48. DEVELOPING TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELLS AS AN ADJUVANT TREATMENT FOR RADIATION THERAPY OF BRAIN METASTASES

Abstract

INTRODUCTIONNon-small cell lung cancer (NSCLC) is the most common primary cancer to metastasize to the brain. Radiation is first-line for multifocal brain metastases, but recurrence is observed in 40% of patients. An adjuvant treatment to radiation is needed to effectively treat post-radiation tumor. Genetically engineered neural stem cells (NSCs) have the unique ability to seek out tumors and deliver therapeutic payloads that significantly reduce tumor burden. Here we have transdifferentiated human fibroblasts into induced neural stem cells (hiNSC) and explored the efficacy of hiNSCs therapy for NSCLC brain metastases.METHODShiNSCs were infused intracerebroventricularly (ICV) into mice with bilateral intracranial H460 NSCLC tumors. Bioluminescent imaging (BLI) was used to determine hiNSCs persistence while fluorescent analysis of brain sections characterized tumor-homing migration. In vitro co-culture assays and isobologram analysis were used to determine the synergistic effect of the cytotoxic protein TRAIL and radiation therapy on NSCLC tumor cells. To determine efficacy in vivo, H460 cells were implanted in the brains of mice and treated with either hiNSC-TRAIL alone or in combination with 2 Gy radiation. Tumor volumes were then tracked via BLI.RESULTS/CONCLUSIONhiNSCs persisted in the brain >1 week after ICV injection, and hiNSCs were found to co-localize with both bilateral tumor foci. Isobologram analysis showed a combination index of 0.64, suggesting radiation and TRAIL have a synergistic cytotoxic effect on NSCLC tumors. In vivo, radiation and hiNSC-TRAIL therapy reduced tumor volumes 90% compared to control-treated animals, while each therapy alone only reduced tumors 21% and 52%, respectively. While neither monotherapy significantly impacted survival, combination therapy demonstrated a 40% extension in survival, with treated mice surviving a median of 28 days while controls animals only survived 20 days. Together, these results demonstrate the therapeutic potential of hiNSC-TRAIL as an adjuvant to radiation for treatment of NSCLC brain metastases.