The Impact of FUS-Mediated Brain Cancer Therapy on BBB Transport, Cytokines, and Immunocyte Trafficking

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Project Abstract Brain cancer survival rates are dismal. After resection of glial tumors, recurrence occurs in the tumor-cell- infiltrated tissue surrounding the area that enhances on contrast enhanced MRI. Antibody-based treatments for brain cancer are extremely promising. However, a remaining obstacle to the delivery of these promising treatments is the blood-brain barrier (BBB). The BBB normally excludes drugs of size 0.4 kDa and higher, while antibodies are 150 kDa. Focused ultrasound (FUS) concentrates ultrasonic energy to a small area. Low intensity ultrasound interacts with intravenously injected microbubbles to open the BBB. Bubble oscillations exert mechanical pressure on endothelial cells. These pressure oscillations result in an increase in the transport of large molecules across the BBB via a variety of mechanisms including transport through cells and through gap junctions. In preclinical studies, FUS BBB opening has been used to deliver chemotherapeutic agents, antibodies, stem cells, and targeted genes. For optimal antibody delivery to the human brain, additional imaging-based tools are urgently needed to make BBB opening safe, accurate, and fully reversible. A potentially game changing characteristic of FUS in combination with immunotherapy protocols is that MRgFUS BBB opening has been shown to upregulate multiple pro- and anti- inflammatory cytokines, chemokines and trophic factors, and cell adhesion molecules from 5 minutes to 24 hours after BBB opening. The implication is that FUS BBB opening may have the potential to not just affect the drug delivery but also to enhance homing of immune cells or to potentiate the effectiveness of an immunotherapy drug. Our goal is to design a strategy to combine therapeutic delivery with the creation of an anti-tumor microenvironment. Developing an understanding of the complex relationship between microbubble expansion and collapse, changes in vascular permeability, changes in cytokine profiles and resulting cell trafficking and micro-hemorrhage is required. We seek to combine the delivery of therapeutics and the homing of immune cells in a regime that avoids micro- hemorrhage. Further, we wish to accomplish this with clinically-relevant frequencies (220 and 650 kHz). We have modeled these scenarios to develop a parameter set to test through experiment. We aim to evaluate this response in both small and large animal models and to demonstrate methods for beam calibration in the large animal model. Our Specific Aims are to: 1) assess the relationship of microbubble oscillation, cytokines, therapeutic delivery, immune cell trafficking and micro-hemorrhage in normal mice with an intact BBB and create a strategy for safely enhancing delivery while generating potentially an anti-tumor microenvironment phenotype, 2) assess therapeutic delivery of EGFR antibodies, immunocyte trafficking, and survival in mice bearing glioblastoma based on the strategy developed in Aim 1, and 3) Determine whether relationships observed in mice in Aim 1 are replicated in a large animal model.