Improving Immune-Mediated Oncolytic Viral Therapy: Engineering Tumor Vaccine Elements into the Virus
Both viral- and immune-mediated tumor lysis contribute to oncolytic viral (OV) therapy. The FDA recently approved the first-in-class oncolytic viroimmunotherapy, providing a new paradigm for treating cancer. While encouraging, there is still room for improvement. C134 is a next-generation oHSV with improved protein translation, replication and antigenic response compared to the first generation oHSVs. Clinical grade C134 has completed biotoxicology assessment and is awaiting IND approval. We propose using C134 to express tumor antigens with enhanced antigen presenting cell (APC) delivery as a way to prime tumor immunity and improve OV activity. HSV encodes immune evasion genes that limit host gene expression and antigen presentation. By expressing tumor antigens from C134 and enhancing tumor antigen recognition, our goal is to overcome viral evasion and improve anti-tumor immunity.
C134-based expression of tumor-associated antigens (TAAs) will bolster tumor-specific cytotoxic T lymphocyte response. Expression of TAAs engineered for secretion and binding to APCs will augment long-term anti-tumor immunity.
To test this, we aim to 1) delineate the cellular immune mechanism responsible for improved C134 anti-tumor immunity. We will use syngeneic orthotopic glioma models, immune-depletion, and tetramer assays, to identify and characterize the immune effectors responsible for OV anti-tumor immunity and survival. 2) Determine whether oHSV-based TAA expression enhances survival and durable anti-tumor immunity using orthotopic GBM models. We will identify whether C134-based tumor antigen expression and APC antigen targeting improves the anti-tumor immune response and tumor clearance in orthotopic GBM model using similar methods as our first goal.