PURPOSE: Activation of the phosphatodylinositol-3-kinase/AKT (PI3K/AKT) signalling pathway promotes tumor immune evasion by suppressing effector T-cell infiltration and enhancing regulatory T-cell activity contributing to resistance to immune checkpoint inhibitors. Preclinical studies have demonstrated that inhibition of this pathway can restore anti-tumor immunity and synergize with PD-1/PD-L1 blockade. We explore the synergistic clinical potential of targeting the PI3K/AKT pathway in combination with atezolizumab to overcome immunotherapy resistance in recurrent glioblastoma and advanced solid tumors. EXPERIMENTAL DESIGN: Phase 1b, investigator-initiated, open-label study (NCT03673787) composed of a proof-of-concept dose escalation Part A of ipatasertib plus atezolizumab in a 3+3 design. Adult patients with treatment refractory advanced cancers were enrolled into Cohort A1 and recurrent glioblastoma onto Cohort A2. Part B enrolled patients into 6 exploratory cohorts. Study aims to evaluate the safety, immune-modulatory effects and preliminary efficacy of the combination of ipatasertib with atezolizumab. RESULTS: The combination was well tolerated, with no dose-limiting toxicities at the recommended phase 2 dose of ipatasertib 400 mg/daily plus atezolizumab 1200mg every 3 weeks. Pharmacodynamic analysis demonstrated depletion of FOXP3+ regulatory T cells and increased infiltration of CD8+ effector T cells within the tumor microenvironment. Durable exceptional responses were seen in some patients with treatment-refractory or recurrent glioblastoma. CONCLUSION: This is the first report in clinical samples showing that ipatasertib efficiently depletes FOXP3+ regulatory T cells and results in increased infiltration of effector CD8+ T cells in the tumor microenvironment. This was associated with preliminary efficacy in a subset of patients with treatment-refractory glioblastoma (GBM).
Tiu et al. (2026) studied this question.