Engineering CAR macrophages in combination with anti-tumor therapies to suppress brain metastasis

Brain metastases pose a significant clinical challenge for patients with HER2-positive breast cancer, with up to 50% of those with metastatic disease developing CNS involvement. Although HER2-targeted therapies such as trastuzumab deruxtecan (T-DXd) have improved systemic outcomes, their limited penetration across the blood-brain barrier (BBB) leaves the brain as a sanctuary site for recurrence. Innovative strategies are urgently needed to overcome BBB restrictions and effectively treat HER2-positive brain metastases.To address this, we leveraged the unique ability of macrophages to cross the BBB and perform phagocytic and immune-modulatory functions. We engineered chimeric antigen receptor macrophages (CARMA) to express tumor antigen-specific scFv and activate down-stream signaling to enhance anti-tumor immunity. We hypothesize that CARMA can penetrate the BBB, exert potent anti-tumor activity, and synergize with tumor antigen-targeted therapy and T-DXd to improve outcomes in brain metastases. In preclinical models, CARMA demonstrated strong antigen-specific phagocytosis and significant suppression of brain metastases. Notably, CARMA exhibited minimal neurotoxicity compared to CAR-T cells and induced a bystander killing effect mediated by cytokines upregulation upon tumor antigen engagement.To further enhance efficacy, we evaluated a combination strategy of CARMA and T-DXd to synergize antibody-dependent cellular cytotoxicity (ADCC) with macrophage-mediated phagocytosis. Our results showed that this combination dramatically suppressed brain metastases. These findings position CARMA as a promising immunotherapy platform for HER2-positive breast cancer brain metastases, offering potential to overcome BBB limitations and improve patient outcomes through multi-modal synergy.