56. TUMOR-HOMING STEM CELL THERAPY INHIBITS THE PROGRESSION OF BREAST CANCER LEPTOMENINGEAL CARCINOMATOSIS
Abstract INTRODUCTION Leptomeningeal carcinomatosis remains one of the most lethal forms of central nervous system metastasis, with a median survival of only 4 months. Effective new therapies are urgently needed to treat this highly aggressive cancer. In this study, we used models of both prophylactic and established leptomeningeal disease to investigate the efficacy of engineered tumor-homing neural stem cells (NSCs) therapy for breast cancer leptomeningeal carcinomatosis. METHODS Personalized NSC carriers were created using Sox2 overexpression to transdifferentiate human fibroblasts into induced NSCs (iNSCs) that home to cancer cells and carry therapeutic agents to induce tumor kill. Leptomeningeal models were created by engineering MDA-MB231-Br human breast cancer cells with fluorescent and bioluminescent reporters, then using intracisternal injection to inoculate Nude mice with the tumor cells. iNSC therapy was evaluated by infusing iNSCs releasing the pro-apoptotic agent TRAIL into the lateral ventricle of mice either 1 week prior to or 3 days after tumor inoculation for prophylactic or established tumor treatment respectively. Tumor progression in the brain and spinal cord was monitored by serial bioluminescence imaging (BLI). RESULTS Serial BLI showed that intracerebroventricular (ICV) iNSC-TRAIL therapy reduced the volume of metastatic tumor burden 99.49% in the brain and 99.80% in the spine within 2 weeks post-infusion and extended survival from 24 to 42 days. Additionally, prophylactic iNSC-TRAIL therapy delivered ICV markedly delayed tumor development, with tumors in the brain remaining >1000-fold smaller than control through 1-month post-treatment, below the limit of detection in the spinal cord through 1 month, and eliminating mortality through 50 days post-therapy. CONCLUSION These data suggest that iNSC therapy could be a promising treatment option for breast cancer patients with leptomeningeal carcinomatosis.