In vivo Safety and Immunoactivity of Oncolytic Jurona Virus in Hepatocellular Carcinoma: A Comprehensive Proteogenomic Analysis

Oncolytic viruses can effectively unwrap a multimodal anti-tumor activity, encompassing a selective tumor cell killing and promoting a systemic anti-tumor immunity, making them a formidable foe against cancer. Among these, several members of the Rhabdoviridae family are particularly attractive as oncolytic agents due to their natural tumor selectivity and non-pathogenicity in humans. In this study, we demonstrated that intratumorally (IT) administration of Jurona virus (JURV), a novel oncolytic Rhabdovirus, induces dynamic tumor regression in human HCC xenograft and syngeneic models. Our data shows that IT injections of JURV trigger the recruitment and activation of cytotoxic T (CTLs) and decrease the tumor-associated macrophages (TAM) infiltration leading to tumor growth delay in both local and distant murine HCC tumors in a syngeneic model. Moreover, when administered concomitantly, JURV and anti-PD-1 therapy profoundly modulate the tumor microenvironment (TME) via enhanced infiltration of CTLs, suggesting that immune checkpoint blockade therapy could potentiate the immunomodulatory effect of JURV and potentially provide durable anti-tumor immunity. Our analysis of the molecular and cellular mechanism of JURV-medicated anti-cancer activity unveiled that JURV and anti-PD-1 antibodies activate different effectors of the immune system but have complementary anti-tumor activities. Furthermore, our results indicate that the abscopal effect induced by JURV is likely mediated by the mechanism regulating the T helper cell responses. Our work supports the further development of JURV as a novel immunovirotherapy platform for hepatocellular carcinoma. ### Competing Interest Statement This work was supported by the National Institute of Health (NIH) through a National Cancer Institute (NCI) grant (CA234324 to BMN); a grant from the American Association for Cancer Research (AACR) to BMN; and start-up funds from the Winthrop P. Rockefeller Cancer Institute to BMN. The UAMS Bioinformatics Core Facility is supported by the Winthrop P. Rockefeller Cancer Institute and NIH/NIGMS grant P20GM121293. The IDeA National Resource for Quantitative Proteomics is supported by NIGMS grant R24GM137786. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.