Neural Stem Cells Secreting Bispecific T Cell Engager to Induce Selective Anti-Glioma Activity

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor in adults. There is no treatment that provides durable relief for the vast majority of GBM patients. In this study, weve tested a bispecific antibody comprised of single-chain variable regions (scFvs) against T cell CD3{varepsilon} and GBM cell interleukin 13 receptor alpha 2 (IL13R2). We demonstrate that this 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 engagement of IL13R2-expressing GBM cells stimulates T cell proliferation as well as production of pro-inflammatory cytokines INF{gamma} and TNF. We have modified neural stem cells (NSCs) to produce and secrete the BiTE (NSCsLLON). When injected intracranially in mice with brain tumor, NSCsLLON show tropism for tumor, secrete BiTELLON, and remain viable for several days. When injected directly into tumor, NSCLLON provide significant survival benefit to mice bearing IL13R2+ GBM. Our results support further investigation and development of this therapeutic for clinical translation.