{
  "abstract": "Background The blood brain barrier (BBB) remains a formidable obstacle to effective treatment of brain malignancies, particularly for macromolecular immunotherapies. Focused ultrasound (FUS) offers a non-invasive, non-ionizing, and spatially precise technique to transiently disrupt the BBB—termed FUS-mediated BBB opening (FUS BBBO)—to enhance delivery of therapeutic agents. 1 While FUS BBBO has demonstrated improved macromolecule penetration in preclinical brain tumor models, its utility across both primary and metastatic brain cancers remains underexplored.2 Here, we investigate the efficacy of single and repeated FUS BBBO for enhancing immunotherapeutic antibody delivery in models of primary glioma and breast cancer brain metastasis.Methods Mice bearing intracranial tumors (GL261, U87, or E0771) underwent neuronavigation- or MRI-guided FUS BBBO (1 MHz) with intravenously administered microbubbles. In the U87 model, serial PET/CT imaging was used to assess delivery and retention of a clinically relevant [Zr-89]-conjugated trispecific antibody following MRI-guided BBBO. Antibody accumulation was quantified ex vivo via automated gamma counter measurements. In GL261 and E0771 models, mice received either a single or three serial FUS BBBO treatments (every 3 days), followed by intravenous delivery of a fluorescent reporter antibody. Antibody accumulation was quantified ex vivo using LAGO optical imaging of perfused brains. Acoustic emissions were monitored in real-time during all FUS treatments ( figure 1).Results FUS BBBO significantly enhanced the delivery and retention of the [Zr-89]-conjugated antibody at both acute (0h) and 24h time points, with sustained uptake trending at 48h ( figure 2A-B). Repeated FUS BBBO yielded superlative antibody delivery compared to a single session or antibody delivery alone in the primary brain cancer model (figure 2C-D). This trend was evident, albeit less striking, in the secondary brain cancer model – in part owing to a significant difference in baseline antibody penetrance (figure 2C).Conclusions FUS BBBO is a repeatable, non-invasive platform that can markedly increase antibody penetration into brain tumors; however, its benefit can be both tumor-type and target-specific. The divergent responses observed between primary glioma and metastatic brain lesions underscore the need for tailoring FUS BBBO parameters to individual tumor biology. These insights will guide the rational design of tumor-specific FUS protocols and accelerate the clinical translation of image-guided BBB disruption for immunotherapy in neuro-oncology.References Labib S, Bright RK, Liu J. Focused ultrasound in cancer immunotherapy: a review of mechanisms and applications. Ultrasound Med. Biol. Jan 2025;51(1):1–14. doi: 10.1016/j.ultrasmedbio.2024.09.008Sheybani ND, et al. ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma. Journal of Controlled Release : Official Journal of the Controlled Release Society Mar. 03 2021;331. doi: 10.1016/j.jconrel.2021.01.023Acknowledgements This work was supported by NIH DP5OD031846 and R21CA292273; U.S. DoD CDMRP Peer-Reviewed Cancer Research Program Idea Award (HT9425-24-1-0940); The Ben and Catherine Ivy Foundation Translational Adult Glioma Grant Award; and The Olive B. and Franklin C. Mac Krell Jefferson Fellowship.Abstract 664 Figure 1Focused ultrasound, BBBO methodology and examplesAbstract 664 Figure 2Focused ultrasound enhances antibody delivery to brain tumors",
  "authors": [
    {
      "affiliations": [
        "University of Virginia, Charlottesville, VA, USA"
      ],
      "name": "Andrew T Thede"
    },
    {
      "affiliations": [
        "University of Virginia, Charlottesville, VA, USA"
      ],
      "name": "Thomas Sherlock"
    },
    {
      "affiliations": [
        "University of Virginia, Charlottesville, VA, USA"
      ],
      "name": "Zehra E Demir"
    },
    {
      "affiliations": [
        "University of Virginia, Charlottesville, VA, USA"
      ],
      "name": "Jiang He"
    },
    {
      "affiliations": [
        "University of Virginia, Charlottesville, VA, USA"
      ],
      "name": "Natasha Sheybani"
    }
  ],
  "title": "664 Focused ultrasound blood brain barrier opening improves antibody access in brain tumors",
  "uid": "57fe7621-a7be-518a-abc0-b99bed3c80b7"
}