Targeting cancer stem cells in glioblastoma and metastatic breast cancer with immunotherapy
Malignant gliomas and metastatic breast cancer with central nervous system involvement, are the most common form of primary adult brain cancer with a high recurrence rate such that more than 90% of individuals die within two years of diagnosis. Initial cancer treatments often involve cytoreductive therapies (radiation and chemotherapy) that can cause tremendous side effects and toxicities as well as often not resulting in long-term relapse-free survival. It is thought that small populations of cancer cells, termed cancer stem cells (CSC) due to their “stem cell-like” nature, are the ultimate cause for cancer relapse. These CSC are not replicating making them resistant to the cancer therapies. Many brain cancers are inoperable, therefore, brain tumors represent a unique opportunity to validate the approach of CSC targeting as it remains relatively localized; the use of immunotherapy offers perhaps the greatest opportunity to specifically attack these CSC. This proposal will combine immunotherapy using the patient’s own immune cells along with an already approved anti-cancer drug to target the CSC and allow for anti-tumor effects to occur in cases of relapsed glioblastoma. Natural killer (NK) cells are lymphocytes that have the ability to spontaneously attack cancer cells. Molecular targeting drugs such as Velcade have been shown to sensitize the cancer to NK cell attack making this a powerful “one-two” punch. This combination has been shown by us to actually result in additive anti-tumor effects particularly on the CSC. By targeting the CSC it allows for the greatest chance to relapse-free survival. This proposal will have significant benefit for not only patients with glioblastoma and metastatic breast cancer which has seeded in the brain, but for other cancers as well. Additionally, by targeting the CSC and using immunotherapy, there is a strong likelihood for significantly less systemic toxicities, thus improving quality of life for cancer patients.
Cancer is one of the leading causes of death in California and the U.S. as well as one of costliest diseases to treat. Initial cancer treatments often involve cytoreductive therapies (radiation and chemotherapy) that can cause tremendous side effects and toxicities as well as often not resulting in long-term relapse-free survival. In a Swiss multi-center study greater than 65% of total medical costs incurred by an individual with malignant glioma occurred following recurrence of their brain cancer. Breast cancer is the second most frequent cancer in the world, and is by far the most common malignant disease in women (22% of all new cancer cases). Worldwide, the ratio of mortality to incidence is about 36%. It ranks fifth as a cause of death from cancer overall. The true prevalence of metastatic disease is high because some women live with the disease for many years. Metastatic breast cancer causes 46,000 deaths annually in the U.S, brain metastasis in breast cancer is associated with an extremely poor prognosis. The ability to prevent or retard highly recurrent cancers would significantly reduce medical costs associated with cancer and greatly improve quality of life. Malignant gliomas and metastatic breast cancer with central nervous system involvement are the primary forms of adult brain cancer in California and are increasing in incidence as our population lives longer. Brain cancer is associated with a greater than 90% rate of recurrence. Natural killer cells are immune cells that are removed from the patient and can be activated to attack these brain cancer cells. Unlike other forms of immune-mediated cancer therapies, these natural killer cells disappear after attacking the cancer and cannot cause ongoing immune-damage to normal brain. Coupled with Velcade, an FDA approved cancer therapy, these activated NK cells target the glioma and metastatic breast cancer “stem” cells that are responsible for the re-growth of the brain cancer. The development of this novel therapy for the treatment of brain tumors would not only have a significant financial benefit to California and the residents by reducing health care expenses, it would also improve the quality and quantity of life for the residents that are impacted by this disease and would put California in the forefront of visibility on a worldwide level for its cutting edge, extraordinary medical care for cancer patients. If CIRM funded, his approach would provide benefit to the state taxpayers by displaying the efficient use of their tax dollars by providing them initial access to this novel therapy, as well as stimulating and advancing the potential for collaborative partnerships and alliances with other cancer centers and affiliates, academic institutions, and philanthropic societies within California, which would further enhance local and state economies