Novel Combination Treatments For Brain Tumors

DESCRIPTION (provided by applicant): The overall goal of this project is to evaluate the effectiveness of using a novel, highly concentrated, immunogene therapy against brain tumors. The therapy incorporates a specialized polymeric delivery system (PPC) formulated with the Interleukin-12 (IL-12) gene and lyophilized to produce highly concentrated nanopolyplexes. High grade gliomas represent the most common form of primary malignant tumors of the adult central nervous system (CNS). Patients with the disease have a very poor prognosis. Consequently, efforts aimed at developing new therapies have focused on new treatment strategies that can maximize anti-tumor effects while minimizing the toxicities associated with treatment. One such modality, immunogene therapy, has shown promise in the spectrum of agents utilized against brain tumors. A specialized polymer delivery system has been identified that allows therapeutic plasmids to be formulated to very high concentrations (up to 10 mg/ml), not possible with other non-viral gene delivery systems. This technology will allow for therapeutically relevant delivery in small volume spaces, such as intracranially, where dose escalation by volume increase could be detrimental to the patient. The research plan of this project is to generate highly concentrated nanopolyplexes and evaluate the ability of this novel, polymeric, non-viral carrier to deliver the IL-12 gene as a treatment for malignant brain tumors and to combine this gene delivery with both locally administered and systemically administered chemotherapy. We hypothesize that use of this non-viral gene therapy system designed specifically for plasmid delivery directly to the brain tumor environment will safely produce high local levels of IL-12, a potent cell mediated anti-tumor effect and lead to an efficacious therapy for brain tumors. It is also hypothesized that efficacy will be further enhanced by combining the gene therapy with standard chemotherapy treatments. Together, these studies will allow us to test the ability of our polymeric vector formulated with IL-12 plasmid to control the growth and progression of malignant brain tumors. These results will provide sufficient data to proceed with a phase II study, the aim of which will be to scale up studies into larger animal models in order to complete dose response and dosing frequency analysis and to perform formal pre-clinical safety/toxicity and biodistribution studies, in preparation of an Investigational New Drug (IND) filing. Brain tumors, a diverse class of diseases, are a major cause of mortality particularly in children and young adults with an estimated 13,000 deaths from primary brain tumors per year. Unfortunately few treatment options currently exist for patients with this disease which is made even more complicated by the intracranial location and subsequently the prognoses is poor. The proposed research will focus on establishing a novel, highly concentrated, gene based therapy for the treatment of brain tumors that works to activate the immune system against cancer cells, inhibit tumor angiogenesis and can work synergistically with available chemotherapeutics. Positive results from this project will facilitate the development of this novel therapeutic approach towards establishing a new treatment option for patients with this particularly devastating disease.