Oncolytic viruses (OVs) are emerging as powerful new therapeutic agents in cancer treatment, employing nature’s own agents to find and destroy malignant cells. After talimogene laherparepvec (T-Vec), the first OV, obtaining US Food and Drug Administration approval, more and more attention in OVs has been paid. Recent advances in viral retargeting, genetic editing, tracking strategies and OV-based gene therapy have the potential to broaden the applications of OV in cancer treatment. Thus, OV-based cancer therapy is becoming more popular for scientists, clinicians, and the public. So far, numerous OVs are being developed pre-clinically and clinically against many kinds of cancers, such as melanoma, pancreatic, breast cancers, glioblastoma, rectal cancer, lung cancer, pancreatic and hepatocellular carcinomas, etc.
Numerous viruses are being developed pre-clinically and clinically. An investigation of all registered clinical trials in 2017 demonstrates 78 interventional trials regarding OVs. This ability for near-universal therapeutic impact in cancer makes OVs a popular therapeutic tool. Today, both preclinical and early-stage clinical trials are intensively investigating the approach to improve oncolytic virotherapy.
Different strategies utilizing viruses have been used in the treatment of cancer for several decades. OVs are characterized by their property to either inherently or after genetic modification replicates selectively in cancer cells. These viruses have multiple mechanisms to harm the host cells including direct lysis, induction of apoptosis and autophagy, expression of toxic proteins and shut-down of protein synthesis. At the end of the replication cycle, cells are destroyed and infective viral progeny is released into the remaining tumor tissue. Several human DNA and RNA viruses such as measles virus (MV), vesicular stomatitis virus (VSV), adenovirus, vaccinia virus (VV), herpes simplex virus (HSV) have been genetically modified to selectively replicate in tumor cells, while their activity in normal cells is attenuated.
Fig.1 Schematic depiction of OV-based gene therapies. (Zheng, 2019)
Various novel therapies used in modern oncologic care have targeted all three layers of tumor biology: tumor, niche, and immune system. OV is one emerging class in both primary and salvage therapy. One featured advantage of OV-based immunotherapy relies on its specificity against tumor cells and not exclusively for targeting replicating cells. Moreover, OVs are independent of the expression of specific receptors and the resultant mutational or transcriptional resistance. Furthermore, OVs can restore already existing but ineffective anti-tumor immunity, or induce a novel non-self antigen response.
OVs kill cancer cells via direct oncolysis and uninfected cells via tumor vasculature targeting or bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells (DCs) but also efficiently present tumor-associated antigens to T cells, inducing adaptive antitumor immunity. With these favorable features, genetically engineered oncolytic viruses and rational combinations further make OVs as potential cancer vaccines.
Fig.2 Overview of OV clinical trials. (Zheng, 2019)
There are many kinds of OVs, including adenovirus, herpesvirus, vaccinia virus, measles virus, vesicular stomatitis virus (VSV), used in the field of cancer virotherapy. Some of the newest OVs include the avian adenovirus, myxoma virus, foamy virus, yaba-like disease virus, bovine herpesvirus, feline panleukopenia virus, Saimiri virus, Sendai virus and the non-human coronaviruses. Although many of these viruses may never make it to the clinics, they may contribute to virotherapy research in other ways, such as functioning as models or providing insights into the mechanisms of oncolysis.
Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses including adenoviruses, herpes simplex viruses, Newcastle disease viruses, reovirus, coxsackie viruses, vaccinia viruses, etc., have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses. See Oncolytic Virus Therapy Clinical Trials Overview.
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