Researchers at UCLA’s Jonsson Comprehensive Cancer Center (JCCC) have successfully combined cellular therapy and gene therapy in a mouse model system to develop a viable treatment strategy for breast cancer that has metastasized, or spread, to the patient’s brain. The laboratory study was led by Carol Kruse, professor of neurosurgery and member of JCCC and the UCLA Brain Research Institute. The study was published in the journal Clinical Cancer Research on August 1, 2013.
Breast cancer is the most common form of cancer in women, and metastasis is a major cause of health deterioration and death from the disease. Management of metastasis is difficult for several reasons. The circulatory network known as the blood-brain barrier prevents many anti-cancer drugs from reaching the areas of the brain to which cancer has spread. Also, the tendency of metastasis to spring up in multiple places in the brain simultaneously makes current treatments such as radiation challenging.
Cellular therapy is a type of immunotherapy (treatment that involves the immune system) that uses T cells, the foot soldiers of the immune system, which have been sensitized in the laboratory to kill breast cancer cells. Those T cells are injected into the part of the brain to which the cancer has spread. The research shows the T cells move through tissue and can recognize and then directly kill the tumor cells.
With the gene therapy, cancer cells are killed by a drug called 5-flurocytosine (5-FC) because they have been gene-modified. To get the gene into the cancer cells, the researchers first insert the gene into a virus that can infect (penetrate and spread among) the tumor cells. After the virus has infected the cells, nontoxic 5-FC is given to the patient. Tumor cells infected by the virus convert the nontoxic drug to a toxic form that kills the cancer cells. Dr. Noriyuki Kasahara, a professor in the department of medicine, developed the gene therapy method in his laboratory.
While the two methods alone each show efficacy in mouse models, the greatest reduction in metastatic brain tumor size happened when the cellular and gene therapies were combined. “There is a significant lack of Federally funded research addressing translational studies on brain metastases of systemic cancers,” Dr. Kruse said, “even though metastatic brain tumors occur ten times more frequently than primary brain tumors in humans. These patients have a dismal prognosis because the brain represents a ‘sanctuary site’ where appropriate access by many chemotherapeutics is ineffective. Our research addresses this unmet need.”
Both experimental therapies are being tested individually in ongoing clinical trials for primary malignant brain tumors, which presents a unique opportunity for rapid translation of this technology from the laboratory to the clinic for breast and other types of cancer that metastasize to the brain. This research was supported by the U.S. Army Research Materiel Command, The California Breast Cancer Research Program, The National Center for Advancing Translational Sciences of the National Institutes of Health, The UCLA Clinical Translational Science Institute, the Joan S. Holmes Memorial Research Fund, the Joan S. Holmes Memorial Postdoctoral Fellowship, and Tocagen, Inc.