Macrophage Depletion Combined With Radiation In A Preclinical Medulloblastoma Model

Abstract BACKGROUND Radiation induces a measurable immune response, yet this anti-tumor immunity is often suboptimal at eliminating residual brain tumor cells. Medulloblastomas, along with other pediatric brain tumors, tend to recur in the primary resection bed following irradiation. Infiltrating macrophage within the tumor (TAM) are radioresistant immune cells that may limit the effectiveness of radiotherapy and promote tumor regrowth through their immunosuppressive and pro-tumorigenic functions. Therefore, we explored whether CSF-1 receptor (CSF1R) inhibition, and essentially TAM depletion, could augment radiation and/or reduce local recurrence. METHODS Selected CSF1R inhibitors were tested on both human and mouse macrophage in vitro. In vivo studies were performed on a patient-derived orthotopic xenograft (PDOX) model of Group 3 medulloblastoma, Med411-FH. Macrophage depletion was achieved using the anti-murine CSF1R antibody, AFS98, injected intra-peritoneally 10 days prior to, concurrently, and after radiation. RESULTS CSF1R antibodies and small molecule tyrosine kinase inhibitors were effective at stanching macrophage survival in culture. In a PDOX medulloblastoma model, both classes of CSF1R inhibitors were effective at reducing macrophage in the brain after approximately 10 days of administration, with maximal effect of 90% depletion achieved after 21 days. In a combinatorial study of AFS98 and irradiation, TAM depletion conferred a very modest effect on tumor growth (p=0.003) and had no effect on overall survival when combined with radiation (p=0.86). Interestingly, we did observe a trend toward reduction in metastatic spinal disease following radiation in the AFS98-treated cohort. CONCLUSION CSF1R antibody administration effectively eliminated macrophage and microglia in the brain and spine, suggesting adequate blood-brain barrier penetration in our xenograft model. While CSF1R inhibition combined with radiation was ineffective at prolonging survival, further studies are needed to investigate a modest effect on brain tumor growth and an observed (yet not statistically significant) difference in metastatic spinal recurrence in drug-treated animals.