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Background The goal of this study is to investigate the impact of focused ultrasound-mediated blood brain barrier opening (BBBO) on α vβ3 CAR-T cell therapy in a pre-clinical breast cancer brain metastasis (BCBM) model.Methods NSG mice were intracranially inoculated with MDA-MB-468 cells to generate a xenograft model recapitulating key characteristics of BCBM. On day 18, α vβ3- or CD19-targeted CAR-T cells were administered intravenously and MR-guided FUS BBBO with microbubbles was performed (figure 1A). Tumor outgrowth was monitored via serial contrast-enhanced MRI. CAR-T cells were enumerated in the blood and brain via flow cytometry and spatially mapped with immunohistochemistry (IHC).Results Combination of FUS BBBO with α vβ3 CAR-T cells significantly constrained BCBM outgrowth compared to sham, CD19 CAR-T cell, and αvβ3 CAR-T cell monotherapy (figure 1B). Absolute frequency of circulating CAR-T cells was significantly higher in the setting of FUS exposure (figure 1C), as was proportion of CD8+ CAR-T cells in BCBM-bearing brains (figure 1D). IHC staining in brains harvested at endpoint revealed a superlative elevation in tumor-localized CD3+ T cell staining relative to controls (figure 1E-F).Conclusions FUS BBBO combined with α vβ3 CAR-T cells offers a promising method for BCBM therapy. Future studies will aim to investigate involved mechanisms of interactivity between FUS and αvβ3 CAR-T cells, optimize acoustic parameters, and extend findings to other neuro-oncologic settings.Acknowledgements This work was supported by NIH DP5OD031846 and T32CA009109; DOD BCRP Era of Hope Scholar Award; DOD PRCRP Idea Award (HT9425-24-1-0940); The Ben and Catherine Ivy Foundation Translational Adult Glioma Grant Award.Abstract 313 Figure 1