Glioblastoma (GBM) remains incurable cancer with a dismal survival rate despite aggressive multimodal therapy that can include surgery, radiation, chemotherapy, and tumor-treating fields. The failure to improve outcome in GBM patients underscores an urgent need to develop new targeted therapies. Bi-specific T cell engager (BiTEs) proteins promote specific killing of cancer cells by activated T cells via BiTE binding to both T-cells and tumor cells. Because this type of therapy is at an early stage of development for solid tumors such as GBM, our knowledge of tumor uptake, pharmacokinetics, and mechanism of action is limited, which hinders the rational design of clinical studies for evaluating BiTEs. To advance BiTEs as a strategy for treating GBM, as well as other solid tumors, we have engineered and characterized a single-chain antibody (scFv) that specifically targets IL13R2, a cell surface receptor that is expressed on GBM cells, but not normal brain cells. We have generated and tested several configurations of BiTE molecules targeting human or murine CD3 T cells. Our data show that the IL13Rα2 BiTE i) binds specifically to human IL13Rα2 on GBM cells, ii) specifically activates T cells upon engagement of the BiTE molecule with these IL13Rα2-expressing GBM cells, iii) mediates T-cell dependent killing of GBM cells at pM concentrations, and iv) significantly improves the survival of mice bearing syngeneic intracranial GBM tumors. Imaging data show that BiTEs penetrate through the blood-tumor barrier and also engage T cells. Preliminary results also suggest that the mechanism of BiTE action is not limited to direct killing of glioma cells by activated T cells but also affects the tumor microenvironment by activating additional host immune function. Based on our robust preclinical data, we hypothesize that (i) GBM access of systemically delivered BiTEs is a T-cell-dependent process, and (ii) BiTEs actively modulate T cell as well as other host immune response compartments, leading to a robust anti-tumor therapeutic response in preclinical GBM models. This hypothesis will be tested in three Specific Aims. SA1 will investigate the dependencies of IL13Rα2 BiTE on T cells for tumor access and retention, tumor uptake, and biodistribution. SA2 will study the mechanism by which IL13Rα2 BiTE primes the host immune system to generate durable anti-tumor immunity. In SA3, we will develop and identify a BiTE treatment regimen using murine and human models of GBM that could subsequently be translated into a therapy for patients. Upon successful completion of these studies, we will acquire knowledge regarding factors that influence BiTE anti-tumor activity. These studies will provide a strong foundation for future clinical application of IL13Rα2 BiTE for GBM treatment and could be broadly applicable to other IL13Rα2-expressing malignancies.
|Effective start/end date||4/1/21 → 3/31/26|
- National Institute of Neurological Disorders and Stroke (5R01NS122395-02)
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