SB-313 is an off-the-shelf cytotoxic T-cell product made resistant to glucocorticoid steroids using ZFN-mediated modification of the glucocorticoid receptor gene. Glucocorticoid-resistance enables this immunotherapeutic to function in the presence of high doses of steroids which are used post-surgery in glioblastoma treatment and ordinarily inhibit T-cell function.
SB-313 for Glioblastoma Multiforme (GBM)
Gliomas are the most common type of primary brain cancers; 20,000 cases are diagnosed and 14,000 glioma-related deaths occur annually in the United States. Glioblastoma multiforme (GBM), the most common type of glioma, is rapidly progressive and nearly universally lethal.
Current Treatments and Unmet Medical Need
Malignant glioma is managed through surgery, chemoradiotherapy, which often exacerbates the already severe symptoms caused by the location of the tumor, antiangiogenic therapy and symptomatic care with glucocorticoids. Recurrent tumors arise from remnants of the original incompletely resected tumor. With modern surgical and radiotherapeutic techniques, the mean duration of survival has increased to 82 weeks, although 5-year survival rates have only increased from 3-6%. Resections of 90% of bulky tumors are usually attempted provided that vital functional anatomy is spared. Chemotherapy, resection and radiation provide only marginal survival advantage to patients. Approximately 80% of recurrent tumors arise from remnants of the original incompletely resected tumor. The median survival of recurrent glioblastoma multiforme patients treated with a second resection is 36 weeks. Due to their minimally invasive ability to infiltrate tissues and destroy cancer cells, T-cell-based immunotherapies are a promising approach to the effective treatment of cancer. However, outside a bone marrow transplant situation, these therapies are autologous and ineffective in the presence of glucocorticoids, which has limited their usefulness in tumors such as GBM.
Sangamo’s Therapeutic Approach
In collaboration with clinicians at City of Hope (COH), we are developing a ZFP Therapeutic that uses our ZFN technology to disrupt the expression of the gene encoding the glucocorticoid receptor. Our collaborators have developed an engineered protein known as an IL-13 “zetakine” that, when expressed in cytotoxic or “killer” T-cells, enables them to seek out and destroy glioblastoma cells in the brain. In an investigator-sponsored IND, patients have been treated with zetakine-modified T-cells which have shown significant anti-tumor activity. In this clinical protocol, donor T-cells are modified to express the zetakine. These modified cells are infused into the brain following surgery for the targeted elimination of residual tumor cells. Frequently, however, a glucocorticoid such as Decadron® must be administered to patients post-surgery to control brain swelling. Glucocorticoids inactivate or kill the therapeutic T-cells through a protein known as the glucocorticoid receptor (GR). Cells without a functional GR are steroid-resistant and are therefore available to destroy tumor cells. Our goal is to generate zetakine positive, GR-negative T-cells, thus enabling the full treatment effect to occur even in the presence of Decadron. In December 2006, we entered into a broad, exclusive license agreement with COH for use of the zetakine with our technology. Sangamo retains commercialization rights and COH receives success-based milestone and downstream payments.
Clinical Development Status
Clinical collaborators at COH have an ongoing investigator-sponsored IND application for a Phase 1 clinical trial of this ZFP Therapeutic in subjects with recurrent/refractory GM.