Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

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 malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, 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 (Treg) 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 Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) 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.

Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer

“…72 The PI3K signaling pathway is also involved in regulating the immune system, so PI3Kis were found to act as immunomodulatory agents, which decreased the number of regulatory T (Treg) cells and enhanced CD8 + cytotoxic T cells in the tumor microenvironment. 73,74 In this study, we formulated mPEGylated NCs to simultaneously encapsulate DTX and PIC to achieve a synergistic anticancer effect. Anti-HER2-IV/mPEG and anti-HER2-II/mPEG BsAbs were successfully prepared to non-covalently decorate NCs via the anti-mPEG fragment, which endowed the NCs with a HER2-targeting ability and dual-HER2 blockade via the anti-HER2-IV and anti-HER2-II fragments.…”

Beyond PI3Ks: targeting phosphoinositide kinases in disease

“…This suggests an opportunity to combine PI3K inhibition with dietary or pharmacological interventions to lower blood glucose levels. Other approaches to moderate toxicity could be through intermittent dosing, as PI3Kδ inhibition in solid tumours has been hampered by severe immune-related adverse events; however, these events could be minimized by a modified treatment regimen with PI3Kδ inhibitor intermittent dosing 286 .…”

Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

“…However, combining PI3K inhibitors with ICI has been challenging as PI3K inhibitors may alter antitumor immunity or lead to immune-related adverse events. This obstacle could be overcome by adopting a modified treatment regimen with intermittent, rather than daily, dosing of PI3K inhibitors [ 191 , 192 ]. Notably, a phase-I/II trial with copanlisib combined with nivolumab and/or ipilimumab is ongoing in patients with advanced solid cancers who have genomic alterations in PIK3CA and PTEN (NCT04317105).…”