Research highlight

Cancer: Evaluating PI3Kδ inhibition in patients with head and neck cancer

Nature

May 5, 2022

The experimental cancer drug AMG319 (an inhibitor of phosphoinositide 3-kinase δ, or PI3Kδ) is found to have anti-cancer effects in patients with head and neck cancer in a phase II clinical trial published this week in Nature. However, immune-related adverse events necessitated the suspension of AMG319 treatment in patients at the tested doses, and mice treated with AMG319 developed colitis (an autoimmune disorder). The results suggest that alternative dosing regimens might limit the toxicity of AMG319.

Studies in mice have demonstrated that a class of drugs called PI3Kδ inhibitors — such as AMG319 — can trigger anti-tumour immunity. However, the effects of PI3Kδ inhibitors on solid tumours in humans have been less well studied, and potential immune-related adverse events have hampered the clinical development of these drugs. In an in-depth investigation of the effects of PI3Kδ inhibitors on immune cells in patients with solid tumours, Christian Ottensmeier and colleagues conducted a randomized phase II trial of AMG319 in 30 patients with head and neck cancer. The authors found that PI3Kδ inhibition led to substantial changes in the cell composition of the tumours by reducing regulatory T cells (which can dampen immune responses against tumours) and activating CD4+ T cells and CD8+ T cells (immune cells that target tumour cells). Of the 15 patients assigned to AMG319 treatment, 9 experienced immune-related adverse events that led to discontinuation of treatment. A reduced dosage also resulted in treatment-ending adverse events in three out of six additional patients.

In mice with solid tumours, PI3Kδ inhibition substantially altered the composition of regulatory T cells in the colon, which is associated with colitis. However, intermittent dosing with PI3Kδ was shown to combine sustained anti-tumour immunity with reduced toxicity in mice. Although further research is needed, the authors conclude that decreased dosages or a modified PI3Kδ treatment regimen are necessary to be able to elicit an anti-tumour immune response in solid tumours while limiting the adverse effects associated with reduced regulatory T cell function in healthy tissues.

doi: 10.1038/s41586-022-04685-2

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