IMMU-10. HSV-1–Mediated Species-Specific Fc-Dependent Antibody Internalization: A Model to Investigate Preexisting Immunity in Glioblastoma Oncolytic Virotherapy

Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant cancers due to tumor heterogeneity and the highly immunosuppressive tumor microenvironment (TME). Our laboratory has been investigating HSV-1 based oncolytic virotherapy for GBM. Findings from our recent clinical trial (NCT03152318) suggest that patients with preexisting immunity to HSV-1 respond more favorably to oncolytic HSV (oHSV) therapy, demonstrating improved survival compared to HSV-1 seronegative patients. Thus, our research aims to understand mechanisms by which HSV-1 pre-existent immunity enhances oHSV therapy. HSV-1 encodes a viral Fc receptor, composed of glycoproteins E and I, which binds to human IgG and promotes degradation of anti-HSV antibodies through the mechanism, antibody bipolar bridge (ABB). In the ABB process, tethered antibodies are internalized into cellular endosomes/lysosomes for degradation, while viral gE-gI is recycled back to the cell surface. However, how this immune evasion mechanism works in HSV-experienced patients during oHSV therapy remains unclear. To investigate this phenomenon, we generated an in vitro model using recombinant anti-HSV1 gD IgG with either human or mouse Fc regions. Immunofluorescence on Vero cells indicates that human Fc antibodies colocalize with lysosomes in HSV-infected cells, suggesting they are targeted for degradation. In contrast, mouse Fc antibodies were not internalized, supporting the idea that HSV-1 mediates species-specific immune evasion to shape tumor immune responses. To test this in vivo, we developed an adeno-associated virus (AAV) vector that expresses anti-gD antibodies with either human or mouse Fc regions. It is expected that this animal model will help in understanding the importance of HSV pre-existing immunity in oHSV therapy and lead to the development of new therapeutic strategies.