ZFN Modified Cells Show Glioblastoma Killing in the Presence of
Dexamethasone in Mouse Tumor Model
SAN DIEGO, April 15 /PRNewswire-FirstCall/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) today announced the presentation of positive data in a mouse tumor model from its ZFP Therapeutic(TM) program for the treatment of glioblastoma multiforme (GBM), a progressive and usually fatal brain cancer. The data were presented in the New Approaches to Biological Therapy Session at the 2008 Annual Meeting of the American Association for Cancer Research (AACR) by Sangamo's collaborator Michael C.V. Jensen, M.D., Associate Chair, Division of Cancer Immunotherapeutics & Tumor Immunology, City of Hope.
"In collaboration with Sangamo, we have successfully generated engineered T-cells that can destroy glioblastoma tumor cells in animals in the presence of glucocorticoids," said Dr. Jensen. "Treatment of recurrent GBM with modified T-cells, an otherwise promising approach for this cancer, is rendered ineffective by the use of glucocorticoids to control inflammation of the brain due to the tumor and surgery. These data show that we have solved that problem and are making significant progress in our efforts to create an 'off-the-shelf' cell-based product for the treatment of GBM. The ZFN(TM)-modification of the glucocorticoid receptor (GR) in our engineered T-cells protects the cells from the effects of glucocorticoids which would normally inhibit T-cell function, and in addition, does not alter their cytolytic or tumor-killing properties."
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. He has already used these engineered cells in clinical trials for malignant gliomas. 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 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 zinc finger DNA-binding protein nuclease (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 immediately available to GBM patients. The data presented at AACR suggest that this strategy is effective in animal models of the disease. Sangamo expects to file an Investigative New Drug (IND) application for this cell therapy in 2008.
"These data demonstrate an important direct therapeutic application of our ZFN technology for the optimization of cell-based pharmaceuticals," 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 AACR
Sangamo scientists have engineered ZFNs specifically targeted to the glucocorticoid receptor (GR) gene. Data were presented demonstrating that treatment of T-cells engineered to kill glioblastoma cells with these ZFNs results in the knockout of the GR gene creating glucocorticoid-resistant T-cells. These zetakine-positive, GR-negative T-cells killed glioblastoma cells in vitro. In addition, data were presented from a mouse model of GBM demonstrating that the T-cells were capable of killing tumor cells in the presence of the glucocorticoid dexamethasone.
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. With modern combination therapy, the mean duration of survival has increased to 82 weeks, although 5-year survival rates have only increased from 3% to 6%. 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.
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 stem cell mobilization, ALS, cancer, 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 http://www.sangamo.com .
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 http://www.cityofhope.org.
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, the initiation and results of 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.
|SOURCE Sangamo BioSciences, Inc.|
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