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

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 CD3 epsilon and GBM cell interleukin 13 receptor alpha 2 (IL13R alpha 2). We demonstrate that this bispecific T cell engager (BiTE) (BiTELLON) engages peripheral and tumor-infiltrating lymphocytes harvested from patients' tumors and, in so doing, exerts anti-GBM activity ex vivo. The interaction of BiTELLON with T cells and IL13R alpha 2-expressing GBM cells stimulates T cell proliferation and the production of proinflammatory cytokines interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). We have modified neural stem cells (NSCs) to produce and secrete the BiTELLON (NSCLLON) When injected intracranially in mice with a brain tumor, NSCLLON show tropism for tumor, secrete BiTELLON, and remain viable for over 7 d. When injected directly into the tumor, NSCLLON provide a significant survival benefit to mice bearing various IL13R alpha 2(+) GBMs. Our results support further investigation and development of this therapeutic for clinical translation.

Automated summary

This study demonstrates the efficacy of a bispecific antibody in activating immune cells in patients' tumors and exerting anti-GBM activity. By modifying neural stem cells to produce and secrete the antibody, significant survival benefits were observed in mice with specific types of brain tumors. Further investigation and development of this therapeutic for clinical translation is supported by the results.