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ZFN Modified Cells Show Glioblastoma Killing in the Presence of Dexamethasone in Mouse Tumor Model

Posted on: 12/19/2007

Sangamo BioSciences Announces Presentation of Data for ZFP Therapeutic for Glioblastoma at American Society for Hematology Meeting


ZFN Modified Cells Show Glioblastoma Killing in the Presence of Dexamethasone in Mouse Tumor Model

RICHMOND, Calif., Dec. 10 /PRNewswire-FirstCall/ -- Sangamo BioSciences, Inc. today announced the presentation of positive data in a mouse tumor model from its program to develop a novel cell therapy using its zinc finger DNA-binding protein nuclease (ZFN(TM)) technology for treatment of glioblastoma multiforme (GBM), a progressive and usually fatal brain cancer. The data were presented at the 49th Annual Meeting of the American Society of Hematology (ASH) by Sangamo's collaborator Michael C.V. Jensen, M.D., Associate Chair, Division of Cancer Immunotherapeutics & Tumor Immunology, City of Hope.

"Working with Sangamo, we have succeeded in generating ZFN-modified engineered T-cells that can destroy glioblastoma cells in vivo in the presence of dexamethasone," said Dr. Jensen. "This is an important result in the progress of our efforts to create a cell-based product which can be used in combination with glucocorticoids such as dexamethasone to treat patients with GBM. The ZFN-modification of GR in these T-cells does not alter their cytolytic or 'killing' properties and enables them to function in the presence of glucocorticoids, which would normally inhibit T-cell function."

Dr. Jensen has developed novel chimeric immunoreceptors called zetakines that can be engineered into human immune cells to generate a population of cells that can specifically recognize and destroy cancer cells. Dr. Jensen has already used these engineered cells in clinical trials for malignant gliomas and lymphoma. In his current clinical protocol, T-cells are removed from a patient with GBM and 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, glucocorticoids, such as dexamethasone, must be administered to patients pre- and post-surgery to stop the brain swelling caused by the tumor and surgery. Glucocorticoids inactivate or kill the desirable T-cells through a protein known as the glucocorticoid receptor (GR) limiting the benefit of this novel therapy. Currently, this approach is also patient-specific or autologous, which makes it time and labor-intensive. Cells without a functional GR are drug-resistant and should therefore be available to destroy tumor cells. The aim of the collaboration is to use Sangamo's ZFN gene modification technology to delete the GR in T-cells engineered to express the zetakine. The specific deletion of GR in the zetakine expressing anti-glioma T-cells allows them to be used in the presence of glucocorticoids and to be developed as an "off the shelf" or allogeneic cell product that can be used rapidly in all GBM patients. Sangamo expects to file an Investigative New Drug (IND) application for this cell therapy in the first half of 2008.

"These data represent another important step forward in this program and we are committed to moving into the clinic as soon as possible," said Edward Lanphier, Sangamo's president and CEO. "We are very pleased to be working with City of Hope and Mike Jensen and his team who have developed this novel approach to the treatment of GBM. We believe that, in combination with our proprietary ZFN technology, we have the opportunity to significantly broaden the patient population that could benefit from these advances."

Data Presented at ASH

Sangamo scientists have engineered ZFNs specifically targeted to the glucocorticoid receptor gene. Data were presented yesterday at the ASH annual meeting held in Atlanta, Georgia, that demonstrate that these ZFNs cleave their intended target sequences with high specificity and efficiency resulting in the knockout of GR and the creation of glucocorticoid resistant cells. These zetakine-positive, GR-negative T-cells were demonstrated to kill glioblastoma cells in the presence of dexamethasone in vitro and in vivo in a mouse model of GBM.

About Gliomas

Gliomas are the most common type of primary brain tumors; 20,000 cases are diagnosed and 14,000 glioma-related deaths occur annually in the United States. Glioblastoma multiforme (GBM), a type of glioma, is rapidly progressive and nearly uniformly lethal. Currently, malignant glioma is managed through a combination of chemotherapy, surgery and radiation that often exacerbates the already severe symptoms caused by the location of the tumor. With modern combination therapy (surgical and radiotherapeutic techniques) the mean duration of survival has increased to 82 weeks, although 5-year survival rates have only increased from 3 to 6%. Resections of >90% of bulky tumors are usually attempted provided that vital functional anatomy is spared. The addition of chemotherapy to resection and radiation provides 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 that are eligible to be treated with re-resection is 36 weeks.

About Sangamo

Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy. Phase 1 clinical trials are ongoing to evaluate a ZFP Therapeutic for peripheral artery disease. Other therapeutic development programs are focused on ALS, cancer and HIV/AIDS, neuropathic pain, nerve regeneration, Parkinson's disease and monogenic diseases. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF(TM)) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN(TM)) for gene modification. Sangamo has established strategic partnerships with companies outside of the human therapeutic space including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying its ZFP Technology to enhance the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at

About City of Hope

City of Hope is a leading research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as a Comprehensive Cancer Center, the highest honor bestowed by the National Cancer Institute, and a founding member of the National Comprehensive Cancer Network, City of Hope's research and treatment protocols advance care throughout the nation. City of Hope is located in Duarte, Calif., just northeast of Los Angeles, and is ranked as one of "America's Best Hospitals" in cancer and urology by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation and genetics. For more information, visit

This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references to the development of a novel cell therapy for the treatment of glioblastoma multiforme, research and development of other novel ZFP TFs and ZFNs, clinical trials and therapeutic applications of Sangamo's ZFP technology platform. Actual results may differ materially from these forward-looking statements due to a number of factors, including technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. See the company's SEC filings, and in particular, the risk factors described in the company's Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.

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