Phase I trial of Ipatasertib plus Atezolizumab enhances PI3K/AKT pathway immune responses in solid tumors and refractory glioblastoma.
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Embargo End Date
Authors
Tiu, C
Yau, W
Silva, D
Waldron, N
Ameratunga, M
Scaranti, M
Biondo, A
Welsh, L
Creak, A
Jones, TL
Martin, AJ
Bridges, L
Zachariou, A
Crespo, M
Ferreira, A
Riisnaes, R
Gurel, B
Figueiredo, I
Bogdan, D
Yuan, W
Morilla, R
Swales, K
Decordova, S
Prout, T
Parmar, M
Baikady, B
Rata, M
Blackledge, M
Tunariu, N
Benjamin, P
Rich, P
Daly, R
Hu, X
Yap, C
Vivanco, I
Paschalis, A
Sharp, A
Banerji, U
Minchom, A
de Bono, J
Lopez, J
Yau, W
Silva, D
Waldron, N
Ameratunga, M
Scaranti, M
Biondo, A
Welsh, L
Creak, A
Jones, TL
Martin, AJ
Bridges, L
Zachariou, A
Crespo, M
Ferreira, A
Riisnaes, R
Gurel, B
Figueiredo, I
Bogdan, D
Yuan, W
Morilla, R
Swales, K
Decordova, S
Prout, T
Parmar, M
Baikady, B
Rata, M
Blackledge, M
Tunariu, N
Benjamin, P
Rich, P
Daly, R
Hu, X
Yap, C
Vivanco, I
Paschalis, A
Sharp, A
Banerji, U
Minchom, A
de Bono, J
Lopez, J
Document Type
Journal Article
Date
2026-04-27
Date Accepted
2026-04-23
Abstract
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).
Citation
Clinical Cancer Research, 2026,
Source Title
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Cell Death and Immunity
Translational Therapeutic
Adult DDU ICR & RM
Cancer Biomarkers
Clin PD Biomarker Group
Magnetic Resonance
Computational Imaging
CTSU EarlyPhas&Adp Trials
Clin Trials & Stats Unit
Translational & Expt Med
Clinical Pharmacology
PrCa Targeted Therapy
Early Phase Drug Develop
Translational Therapeutic
Adult DDU ICR & RM
Cancer Biomarkers
Clin PD Biomarker Group
Magnetic Resonance
Computational Imaging
CTSU EarlyPhas&Adp Trials
Clin Trials & Stats Unit
Translational & Expt Med
Clinical Pharmacology
PrCa Targeted Therapy
Early Phase Drug Develop