ID #1037 Pediatric high-grade glioma chemoattract migratory interneuron precursors modified to deliver therapeutic proteins

Abstract

Pediatric high-grade glioma (pHGG) have a poor prognosis with limited therapeutic options. Cellular therapies, like CAR-T therapy, have revolutionized the treatment of some cancers. Unfortunately, T-cell based therapies have so far shown limited efficacy for brain tumors, due to the lack of unique tumor antigens, the downregulation of targeted antigens, and the immune suppressive tumor microenvironment (TME). To circumvent these obstacles, we developed a cellular delivery system where implanted post-mitotic Migratory Inhibitory Interneuron Precursors (MIPs) migrate to pHGG by chemoattraction and induce a cytotoxic tumor response via secretion of bispecific T-cell engagers (BiTEs). The inhibitory interneurons of the cerebral cortex originate predominantly in the ventral/subcortical portion of the telencephalic neural tube. During fetal brain development, canonical chemoattractants induce MIP migration over long distances from subcortical origins to the cerebral cortex. MIPs can be differentiated from ES cells or iPSCs. Our in vitro and in vivo data show that MIPs robustly migrate to the majority of pHGG evaluated. We have also modified these MIPs to drive chemoattraction to other factors in order to expand the number of pHGG MIPs can migrate to. As a proof of principle, we were able to significantly prolong (double) surival of pHGG mouse models by injecting MIPs that locally, at the tumor, secrete an EGFR-BiTE that engages with bystander T-cells. It is our goal for our therapy to become fully T-cell independent, therefore we are exploring the delivery of alternate therapeutic proteins.