Abstract 1912: Evasion of neutralizing antibodies and enhanced anti-tumor effects of hexon-modified Delta-24-RGD oncolytic adenovirus

Abstract

Abstract Oncolytic viruses are a new form of cancer immunotherapy that harnesses the combined abilities of the virus to directly lyse cancer cells and to induce immunogenic environments to activate anti-tumor immunity. Our oncolytic adenovirus Delta-24-RGD has demonstrated significant clinical benefits for a subset of patients with recurrent malignant gliomas in a recent phase 1 clinical trial. However, the backbone of Delta-24-RGD is derived from adenovirus serotype 5 to which 40 percent of the human population has prior exposure and harbor neutralizing antibodies that can block virus infection and replication. We hypothesized that replacing the major targets of antibodies in the oncolytic virus will protect it from neutralizing antibodies, resulting in enhanced efficacy of the cancer virotherapy. Because hexon hypervariable regions are the dominant targets of antibodies, we replaced these regions with those from a lesser prevalent serotype 43 to create a hybrid virus called Delta-24-RGD-H43m. Transmission electron microscopy imaging of the viruses revealed the assembly of viable virions after infection with either Delta-24-RGD or Delta-24-RGD-H43m in human and mouse cancer cell lines, signifying successful virus replication, that was corroborated by quantification of viral replication using hexon-staining dilution method. Accordingly, the inherent anti-tumor effect of the virus was not perturbed after the genetic modification, as Delta-24-RGD and Delta-24-RGD-H43m showed comparable efficacies both in vitro (P= 0.568) and in vivo using mice without prior immunity to adenovirus (P= 0.228). Importantly, the oncolytic ability of Delta-24-RGD-H43m was not compromised by neutralizing antibodies generated against adenovirus serotype 5 that efficiently neutralized Delta-24-RGD (P< 0.0001) as assessed by measuring cell viability after virus infection. In immunized mice with prior adenovirus exposure, Delta-24-RGD-H43m treatment yielded higher occurrences of complete tumor remission compared to Delta-24-RGD (89% versus 67%). Despite our growing understanding of viruses, the immune system, and cancer, the specific interaction between oncolytic viruses and the host immune system is still very limited. Strategies to protect the therapeutic viruses from virus-specific immune responses should prolong their persistence in tumors and result in better therapeutic outcomes. Further research in this field will aid the development of enhanced cancer virotherapies. Citation Format: Dong Ho Shin, Teresa T. Nguyen, Hong Jiang, Xuejun Fan, Yanhua Yi, Sagar S. Sohoni, Sumit Gupta, Ashley Ossimetha, Candelaria Gomez-Manzano, Juan Fueyo. Evasion of neutralizing antibodies and enhanced anti-tumor effects of hexon-modified Delta-24-RGD oncolytic adenovirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1912.