Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Simon Eschweiler, Ciro Ramírez-Suástegui, Yingcong Li, Emma King, Lindsey Chudley, Jaya Thomas, Oliver Wood, Adrian von Witzleben, Danielle Jeffrey, Katy McCann, Hayley Simon, Monalisa Mondal, Alice Wang, Martina Dicker, Elena Lopez-Guadamillas, Ting-Fang Chou, Nicola A Dobbs, Louisa Essame, Gary Acton, Fiona KellyGavin Halbert, Joseph J Sacco, Andrew Graeme Schache, Richard Shaw, James Anthony McCaul, Claire Paterson, Joseph H Davies, Peter A Brennan, Rabindra P Singh, Paul M Loadman, William Wilson, Allan Hackshaw, Gregory Seumois, Klaus Okkenhaug, Gareth J Thomas, Terry M Jones, Ferhat Ay, Greg Friberg, Mitchell Kronenberg, Bart Vanhaesebroeck, Pandurangan Vijayanand, Christian H Ottensmeier

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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 malignancies . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity , 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 (T ) 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 cells. Accordingly, in mouse models, PI3Kδi decreased the number of T cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T cells, accompanied by expansion of pathogenic T helper 17 (T 17) and type 17 CD8 T (T 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 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.
Original languageEnglish
Pages (from-to)741–746
Number of pages6
JournalNature
Volume605
Issue number7911
Early online date4 May 2022
DOIs
Publication statusPublished - 26 May 2022

Keywords

  • Phosphoinositide 3-kinase δ (PI3Kδ)
  • cancer cells
  • immunotherapeutic agents
  • chronic lymphocytic leukaemia
  • immunomodulatory agents
  • solid tumours

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