To understand the impact of PI3Kδ inhibitors in solid tumors, Eschweiler et al. tested them in the neoadjuvant setting in patients with therapy-naive HNSCC. Daily PI3Kδi therapy led to severe, treatment-discontinuing immune-related adverse events in about half of the patients. RNAseq and flow cytometry of post-resection tumors revealed a significant decrease in Tregs and a modest increase in the cytotoxic potential of T cells. Mouse models demonstrated a significant reduction of highly immunosuppressive Treg subtypes in the colon; this reduction was associated with increased inflammation and enhanced colitis. Intermittent dosing reduced this effect in mice.
Contributed by Ed Fritsch
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.
Author Info: (1) La Jolla Institute for Immunology, La Jolla, CA, USA. (2) La Jolla Institute for Immunology, La Jolla, CA, USA. (3) La Jolla Institute for Immunology, La Jolla, CA, USA. Divisi
Author Info: (1) La Jolla Institute for Immunology, La Jolla, CA, USA. (2) La Jolla Institute for Immunology, La Jolla, CA, USA. (3) La Jolla Institute for Immunology, La Jolla, CA, USA. Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA. (4) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole, UK. (5) Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. (6) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. (7) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. (8) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany. (9) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. (10) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. (11) La Jolla Institute for Immunology, La Jolla, CA, USA. (12) La Jolla Institute for Immunology, La Jolla, CA, USA. (13) La Jolla Institute for Immunology, La Jolla, CA, USA. (14) La Jolla Institute for Immunology, La Jolla, CA, USA. (15) UCL Cancer Institute, University College London, London, UK. (16) La Jolla Institute for Immunology, La Jolla, CA, USA. (17) Centre for Drug Development, Cancer Research UK, London, UK. (18) Centre for Drug Development, Cancer Research UK, London, UK. (19) Centre for Drug Development, Cancer Research UK, London, UK. (20) Centre for Drug Development, Cancer Research UK, London, UK. (21) Cancer Research UK Formulation Unit, University of Strathclyde, Glasgow, UK. (22) Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. Clatterbridge Cancer Centre NHS Foundation Trust and Liverpool Cancer Research UK Experimental Cancer Medicine Center Liverpool, Liverpool, UK. (23) Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK. (24) Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK. (25) Queen Elizabeth University Hospital, Glasgow, UK. (26) Beatson West of Scotland Cancer Centre, Glasgow, UK. (27) Dorset Cancer Centre, Poole Hospital NHS Foundation Trust, Poole, UK. (28) Queen Alexandra Hospital, Portsmouth, UK. (29) Southampton University Hospitals NHS Foundation Trust, Southampton, UK. (30) University of Bradford, Institute of Cancer Therapeutics, Bradford, UK. (31) Cancer Research UK and UCL Cancer Trials Centre, London, UK. (32) Cancer Research UK and UCL Cancer Trials Centre, London, UK. (33) La Jolla Institute for Immunology, La Jolla, CA, USA. (34) Department of Pathology, University of Cambridge, Cambridge, UK. (35) CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. (36) Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK. (37) La Jolla Institute for Immunology, La Jolla, CA, USA. (38) Amgen, Thousand Oaks, CA, USA. (39) La Jolla Institute for Immunology, La Jolla, CA, USA. Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA. (40) UCL Cancer Institute, University College London, London, UK. (41) La Jolla Institute for Immunology, La Jolla, CA, USA. vijay@lji.org. Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. vijay@lji.org. Department of Medicine, University of California San Diego, La Jolla, CA, USA. vijay@lji.org. (42) La Jolla Institute for Immunology, La Jolla, CA, USA. c.ottensmeier@liverpool.ac.uk. CRUK and NIHR Experimental Cancer Medicine Center, University of Southampton, Southampton, UK. c.ottensmeier@liverpool.ac.uk. Liverpool Head and Neck Center and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. c.ottensmeier@liverpool.ac.uk. Clatterbridge Cancer Centre NHS Foundation Trust and Liverpool Cancer Research UK Experimental Cancer Medicine Center Liverpool, Liverpool, UK. c.ottensmeier@liverpool.ac.uk.
