Project Title: Developing a Glioblastoma Brain Slice Model for Immunotherapy Testing
Faculty Mentor’s Name: Dr. Todd Golde
Student’s Name: Samuel Malnik
In the past decade, immunotherapy has rapidly emerged as one of the most promising tools in the “War on Cancer”. Monoclonal antibodies targeting the CTLA-4 and PD-1 pathways have been effectively applied in the treatment of melanoma, non-small cell lung cancer, and Hodgkin’s lymphoma among many other cancers (Hargadon et al., 2018). The significant cytotoxic T-cell infiltration of glioblastomas, highly aggressive primary brain tumors with a median overall survival of 10-12 months, have made these tumors particularly high value targets for treatment by immunotherapy (Ostrum et al., 2016; Cai and Sughrue, 2018). Traditionally, glioblastomas are treated by initial surgical resection followed by adjuvant radiation therapy and temozolomide; however, the location and heterogeneity of the tumors make them resistant to such therapies (Chang et al., 2005). While application of antibody based immune checkpoint blockade has been applied in numerous clinical trials, these biologics have failed to deliver the same astonishing results as the biologics delivered in the aforementioned cancers. This discordancy in response has largely been attributed to the blood-brain barrier and the unique immune environment of the central nervous system.
The harmony of gene therapy and immunotherapy has been proposed as an alternative to antibody mediated immune checkpoint blockade for the treatment of glioblastoma. Specifically, it has been hypothesized that genetically-modified adenoviruses, polio viruses, and adeno-associated viruses (AAV) could deliver immune modulatory molecules to glioblastomas post-surgical excision, thereby bypassing the blood-brain barrier and the systemic effects of immune overactivation. Dozens of these viruses expressing molecules as diverse as IFN-gamma and scFv’s against PD-1 are in laboratory and clinical pipelines and have shown promising results. The limits are quickly becoming not what macromolecules can be designed to upregulate the immune system, but rather, which macromolecules can upregulate the immune system most uniquely and most effectively. This demand beckons a high-throughout, inexpensive glioblastoma model for testing virus-based delivery of immune modulating molecules.
The specific aims of this project are
1) To develop an in vitro murine glioblastoma brain slice model with anti-tumor CTL activity
2) To assess the effect of AAV-mediated delivery of immune modulatory molecules on anti-tumor CTL activity