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Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.
Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.
Phosphoinositide 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.
0028-0836
741-746
Eschweiler, Simon
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Ramírez-suástegui, Ciro
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Li, Yingcong
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King, Emma
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Chudley, Lindsey
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Jaya, Thomas
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Wood, Oliver
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Witzleben, Adrian von
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Jeffrey, Danielle
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Mccann, Katy
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Singh, Rabindra P.
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Thomas, Gareth
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Vijayanand, Pandurangan
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Ottensmeier, Christian H.
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Eschweiler, Simon
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Ramírez-suástegui, Ciro
d974b1fe-f22e-46bf-8da9-884ff8459540
Li, Yingcong
1999b484-e160-46b1-a3ba-280daab80828
King, Emma
d85e0e8f-7295-4912-9052-646a790d99db
Chudley, Lindsey
ad364505-e3c8-4d6d-8f25-aa80cb7636fe
Jaya, Thomas
109d22c0-1e01-4e72-a07c-980938244718
Wood, Oliver
b9b57016-5f60-466c-983f-38958426c4b5
Witzleben, Adrian von
cb3adebe-4aa8-4723-95ff-4649913d1aac
Jeffrey, Danielle
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Mccann, Katy
154f6b6d-c8b2-43b2-a8a9-ffe243da40c6
Singh, Rabindra P.
2d7bfc81-9d61-4a04-871b-5e87bb5bda47
Thomas, Gareth
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Vijayanand, Pandurangan
048179ec-320b-469e-b9a2-28243bcb0f5d
Ottensmeier, Christian H.
6805eed3-1cf2-4083-bd11-b49817c24cb1

Eschweiler, Simon, Ramírez-suástegui, Ciro, Li, Yingcong, King, Emma, Chudley, Lindsey, Jaya, Thomas, Wood, Oliver, Witzleben, Adrian von, Jeffrey, Danielle, Mccann, Katy, Singh, Rabindra P., Thomas, Gareth, Vijayanand, Pandurangan and Ottensmeier, Christian H. (2022) Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. Nature, 605, 741-746, [10.1038/s41586-022-04685-2]. (doi:10.1038/s41586-022-04685-2).

Record type: Article

Abstract

Phosphoinositide 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.

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Accepted/In Press date: 24 March 2022
e-pub ahead of print date: 4 May 2022
Published date: 26 May 2022

Identifiers

Local EPrints ID: 468648
URI: http://eprints.soton.ac.uk/id/eprint/468648
ISSN: 0028-0836
PURE UUID: 70d2556e-081a-4aa5-86ae-45232c985b23

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Date deposited: 19 Aug 2022 16:38
Last modified: 19 Aug 2022 17:18

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Contributors

Author: Simon Eschweiler
Author: Ciro Ramírez-suástegui
Author: Yingcong Li
Author: Emma King
Author: Lindsey Chudley
Author: Thomas Jaya
Author: Oliver Wood
Author: Adrian von Witzleben
Author: Danielle Jeffrey
Author: Katy Mccann
Author: Rabindra P. Singh
Author: Gareth Thomas
Author: Pandurangan Vijayanand
Author: Christian H. Ottensmeier

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