EXTH-02. TUMOR-HOMING INDUCED NEURAL STEM CELL THERAPY INHIBITS THE PROGRESSION OF BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL CARCINOMATOSIS

Abstract

Abstract INTRODUCTION Breast cancer brain metastasis, including leptomeningeal carcinomatosis (LC), remains one of the most lethal CNS diseases. New therapies are urgently needed to treat this highly aggressive disease. Here we used models of both breast cancer brain parenchymal metastasis and leptomeningeal metastasis to investigate the efficacy of engineered tumor-homing neural stem cells (NSCs) therapy. METHODS Personalized NSCs were created using Sox2 overexpression to transdifferentiate human fibroblasts into induced NSCs (iNSCs), followed by genetic engineering to enable iNSCs to secrete cytotoxic TRAIL (iNSC-TRAIL). For the parenchymal metastasis study, iNSC-TRAIL therapy was infused intracerebroventricularly (ICV) into Nude mice bearing established intracranial MDA-MB-231-Br human breast cancer cells expressing fluorescent and bioluminescent reporters. For LC studies, we established the disease model by inoculating Nude mice with MDA-MB-231-Br tumor cells via intracisternal infusion. iNSC-TRAIL therapy was evaluated by infusing therapy ICV either 1 week prior to or 3 days after tumor inoculation to mirror prophylactic or established tumor treatment, respectively. Tumor progression in the brain and spine was monitored by serial bioluminescence imaging (BLI), and survival was analyzed. RESULTS Serial BLI showed ICV-infused iNSC-TRAIL reduced parenchymal tumor volumes by 72% 3 weeks post-ICV infusion, and extended median survival from 37 to 52 days. Testing iNSC-TRAIL therapy against established LC tumors, serial BLI showed ICV iNSC-TRAIL therapy reduced established tumors 196-fold in the brain and 500-fold in the spine within 2 weeks post-infusion, while extending median survival from 25 to 47 days. In the prophylactic LC model, iNSC-TRAIL therapy markedly delayed tumor development with tumors in the brain remaining > 1000-fold smaller than control, and tumors in the spine below the limit of detection through 1 month post-treatment. The therapy also eliminated mortality through 50 days post-therapy. CONCLUSION These data suggest iNSC therapy could be a promising treatment option for breast cancer brain metastasis patients.