Scientific publications
Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice
Dong Ho Shin 1 , Hong Jiang 2 , Andrew Gillard 1 , Debora Kim 2 , Xuejun Fan 2 , Sanjay Singh 3 , Teresa T Nguyen 1 , Sagar Sohoni 2 , Andres Lopez-Rivas 1 , Akhila Parthasarathy 1 , Chibawanye I Ene 3 , Joy Gumin 3 , Frederick Lang 4 , Marta M Alonso 5 , Candelaria Gomez-Manzano 6 , Juan Fueyo 6
Abstract
Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections.
Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients.
Past studies have examined the effects of neutralizing antibodies during systemic virus injections but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis.
Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein hexon hypervariable regions from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-adenovirus serotype 5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial.
These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.
CITATION Mol Ther. 2024 Feb 3:S1525-0016(24)00035-2. doi: 10.1016/j.ymthe.2024.01.035
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