences and Karus 
      Therapeutics and has received research funding from GSK. M.K. is on the 
      scientific advisory board of Prometheus. C.H.O. led the clinical trial of AMG319 
      with funding by Cancer Research UK, Amgen provided clinical grade compound free 
      of charge for this trial. All other authors declare no conflicts of interest.
EDAT- 2022/05/05 06:00
MHDA- 2022/05/28 06:00
PMCR- 2022/05/04
CRDT- 2022/05/04 23:49
PHST- 2021/03/17 00:00 [received]
PHST- 2022/03/24 00:00 [accepted]
PHST- 2022/05/05 06:00 [pubmed]
PHST- 2022/05/28 06:00 [medline]
PHST- 2022/05/04 23:49 [entrez]
PHST- 2022/05/04 00:00 [pmc-release]
AID - 10.1038/s41586-022-04685-2 [pii]
AID - 4685 [pii]
AID - 10.1038/s41586-022-04685-2 [doi]
PST - ppublish
SO  - Nature. 2022 May;605(7911):741-746. doi: 10.1038/s41586-022-04685-2. Epub 2022 
      May 4.