DDIS-06. AAV TOOLKIT ENABLING PRECISION COMBINATORIAL VIROTHERAPY FOR GLIOBLASTOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: Futch, Hunter; Grippin, Adam; Kuhn, Zino; Hoang-Minh, Lan; Truong, Van; Nelson, Joshua; Hao, Nicole; Cruz, Pedro; Ran, Yong; Reynolds, Brent; Mitchell, Duane; Golde, Todd
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi70
• Page End: vi70
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.285
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Glioblastoma represents the most common and deadly type of brain tumor in adults. Although it is widely recognized that combinatorial therapeutic approaches may be necessary to achieve lasting remission or cure, identification of novel combinatorial therapies is challenging. Despite the availability of a number of potent and intuitively combined biologic monotherapies, the cost of performing studies using multiple biologic agents is prohibitive, and delivery of therapeutics within the brain is often difficult. Recombinant Adeno Associated Viral (rAAV) vectors have become the preferred vector for human gene therapy applications because of their flexibility, ease of production, and translatability from mouse to human studies. METHODS: We developed a method for rapid screening of cell lines for rAAV transduction efficiency using 29 different capsid serotypes. In addition, we created a large array of rAAV-encoded transgenes that are designed to enhance immune recognition or to have anti-proliferative, anti-invasive, or direct cytotoxic effects on brain tumor cells. The transgenes were engineered with a novel multimerization domain that increases expression several fold compared to unmodified transgenes. Our methods allow for high expression of transgene products that are secreted into the brain tumor microenvironment and act in a non cell-autonomous manner, while potentially avoiding the systemic toxicities associated with such therapeutic cocktails. RESULTS: We screened 14 primary human glioblastoma cell lines and several murine glioma cell lines, identifying AAV capsid serotypes that are capable of high efficiency transduction in vitro . This in vitro screen was reflective for the transduction of tumor and brain microenvironment seen by the serotypes in vivo . Efficacy studies of cocktails of anti-tumor transgenes delivered via rAAV in vivo are under way. CONCLUSION: We present the use of rAAV vectors encoding biologic agents as a technology accelerator for the preclinical identification of novel combinatorial therapy regimens for glioblastoma.