EXTH-29. INTERNEURONS THAT BITE, A CELLULAR THERAPY FOR HIGH GRADE GLIOMA

Abstract

Abstract Glioblastoma has a poor prognosis with limited therapeutic options. Cellular therapies, like CAR-T therapy, have unfortunately 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 brain tumor specific obstacles, we developed a cellular immunotherapy delivery system, derived from post-mitotic Migratory Cortical Inhibitory Interneuron Precursors (MCIPs), that induces a cytotoxic tumor response in glioblastoma independent of unique tumor antigens. During fetal brain development, MCIPs are chemoattracted to migrate long distances from their subcortical origins into the cerebral cortex. The MCIP chemoattractant CXCL12 activates CXCR4 to induce this migration. Intriguingly, CXCL12 is secreted by glioblastoma, suggesting they chemoattract MCIPs. Excitingly, our in vitro and in vivo data indeed show that MCIPs robustly migrate to the majority of glioblastoma cell lines evaluated. Crucially, this migration is independent of unique tumor antigens and the TME and provides us with the opportunity to use MCIPs as a delivery vector for cytotoxic agents. In one approach, we successfully eliminated EGFR expressing glioblastoma in vivo by modifying MCIPs to secrete EGFR Bispecific T-cell Engagers (BiTE). BiTE engagement with a tumor cell results in T-cell activation and elimination of the engaged tumor cell. Importantly, the T-cells have no innate recognition of the tumor cell, this is provided by the BiTE. Local EGFR BiTE secretion has limited systemic toxicity, thereby making EGFR a viable non-unique target. MCIPs can be equipped with a range of agents that eliminate glioblastoma. As a therapy, we envisage injecting modified MCIPs, differentiated from patient or donor “off the shelf” induced pluripotent stem cells, into the margin of the surgical cavity to “clean-up” tumor cells remaining post-surgery. An interneuron clinical trial for epilepsy (NCT05135091) is ongoing, highlighting the translational potential of our MCIP cellular therapy.