Brain Tumor Focused Ultrasound Immunotherapy

In the setting of malignant lesions in the brain, therapeutic interventions are often met with the challenge of overcoming two major barriers: (1) the blood brain barrier (BBB) and (2) the blood tumor barrier (BTB). The BBB is a dense vascular network protecting the brain, which largely excludes that passage of most molecules – including drugs and antibodies – into the central nervous system. BTB is a term ascribed to the heterogeneously permeable vasculature and high interstitial fluid pressure characteristic of the tumor periphery. The application of MRI-guided focused ultrasound (MRg-FUS) with concomitant delivery of microbubbles (MB) has been demonstrated to non-invasively induce safe, localized, transient BBB/BTB disruption. This perturbation of the tumor microenvironment has the potential to increase tumor accessibility and immunogenicity, which can in turn lead to more durable immune infiltration and activation. Thus, the goal of our ongoing studies in intracranial melanoma and glioma is to explore the immunomodulatory capacity of FUS-mediated BBB/BTB opening and the compounding of this effect with adjuvant approaches (e.g. checkpoint blockade, nanoparticle delivery, etc.). Key partners on these studies include Dr. Timothy Bullock (UVa Pathology) and Dr. Victor Engelhard (UVa Microbiology, Immunology, and Cancer Biology).