Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs
Simon Eschweiler, Ciro Ramírez-Suástegui, Yingcong Li, Emma V. King, Lindsey Chudley, Jaya Thomas, Oliver Wood, Adrian von Witzleben, D. Lifson Jeffrey, Katy J. McCann, Hayley Simon, Monalisa Mondal, Alice Wang, Martina Dicker, Elena Lopez-Guadamillas, Ting-Fang Chou, Nicola Dobbs, Louisa Essame, Gary D Acton, Fiona Kelly, Gavin Halbert, Joseph J. Sacco, Andrew Schache, Richard Shaw, James McCaul, Claire Paterson, Joseph H. Davies, Peter A. Brennan, Rabindra Prasad Singh, Paul M. Loadman, William Wilson, Allan Hackshaw, Grégory Seumois, Klaus Okkenhaug, Gareth J. Thomas, Terry M. Jones, Ferhat Ay, Greg Friberg, Mitchell Kronenberg, Bart Vanhaesebroeck, Pandurangan Vijayanand, Christian H. Ottensmeier
Abstract
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 1–3 . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity 4,5 , 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 (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, PI3Kδi decreased the number of T reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-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 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.