Naturally Existing Oncolytic Virus M1 Is Nonpathogenic for the Nonhuman Primates After Multiple Rounds of Repeated Intravenous Injections

Abstract

Cancers figure among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next 2 decades. Development of novel therapeutic agents is urgently needed for clinical cancer therapy. Alphavirus M1 is a Getah-like virus isolated from China with a genome of positive single-strand RNA. We have previously identified that alphavirus M1 is a naturally existing oncolytic virus with significant anticancer activity against different kinds of cancer (e.g., liver cancer, bladder cancer, and colon cancer). To support the incoming clinical trial of intravenous administration of alphavirus M1 to cancer patients, we assessed the safety of M1 in adult nonhuman primates. We previously presented the genome sequencing data of the cynomolgus macaques (Macaca fascicularis), which was demonstrated as an ideal animal species for virus infection study. Therefore, we chose cynomolgus macaques of either sex for the present safety study of oncolytic virus M1. In the first round of administration, five experimental macaques were intravenously injected with six times of oncolytic virus M1 (1 × 10(9) pfu/dose) in 1 week, compared with five vehicle-injected control animals. The last two rounds of injections were further completed in the following months in the same way as the first round. Body weight, temperature, complete blood count, clinical biochemistries, cytokine profiles, lymphocytes subsets, neutralizing antibody, and clinical symptoms were closely monitored at different time points. Magnetic resonance imaging was also performed to assess the possibility of encephalitis or arthritis. As a result, no clinical, biochemical, immunological, or medical imaging or other pathological evidence of toxicity was found during the whole process of the study. Our results in cynomolgus macaques suggested the safety of intravenous administration of oncolytic virus M1 in cancer patients in the future.

Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma

“…In our efforts to further translate OV M1 to the clinic, we have completed a safety evaluation of intravenously injected OV M1 in nonhuman primates (36). Here, we evaluated the safety of EerI alone and EerI/M1 in combination in treatment groups of six animals each.…”

Maraba virus-vectored cancer vaccines represent a safe and novel therapeutic option for cats

“…Studies in both dogs and non-human primates have reported autopsy results showing that oncolytic viral therapies are non-pathogenic to normal tissues 26 , 27 , 38 , 39 . Autopsy of the cats in this study revealed that a few tissues had lesions of undetermined etiology.…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…M1 has tumor selectivity related to zinc-finger antiviral protein (ZAP) deficiency in tumor cells and therefore can selectively replicate in tumor cells and induce apoptosis of the infected tumor cells by inducing irreversible endoplasmic reticulum (ER) stress [72]. M1 showed high tumor cell selectivity and tumor-killing activity during in vitro and in vivo experiments [73]. Moreover, its antitumor activity can be considerably increased by targeted inhibitors, such as valosin-containing protein (VCP) inhibitor and DNA-dependent kinase (DNA-PK) inhibitor [74,75], suggesting that combining M1 with these inhibitors is an important strategy.…”