Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes

• Published in: Biomedicines Vol. 8; no. 11; p. 484
• Main Authors: Chouljenko, Dmitry V., Ding, Jun, Lee, I-Fang, Murad, Yanal M., Bu, Xuexian, Liu, Guoyu, Delwar, Zahid, Sun, Yi, Yu, Sheng, Samudio, Ismael, Zhao, Ronghua, Jia, William Wei-Guo
• Format: Journal Article
• Language: English
• Published: MDPI 09.11.2020; MDPI AG
• Subjects: antitumor immunity; cancer vaccine; combinatorial therapy; herpes simplex virus; immunotherapy; oncolytic virus
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines8110484

Oncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic herpes simplex virus type 1 (VG161) that carries genes coding for IL-12, IL-15, and IL-15 receptor alpha subunit, along with a peptide fusion protein capable of disrupting PD-1/PD-L1 interactions. The VG161 virus replicates efficiently and exhibits robust cytotoxicity in multiple tumor cell lines. Moreover, the encoded cytokines and the PD-L1 blocking peptide work cooperatively to boost immune cell function. In vivo testing in syngeneic CT26 and A20 tumor models reveals superior efficacy when compared to a backbone virus that does not express exogenous genes. Intratumoral injection of VG161 induces abscopal responses in non-injected distal tumors and grants resistance to tumor re-challenge. The robust anti-tumor effect of VG161 is associated with T cell and NK cell tumor infiltration, expression of Th1 associated genes in the injection site, and increased frequency of splenic tumor-specific T cells. VG161 also displayed a superb safety profile in GLP acute and repeated injection toxicity studies performed using cynomolgus monkeys. Overall, we demonstrate that VG161 can induce robust oncolysis and stimulate a robust anti-tumor immune response without sacrificing safety.