Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Eschweiler, Simon and Ramírez-Suástegui, Ciro and Li, Yingcong and King, Emma and Chudley, Lindsey and Thomas, Jaya and Wood, Oliver and von Witzleben, Adrian and Jeffrey, Danielle and McCann, Katy and Simon, Hayley and Mondal, Monalisa and Wang, Alice and Dicker, Martina and Lopez-Guadamillas, Elena and Chou, Ting-Fang and Dobbs, Nicola A and Essame, Louisa and Acton, Gary and Kelly, Fiona and Halbert, Gavin and Sacco, Joseph J and Schache, Andrew Graeme and Shaw, Richard and McCaul, James Anthony and Paterson, Claire and Davies, Joseph H and Brennan, Peter A and Singh, Rabindra P and Loadman, Paul M and Wilson, William and Hackshaw, Allan and Seumois, Gregory and Okkenhaug, Klaus and Thomas, Gareth J and Jones, Terry M and Ay, Ferhat and Friberg, Greg and Kronenberg, Mitchell and Vanhaesebroeck, Bart and Vijayanand, Pandurangan and Ottensmeier, Christian H (2022) Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. Nature, 605 (7911). 741–746. ISSN 0028-0836 (https://doi.org/10.1038/s41586-022-04685-2)

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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.

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