Glioblastoma (GBM) is the most aggressive malignant brain cancer in adults. People diagnosed with GBM have limited therapeutic options and their survival is short. 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 development of bi-specific tandem single–chain antibodies (biscFv) that are used to engage T-cells and tumor cells, thereby promoting T-cell-tumor cell interactions that, in turn, kill the tumor cells. However, biscFv have short half-lives and fast renal clearance, necessitating frequent or continuous infusion of biscFv to achieve therapeutic effect. We propose to overcome these hurdles through the generation of “off-the-shelf” neural stem cells (NSCs) that produce biscFv. NSCs are able to track brain tumor cells after systemic, local, and intranasal delivery, and efficiently deliver therapeutic payload to the tumors site 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 tumor. Recently, we developed and characterized a monoclonal antibody specifically targeting IL13R2, a cell surface receptor that is selectively expressed in glioma cells, but not normal brain cells or other tissues. We demonstrated that single-chain antibody from the hybridoma cell line retains an exclusive specificity as well as a high affinity to IL13R2, and successfully re-targets engineered adenovirus and therapeutic CAR T cells to IL13R2-expressing glioma cells in pre-clinical models of GBM, in vitro and in vivo. In addition to being overexpressed in the majority of GBMs, IL13R2 expression has been associated with the highly aggressive mesenchymal subtype gene expression signature, and poorer patient prognosis, all of which suggest that targeting IL13R2-expressing glioma cells could improve GBM patient outcomes. 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 therapeutic for clinical application will be accomplished through the detailed analysis of engineered NSCs for antibody expression and secretion, and when used in immune-competent and patient-derived xenograft models of GBM.
|Effective start/end date||5/1/17 → 4/30/19|
- National Institute of Neurological Disorders and Stroke (5R21NS101150-02 REVISED)
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