IMMU-29. A CHIMERIC ONCOLYTIC ADENOVIRUS CIRCUMVENTS NEUTRALIZING ANTIBODIES DEVELOPED BY PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED WITH DELTA-24-RGD

Abstract

Abstract Oncolytic virotherapy holds great potential to treat high-grade gliomas by harnessing virus-mediated oncolysis to stimulate anti-tumor immune responses. However, the efficacy of oncolytic adenoviruses can be hampered by neutralizing antibodies. In this study, we examined sera obtained from a phase 1 clinical trial using oncolytic adenovirus Delta-24-RGD to treat patients with recurrent malignant gliomas. We found that a single intratumoral injection of Delta-24-RGD induced the development of neutralizing antibodies in less than half of the patients but demonstrated remarkable outcomes, with 20% of the patients surviving beyond three years. Conversely, multiple injections of the oncolytic adenovirus induced neutralizing antibodies in 80% of patients (P=0.05) but resulted in no long-term survivors. This inverse correlation led us to further investigate the role of neutralizing antibodies during glioma virotherapy. Examination of Delta-24-RGD-treated murine brain tumors using immunofluorescence displayed colocalization of antibodies and viral proteins. To counteract virus neutralization and maximize oncolysis, we engineered a chimeric virus, Delta-24-RGD-H43m, by replacing the hypervariable regions of the hexon protein from the prevalent serotype 5-based Delta-24-RGD with those from the rare serotype 43. The infectivity, replication, and oncolytic capabilities of Delta-24-RGD-H43m were similar to those of the parental virus. Using clinical trial patient sera, we observed that Delta-24-RGD-H43m displayed significant resilience against the inhibitory effects of neutralizing sera from patients (P=0.01). In murine models with pre-existing immunity to adenovirus, Delta-24-RGD-H43m treatment led to a significantly extended median survival and resulted in a higher percentage of long-term survivors than the parental virus (P=0.005). These results underscore the effectiveness of hexon swapping as a strategy to overcome the dominant immune response against oncolytic viruses, provide valuable insights into the interaction between oncolytic viruses and the host immune system, and lay the foundation to translate to the clinical setting immune-evading virotherapies for glioma patients.