Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Phosphoinositide 3-kinase delta (PI3K delta) 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 PI3K delta inhibitors (PI3K delta i) can induce anti-tumour immunity(4,5), its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3K delta i 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). PI3K delta 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, PI3K delta i decreased the number of T-reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3K delta i-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 PI3K delta i 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.

Automated summary

This study assessed the effects of PI3K delta inhibitors in patients with head and neck cancer, finding that it reduced the number of regulatory T cells in tumors and enhanced the cytotoxic potential of tumor-infiltrating T cells. However, high doses of the inhibitors led to immune-related adverse events, indicating the need for alternative dosing regimens to limit toxicity.