Emerging applications of image-guided therapeutic ultrasound for brain tumor-directed immunomodulation and immunotherapy

Immunotherapy has been established as a disruptive pillar of cancer treatment. However, the impact of immunotherapy has yet to be fully realized in neuro-oncology owing to the unique physical barriers (i.e., blood brain/tumor barriers [BBB/BTB]) and distinct immune microenvironment within brain tumors. These obstacles may be overcome through the alliance of image-guided interventions, such as therapeutic ultrasound, with immunotherapies. Specifically, transient disruption of the BBB/BTB via focused ultrasound (FUS) and circulating microbubbles is a promising strategy for potentiating immunotherapy through both immuno-modulation and drug delivery – notably, in a non-invasive, non-ionizing, and precisely targeted manner. We have demonstrated that FUS BBB/BTB disruption invokes mild, transient shifts in the immune milieu of brain tumor-bearing mice. Additionally, we have leveraged immuno-PET imaging to rationally deploy a therapeutic approach combining innate immune checkpoint inhibitor delivery with FUS. We show that this immunoPET-informed paradigm achieves superlative targeted antibody delivery and improved therapeutic outcomes in murine glioblastomas, with markedly reduced systemic antibody dose. Our ongoing investigations seek to advance the nexus of FUS, molecular imaging, and biomarker discovery with the goal of enabling non-invasive, precision immunotherapy paradigms for brain tumors.