Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16-20 months and a 5-year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony-stimulating factor 1 (CSF-1) signaling pathway of tumor-associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer-mediated immunotherapy to deliver CSF-1R inhibitor BLZ945 (D-BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D-BLZ targeted to TAMs decreases pro-tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer-drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off-target effects.