Intermittent dosing enhances the immune-mediated anti-tumour activity of the PI3Kα/δ inhibitor AZD8835
Larissa S. Carnevalli1*, Charles Sinclair1*, Sophie Langdon1,3, Molly A. Taylor1, Pablo Morentin Gutierrez1, Lorraine Mooney2, Adina Hughes1, Laura Jarvis1,Anna Staniszewska1, Claire Crafter1, Kevin Hudson2,4, Simon T. Barry1# 1Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK; 2Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, UK; 3Present address: University of Birmingham, Birmingham, B15 2TT, United Kingdom; 4Present address: 2theNth, Adelphi Group, Bollington, Cheshire, UK *authors contributed equally
PI3K inhibitors with differential selectivity versus PI3K isoforms have been tested extensively in clinical trials, largely targeting tumor epithelial cells. PI3K also plays a role in the immune system, but the effects of specific inhibitors in immune competent tumor models is not well studied. Recently inhibition of PI3Kδ was shown to modulate the tumor immune micro-environment in pre-clinical solid tumor models by relieving Treg-mediated immunosuppression, while PI3K inhibitors as a class and PI3Kδ specifically are associated with immune-like side effects. However, the impact of mixed PI3K inhibitors in tumor immunology is under-explored. Here we examine the effects in the tumor immune microenvironment of PI3Kα/δ dual inhibition using AZD8835 a potent PI3Kα/δ dual inhibitor. AZD8835 had a direct impact on Treg and CD8 T cell activation in primary cells ex vivo and was associated with enhanced secretion and availability of the pro-survival cytokine IL-2. AZD8835 delivered strong monotherapy anti-tumor activity which was associated with dynamic suppression of Tregs and improved CD8+ T cell function in mouse syngeneic tumor models. Interestingly chronic suppression of PI3Kδ or PI3Kα/δ was not required for anti-tumor activity and as tumor growth inhibition was potentiated by an intermittent dosing/schedule. Together these data reveal novel mechanisms by which PI3Kδ inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells and support further investigation of the impact of dose/schedule regimens for PI3K pathway inhibitors.
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