Peritoneal carcinomatosis (PC) is a kind of gastrointestinal cancer, in patients with advanced tumors caused by gynecological malignant tumors or primary peritoneal cancer. The direct cause is the spread of malignant tumors throughout the abdominal wall, which is called peritoneal cancerization. Since most of the current therapies are ineffective, new treatment options are urgently needed. Oncolytic virus (OV) therapy is an emerging treatment for cancers of various origins and specifications. OV can selectively infect tumor cells without affecting normal cells. Based on the promising results of preclinical research, a variety of different OV species are currently in the early stages, clinical research is progressing rapidly. So far, regardless of the OV vaccine, several vaccinia viruses (such as GL-ONC1, Pexa-Vec, vvDD, and MVA-FCU1) have shown excellent safety in multiple phase I studies.
Fig.1 Peritoneal fluid flow area. (Singh, 2016)
The peritoneum is the mesothelial lining that covers the abdominal cavity and intraperitoneal organs. It contains a small amount of liquid and circulates under the influence of the diaphragm, gravity, and negative pressure generated by intestinal peristalsis. This natural flow pattern determines the transmission route of the disease process in the peritoneal cavity. Therefore, PC is one of the most common diffuse peritoneal diseases. Most common PCs are spread to the peritoneum rather than any tumors originating from the peritoneum itself. Several gastrointestinal and gynecological malignancies may spread and grow in the peritoneal cavity. This condition is usually related to disease progression and poor prognosis. The occurrence of peritoneal cancer has been shown to significantly reduce the overall survival rate of patients with liver and/or extraperitoneal metastases of gastrointestinal cancer. In addition, the overall survival of PC chemotherapy patients is usually only slightly affected by systemic chemotherapy, so the appearance of PC is usually regarded as an end-stage disease by surgeons.
Over the past few decades, with advances in cancer biology, scientists have recognized that PC is a localized disease, and have developed multimodal treatments that combine aggressive cell reduction (CRS), intraperitoneal high temperature chemotherapy (HIPEC), and systemic chemotherapy. These methods can help improve the local control of the disease and ultimately increase the survival rate, but most of them are currently in the clinical research stage. Among them, the advantage of HIPEC is that it can increase the concentration of the drug in the local area and prevent it from spreading to the whole body, thereby limiting its toxicity and adverse reactions. Besides, hyperthermia also enhances the efficacy and permeability of many drugs.
In addition to its cytolytic ability against a variety of tumor cell types, OV also has many characteristics required for clinical applications. These include short life cycles, well-defined characteristics, effective cell-to-cell spread, high genetic stability, and limited cytoplasmic replication capacity of infected cells. At present, oncolytic vaccinia virus has been developed for the treatment of PC. Since there is no natural host, vaccinia virus will not cause any known diseases in healthy humans. Even in the rare cases of uncontrolled systemic infections, the vaccinia-specific antidote can be used.
The oncolytic vaccinia virus GL-ONC1 is a double-stranded DNA virus that is a prototype member of the genus Orthopoxvirus and contains three integrated transgenes (encoding Ruc-GFP, β-glucuronidase and β-galactosidase). By inserting these three foreign gene expression cassettes to destroy non-essential vaccinia genes, it not only attenuated the virus, but also enhanced its targeting to tumors, and opened up the possibility of monitoring tumor cell infections in real-time. In clinical trials for patients with advanced PC, GL-ONC1 was well tolerated, and all adverse events were limited to transient flu-like symptoms. In one word, this novel approach allows personal monitoring of patients during viral treatment and also paves the way for personalized viral therapy in other malignancies.
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