TY - JOUR
T1 - Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs
AU - Eschweiler, Simon
AU - Ramírez-Suástegui, Ciro
AU - Li, Yingcong
AU - King, Emma
AU - Chudley, Lindsey
AU - Thomas, Jaya
AU - Wood, Oliver
AU - von Witzleben, Adrian
AU - Jeffrey, Danielle
AU - McCann, Katy
AU - Simon, Hayley
AU - Mondal, Monalisa
AU - Wang, Alice
AU - Dicker, Martina
AU - Lopez-Guadamillas, Elena
AU - Chou, Ting-Fang
AU - Dobbs, Nicola A
AU - Essame, Louisa
AU - Acton, Gary
AU - Kelly, Fiona
AU - Halbert, Gavin
AU - Sacco, Joseph J
AU - Schache, Andrew Graeme
AU - Shaw, Richard
AU - McCaul, James Anthony
AU - Paterson, Claire
AU - Davies, Joseph H
AU - Brennan, Peter A
AU - Singh, Rabindra P
AU - Loadman, Paul M
AU - Wilson, William
AU - Hackshaw, Allan
AU - Seumois, Gregory
AU - Okkenhaug, Klaus
AU - Thomas, Gareth J
AU - Jones, Terry M
AU - Ay, Ferhat
AU - Friberg, Greg
AU - Kronenberg, Mitchell
AU - Vanhaesebroeck, Bart
AU - Vijayanand, Pandurangan
AU - Ottensmeier, Christian H
PY - 2022/5/26
Y1 - 2022/5/26
N2 - 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.
AB - 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.
KW - Phosphoinositide 3-kinase δ (PI3Kδ)
KW - cancer cells
KW - immunotherapeutic agents
KW - chronic lymphocytic leukaemia
KW - immunomodulatory agents
KW - solid tumours
U2 - 10.1038/s41586-022-04685-2
DO - 10.1038/s41586-022-04685-2
M3 - Article
C2 - 35508656
SN - 0028-0836
VL - 605
SP - 741
EP - 746
JO - Nature
JF - Nature
IS - 7911
ER -