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dc.contributor.authorEschweiler, S.
dc.contributor.authorRamirez-Suastegui, C.
dc.contributor.authorLi, Y.
dc.contributor.authorKing, E.
dc.contributor.authorChudley, L.
dc.contributor.authorThomas, J.
dc.contributor.authorWood, O.
dc.contributor.authorvon Witzleben, A.
dc.contributor.authorJeffrey, D.
dc.contributor.authorMcCann, K.
dc.contributor.authorSimon, H.
dc.contributor.authorMondal, M.
dc.contributor.authorWang, A.
dc.contributor.authorDicker, M.
dc.contributor.authorLopez-Guadamillas, E.
dc.contributor.authorChou, T.-F.
dc.contributor.authorDobbs, N.A.
dc.contributor.authorEssame, L.
dc.contributor.authorActon, G.
dc.contributor.authorKelly, F.
dc.contributor.authorHalbert, G.
dc.contributor.authorSacco, J.J.
dc.contributor.authorSchache, A.G.
dc.contributor.authorShaw, R.
dc.contributor.authorMcCaul, J.A.
dc.contributor.authorPaterson, C.
dc.contributor.authorDavies, J.H.
dc.contributor.authorBrennan, Peter A.
dc.contributor.authorSingh, R.P.
dc.contributor.authorLoadman, Paul M.
dc.contributor.authorWilson, W.
dc.contributor.authorHackshaw, A.
dc.contributor.authorSeumois, G.
dc.contributor.authorOkkenhaug, K.
dc.contributor.authorThomas, G.J.
dc.contributor.authorJones, T.M.
dc.contributor.authorAy, F.
dc.contributor.authorFriberg, G.
dc.contributor.authorKronenberg, M.
dc.contributor.authorVanhaesebroeck, B.
dc.contributor.authorVijayananad, P.
dc.contributor.authorOttensmeier, C.H.
dc.date.accessioned2022-06-08T09:11:18Z
dc.date.available2022-06-08T09:11:18Z
dc.date.issued2022-05-26
dc.identifier.citationEschweiler S, Ramírez-Suástegui C, Li Y et al (2022) Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. Nature. 605: 741-746.en_US
dc.identifier.urihttp://hdl.handle.net/10454/18980
dc.descriptionYesen_US
dc.description.abstractPhosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi 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). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) 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 Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) 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 PI3Kδi 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.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1038/s41586-022-04685-2-2en_US
dc.rights(c) 2022 The Authors. This is an Open Access article distributed under the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/)en_US
dc.subjectPI3Kδ inhibitionen_US
dc.subjectAMG319en_US
dc.subjectHead and neck surgeryen_US
dc.subjectImmunotherapyen_US
dc.subjectResearch Development Fund Publication Prize Award
dc.titleIntermittent PI3Ko inhibition sustains anti-tumor immunity and curbs irAEsen_US
dc.status.refereedYesen_US
dc.date.Accepted2022-03-24
dc.date.application2022-05-04
dc.typeArticleen_US
dc.type.versionPublished versionen_US
dc.description.publicnotesResearch Development Fund Publication Prize Award winner, May 2022.
dc.rights.licenseCC-BYen_US
refterms.dateFOA2022-06-08T09:11:19Z
dc.openaccess.statusopenAccessen_US


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