Neural stem cells secreting bispecific T cell engager to induce selective antiglioma activity

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor in adults. No treatment provides durable relief for the vast majority of GBM patients. In this study, we've tested a bispecific antibody comprised of single-chain variable fragments (scFvs) against T cell CD3ε and GBM cell interleukin 13 receptor alpha 2 (IL13Rα2). We demonstrate that this bispecific T cell engager (BiTE) (BiTE^LLON) engages peripheral and tumor-infiltrating lymphocytes harvested from patients' tumors and, in so doing, exerts anti-GBM activity ex vivo. The interaction of BiTE^LLON with T cells and IL13Rα2-expressing GBM cells stimulates T cell proliferation and the production of proinflammatory cytokines interferon γ (IFNγ) and tumor necrosis factor α (TNFα). We have modified neural stem cells (NSCs) to produce and secrete the BiTE^LLON (NSC^LLON). When injected intracranially in mice with a brain tumor, NSC^LLON show tropism for tumor, secrete BiTE^LLON, and remain viable for over 7 d. When injected directly into the tumor, NSC^LLON provide a significant survival benefit to mice bearing various IL13Rα2⁺ GBMs. Our results support further investigation and development of this therapeutic for clinical translation.