AZD3458 / AstraZeneca - LARVOL DELTA

Synergistic Anticancer Effects of Combined Immunotherapy and PI3Kγ Inhibitors in Liver Cancer (APASL 2024) - "We used PI3Kγ inhibitor (AZD3458; 30 mg/kg, orally, daily), tyrosine kinase inhibitor (TKI; lenvatinib; 10 mg/kg, orally, daily), and ICI (anti-PD-1 mAb; 10 mg/kg, intraperitoneally, daily). The PI3Kγ inhibitor specifically targets TAMs and alters their function to achieve anti-tumor effects. These findings suggest that inhibiting PI3Kγ could be a crucial part of the combined anti-tumor treatment using ICI and TKI in HCC."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • PIK3CG

Synergistic Anticancer Effect of Immunotherapy and PI3Kγ Inhibition Combination Therapy in Liver Cancer (LCS 2023) - "We used PI3Kγ inhibitor (AZD3458; 30 mg/kg administered orally, daily), TKI (lenvatinib; 10 mg/kg administered orally, daily) and ICI (anti-PD-1 mAb; 10 mg/kg intraperitoneally, daily). The results indicate that the PI3Kγ inhibitor specifically targets TAMs and alters their function to achieve anti-tumor effects. The findings of the study suggest that inhibiting PI3Kγ could be a crucial part of the combined anti-tumor treatment using ICI and TKI in HCC."

Combination therapy • IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CCL2 • IL10 • IL12A • IL1B • IL23A • IL6 • PIK3CG • TNFA

Macrophage activation status rather than repolarization is associated with enhanced checkpoint activity in combination with PI3Kg inhibition. (PubMed, Mol Cancer Ther) - "AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore rather than polarizing tumor macrophages, PI3Kg inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T cell mediated anti-tumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation."

Combination therapy • IO biomarker • Journal • Immune Modulation • Inflammation • Oncology • CD8 • IL10 • IL12A

Mechanistic insights and dose optimization for AZD3458, a novel selective PI3Kg immuno-modulator, using a quantitative systems approach (AACR 2019) - "This study provides quantitative mechanistic insights into the links between PI3Kγ inhibition and anti-tumor immune responses, supporting our understanding of how AZD3458 may alleviate brakes in a myeloid immuno-suppressive TME and revert resistance to immunotherapy. This mechanistic understanding is critical when proceeding with dose escalation in an early clinical trial setting, as it allows to contextualize any potential compound-induced immuno-modulation in patients, for given doses and schedules."

IO Biomarker

Novel selective PI3Kγ inhibitor AZD3458 promotes anti-tumor immune responses and reverts resistance to immunotherapy in checkpoint blockade refractory preclinical models (AACR 2019) - "Consistent to the observed tumor remodeling, combination with checkpoint inhibitors α-PD-1 or α-PD-L1 antibodies (10mg/kg 3x week) had greater anti-tumor effects than checkpoint inhibitor alone in 4T1, LLC, CT-26 and MC-38 mouse syngeneic models. These data demonstrate that AZD3458 can reverse myeloid suppressive tumor microenvironment and revert tumor resistance to immunotherapy in myeloid-enriched immunosuppressive tumor types."

Checkpoint inhibition • IO Biomarker • PD(L)-1 Biomarker • Preclinical

Newly added product (AstraZeneca Press Release) - Preclinical, Oncology

Pipeline update