Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

• Authors: Hohyun Lee, Emory University; Yutong Guo, Emory University; James L Ross, Emory University; Scott Schoen, Massachusetts General Hospital; Levent F Degertekin, Georgia Institute of Technology; Costas Arvanitis, Emory University
• Journal Title: Science Advances
• Volume: Volume 8, Number 46
• Publisher: American Association for the Advancement of Science | 2022-11-16, Pages eadd2288-eadd2288
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1126/sciadv.add2288
• Subjects: Engineering, Mechanical; Health Sciences, Immunology; Biology, Microbiology
• Keywords: Animals; Mice; Immune Checkpoint Inhibitors; Immunotherapy; Brain Neoplasms; Brain; Immunologic Factors; Glioblastoma; Tumor Microenvironment

Abstract

Despite the challenges in treating glioblastomas (GBMs) with immune adjuvants, increasing evidence suggests that targeting the immune cells within the tumor microenvironment (TME) can lead to improved responses. Here, we present a closed-loop controlled, microbubble-enhanced focused ultrasound (MB-FUS) system and test its abilities to safely and effectively treat GBMs using immune checkpoint blockade. The proposed system can fine-tune the exposure settings to promote MB acoustic emission–dependent expression of the proinflammatory marker ICAM-1 and delivery of anti-PD1 in a mouse model of GBM. In addition to enhanced interaction of proinflammatory macrophages within the PD1-expressing TME and significant improvement in survival (P < 0.05), the combined treatment induced long-lived memory T cell formation within the brain that supported tumor rejection in rechallenge experiments. Collectively, our findings demonstrate the ability of MB-FUS to augment the therapeutic impact of immune checkpoint blockade in GBMs and reinforce the notion of spatially tumor-targeted (loco-regional) brain cancer immunotherapy.