First-in-Class Immuno-Oncology Drug APG157DS Repolarizes Innate Immune Cells and Induces Durable Remission in a Syngeneic Glioblastoma Model

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Abstract
APG157DS is a multi-component investigational drug which is currently the subject of multiple cancer trials. It has shown promising efficacy in patients with head and neck cancer. We report its immuno-modulatory effect in a syngeneic mouse model of glioblastoma (GBM). Long-term treatment with APG157DS led to durable tumor remission in 50% of mice, while all vehicle-treated mice reached humane endpoints within 42 days. Mechanistically, the drug induced selective repolarization of tumor-associated macrophages (TAMs) from an immunosuppressive Arg1high/iNOSlow phenotype to a tumoricidal Arg1low/iNOShigh state, accompanied by increased intratumoral recruitment of activated (NKp46+) natural killer cells and CD8+ cytotoxic T-cells. APG157DS also suppressed vascular endothelial growth factor (VEGF) and Hypoxia-inducible factor 1-alpha (HIF-1α) expression in tumors, further impairing tumor growth. Notably, APG157DS did not elicit off-target macrophage activation in peripheral tissues such as the spleen, highlighting its selective immune targeting. These findings provide a mechanistic rationale for further clinical development of APG157DS in GBM and potentially other immune-evasive cancers.
Funding Information
  • Aveta Biomics, Inc. (Award 55)
  • NYU Grossman School of Medicine Preclinical Imaging Laboratory (NIH/SIG 1S10OD018337-01)
  • the Laura and Isaac Perlmutter Cancer Center Support Grant (NIH/NCI 5P30CA016087)
  • the NIBIB Biomedical Technology Resource Center Grant (NIH P41 EB 017183)

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