Neural Stem Cell Carriers for Glioblastoma Immunotherapy

Glioblastoma (GBM) is the most aggressive brain cancer in adults. A major problem with existing therapeutic approaches is their lack of specificity for neoplastic cells, which results in substantial treatment toxicity. Antibody-mediated specific targeting of tumor-associated antigens has been a successful strategy for cancer therapy as it limits the off-target effect of systemically infused drugs. Genetic modifications of such antibodies coupled with efficient delivery strategies can greatly improve the anti-tumor efficacy of these molecules. One such modification is bi-specific tandem single–chain antibodies (biscFv) that promote T-cell-tumor cell interactions that, in turn, kill the tumor cells. However, biscFv have short half-lives and fast clearance, necessitating frequent or continuous infusions to achieve a therapeutic effect. We propose to overcome these hurdles through the generation of neural stem cells (NSCs) producing biscFv. NSCs can track brain tumor cells after systemic, local, and intranasal delivery, and efficiently deliver a therapeutic payload to tumors sites in preclinical models of GBM. NSCs secreting biscFv can be directly mixed with autologous patients T cells for the production of a local immune response aimed at eradicating tumors. Recently, we developed and characterized a monoclonal antibody specifically targeting IL13R2, a cell surface receptor that is selectively expressed in glioma cells, but not normal brain cells or other tissues. We demonstrated that engineered scFv retains an exclusive specificity as well as a high affinity to IL13R2, and successfully re-targets engineered adenovirus and therapeutic CAR T cells to IL13R2-expressing glioma cells in pre-clinical models of GBM, in vitro and in vivo. We hypothesize that NSCs engineered to secrete bi-specific tandem IL13Rα2xCD3 scFv antibody (biscFvNSCs) will promote anti-tumor immune response through the activation and engagement of T cells with GBM cells. Advancing this th