Non-Clinical Studies Of Systemic Delivery Of Oncolytic Virus Arms With Il-12 And Anti-Pd-1 Antibody.

Abstract Background: Limited success has been reported with intravenous delivery of oncolytic viruses because of dilution of viruses in the blood volume, rapid clearance of viral particles and sequestration in non-target organs. We have reported construction of MVR-T3011, a recombinant oncolytic herpes virus embodies immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody. Intratumoral Injection of MVR-T3011 has entered into clinical stage for the study of its safety and preliminary efficacy. Here we propose systemic delivery of MVR-T3011 by intravenous (IV) injection to treat tumor types that are not easily accessible by local injection. Methods: The pharmacological activity, safety and biodistribution of MVR-T3011 by intravenous injection have been studied in immune deficient and competent mouse model. Results: (i) In immune deficient mice, MVR-T3011 is enriched in tumor following tail vein injection. MVR-T3011 inhibits tumor growth of A549 xenograft. (ii) In immune competent mice, MVR-T1013L, the virus backbone carries a reporter gene encodes luciferase was enriched in upper abdomen and thorax 24hr following IV injection. (iii) IV administration of mouse surrogate oncolytic virus MVR-T3855 extended survival of mice in B16-F10 mouse melanoma lung metastasis model, LLC mouse orthotopic lung cancer model and H22 mouse orthotopic hepatocarcinoma model significantly. (iv) IV administration of MVR-T3855 delayed the onset of peritoneal effusion in H22 mouse hepatocarcinoma model significantly. (v) The biodistribution studies showed: following IV injection, tumor viral DNA reached peak level at 24hr, and dropped to baseline at 48hr; Subsequent injection showed similar patterns with lower peak levels. Consistent virus DNA level in the blood was detected without spike of viral DNA in other tissues probably due to non-complete virus genome circulating following virus clearance. Both IL-12 and anti-PD-1 antibody were detected in tissue and/or blood with low level 24hr following injection. Conclusions: MVR-T3011 is a suitable herpes oncolytic virus agent for intravenous injection through studies of pharmacological activity, safety and biodistribution. The significant finding reported in this article is clinical potential of herpes oncolytic virus for extensive metastatic tumors. Citation Format: Yanxin Zheng, Runbin Yan, Yuxin Tang, Borui Zhan, Yue Huang, Dongyao Ni, Xiaoqing Chen, Grace Zhou. Non-clinical studies of systemic delivery of oncolytic virus arms with IL-12 and anti-PD-1 antibody [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 2597.