Enhancing Local delivery of Macrophage Checkpoint Inhibitors with Chemokine Gradients to Lure and Destroy Pediatric Brain Tumor Cells

Thesis (Ph.D.)--University of Washington, 2021Pediatric brain tumors (PBTs) are the leading cause of cancer-related death in children. These malignancies tend to occur in locations of the brain where complete resection and adjuvant therapy could lead to an impaired quality of life. Residual cells from incompletely resected tumors may invade nearby areas of the brain where they can cause recurrence and ultimately lead to patient death. This thesis explores whether hydrogel-based delivery chemokine gradients and macrophage checkpoint inhibitors (MCIs) into orthotopic xenograft PBTs can result in enhanced elimination of tumor cells. Tumor cells lured to an immunotherapy “trap” by chemokines would then become exposed to MCIs they would have otherwise avoided, and targeted for elimination by phagocytic cells in the brain. Our data confirms that gradients of CXCL12 are effective at eliciting chemotaxis of patient-derived, pediatric high grade glioma (pHGG) tumor cells in vitro. Use of CD47 mAb as a single agent was effective at promoting pHGG tumor cell phagocytosis in co-cultures with murine macrophages. Therefore, we engineered slow-release hydrogels to locally deliver CXCL12 and CD47mAb to mice bearing orthotopic xenograft pHGGs for timescales up to one month. Mice receiving intratumorally injected gels containing this combination demonstrated attenuated tumor growth compared to mice receiving gels containing CD47mAb alone. These pre-clinical results suggest a combination of chemokines and MCIs could be a safe and effective means to promote recruitment and immunological clearance of remnant PBT cells in patients