Abstract High-grade gliomas (HGG) represent the most common cause of cancer-related mortality in the pediatric population due to a lack of curative therapies. Limitations for cellular-based therapies include the lack of unique tumor antigens, down regulation of surface antigens being targeted, marked tumor heterogeneity, and the immune suppressive tumor microenvironment. Here we describe a cellular delivery system using derived from post-mitotic migratory inhibitory interneuron precursors (MIPs) which are chemoattracted to tumors in an independent manner and are capable of delivering a therapeutic payload. During normal fetal development, MIPs migrate long distances from the medial ganglionic eminence to the cortex driven by several chemoattractants such as CXCL12. Notably, HGGs secrete these same factors, leading us to postulate that transplanted MIPs could migrate in a targeted manner to these tumors. Using transwell migration assays, we observed robust migration to conditioned media. This migration was recapitulated in vivo using orthotopic xenograft models transplanted in nude mice. MIPs were equipped with an EGFR or CD19 control bispecific T-cell engager (BITE) then co-cultured with HGG cells and CD8 T-cells at an effector to target ratio of 4:1. EGFR-BiTE secreting MIPs, but not CD19 control BiTEs, kill HGG cells. Results were validated in vivo via orthotopic xenografts of HGG in nude mice. CD8 T-cells were either administer as a single dose or weekly via interventricular cannula. Mice treated with EGFR-expressing MIPs had extended survival compared to CD19 BiTE expressing controls. Collectively, these data suggest that MIPs may be a viable cellular delivery system with flexibility to be equipped with a wide range of agents targeting HGG. MIPs can be engineered to modulate this migration, could also play a role in treating tumor-related epilepsy, and could be differentiated from induced pluripotent stem cells that are HLA-matched to avoid need for immunosuppression in humans.
Brosius et al. (Fri,) studied this question.