PI3Kalpha/delta inhibitor AZD8835 drives modulation of the tumour microenvironment and pre-clinical efficacy in solid tumours
Larissa S. Carnevalli1, Charles Sinclair1, Molly Taylor1, Lorraine Mooney1, Adina Hughes1, Anna Staniszewska1, Kevin Hudson1, Simon Barry1
1Oncology iMED, AstraZeneca 1 Francis Crick Ave, Cambridge CB2 0RE, United Kingdom
While phosphoinositide 3-kinase (PI3K) signalling is frequently mutated in cancer promoting tumour cell proliferation and survival it also plays a role regulating the immune system. PI3K isoforms have discrete expression profiles, PI3Kalpha and beta are ubiquitously expressed, but the PI3Kdelta isoform largely exhibits a leukocyte-restricted expression profile and has been implicated as a key driver of the immunosuppressive tumour microenvironment (TME). A range of PI3K inhibitors with selectivity versus different isoforms have been progressed to clinical trials, however effect of PI3K isoform specific inhibitors in tumour models in the context of fully intact immune system is still poorly understood. To investigate differences between compounds a panel of PI3K isoform selective inhibitors were compared across models. The PI3Kdelta inhibitor PI-3065 showed minimal efficacy across pre-clinical tumour models at clinically relevant doses, but promoted favourable changes in the tumour-immune infiltrate, indicative of an elevated anti-tumour immune response. In contrast AZD8835 (a potent and selective PI3Kalpha/delta dual inhibitor) delivered anti-tumour activity, associated with changes in the immune cell profile of the tumour. The anti-tumour benefit in CT-26 model was only observed in immunocompetent mice, and was T-cell dependent. This suggests a dual alpha/delta profile will be superior to a PI3Kdelta selective compound by targeting both tumour cells and the TME in concert. Together these data reveal novel mechanisms by which PI3Kdelta inhibitors interact with the immune system and suggest that dual targeting of PI3Kalpha and delta may be a superior therapeutic strategy, allowing for synergistic inhibition of tumour cell-intrinsic proliferation and survival concurrent with anti-tumour cytotoxic immunity. Such synergy may facilitate therapeutic response at lower inhibitor doses, which could also circumvent tolerability issues observed with PI3K inhibitors in the clinic.
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