Metastasis to the brain from breast cancer remains a significant clinical challenge， and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here， we have optimized HER2-CAR T cells for the treatment of breast to brain metastases， and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors， including multifocal and leptomeningeal disease. HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity by measuring cytokine production， T-cell proliferation， and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous， local intratumoral， or regional intraventricular routes of administration using human xenograft models of breast cancer that have metastasized to the brain. Here， we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent antitumor activity in orthotopic xenograft models. Importantly， we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Our study shows the importance of CAR design in defining an optimized CAR T cell， and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. .