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Definition of an oncolytic virus
Oncolytic virus is a group of virus which specifically infect and lyze tumor cells but not healthy cells. Oncolytic viruses use attenuated viruses to infect tumor cells and generate de novo or boost pre-existing native immune response. Most of the available oncolytic viruses are genetically modified to enhance tumor tropism and reduce virulence for non-neoplastic host cells. Thus, they can stimulate a proinflammatory environment through enhancing antigen release/recognition and subsequent immune activation to counteract the immune evasiveness of malignant cells. In fact, oncolytic viruses also aim to take advantage of the tumor’s tolerogenic mechanisms, which can facilitate viral infection and killing of cells that are not protected by the immune system.
Mechanisms of OV action
A general mechanistic understanding of OV action is emerging in which therapeutic efficacy is achieved by a combination of selective tumor cell killing and establishment of antitumor immunity (Figure 1). Immune stimulation is caused by release of cell debris and viral antigens in the tumor microenvironment.
Figure 1. The mechanisms of action of oncolytic viruses.
Tumor selectivity in OV therapy is driven by multiple factors. The first of these is cellular entry via virus-specific, receptor-mediated mechanisms. A specific viral entry receptor is usually highly expressed on tumor cells. However, there are also efforts to improve tumor selectivity by retargeting OVs to enter cells through tumor-specific receptors. Second, rapid cell division in tumor cells with high metabolic and replicative activity may support increased viral replication compared with normal quiescent cells. Moreover, tumor-driver mutations specifically increase the selectivity of virus replication in tumor cells. Third, a number of tumor cells have deficiencies in antiviral type I interferon signaling, thus supporting selective virus replication. Viral replication within the tumor microenvironment results in innate and adaptive immune activation. This activation limits virus spread; nevertheless, the presence of virus together with cell lysis, with release of tumor antigens and danger-associated molecular patterns, may overcome immunosuppression in the tumor microenvironment and promote antitumor immunity.
Innovative oncolytic viral therapy types
There are presently many viral species in different stages of investigation for immuno-oncologic use. So far, the best studied may be Herpes viruses of which some strains have been found to have native tumor cell tropism while others have been engineered to improve selectivity. In addition, various strains of recombinant vaccinia virus have shown promise as antineoplastic agents. Other viruses that have been explored as possible vehicles for immunomodulation in cancer include Newcastle Disease Virus, reovirus, Vaccinia Virus, and even measles.
|ECHO virus (enteric cytopathic human orphan)||A type of RNA virus that represent the enterovirus species. It shows very promising results in melanoma treatment.|
|HSV (Herpes simplex virus)||A genetically modified virus to include a gene that codes for GM-CSF, a protein that stimulates the production of immune cells in the body. It is showing promise for treating melanoma.|
|Reovirus||This naturally occurring virus is one that affects the respiratory and gastrointestinal systems and is replication proficient. However, a derivative of its live form assists in replicates in and eventually kills Ras-activated tumor cells. Used for a variety of tumor-related cancers such as melanoma, lung, ovarian, pancreatic, and colorectal cancers.|
|Adenovirus||This is a DNA type of virus which spread respiratory type illnesses. Used as a cancer treatment, it takes the most effective genetically modified genes and uses them to replace mutated genes. Showing exceptional treatment for several cancer types, it is gaining attention for its use for bladder cancer.|
|Newcastle Disease Virus||A naturally occurring virus thought to infect only avian species, but it also infects humans. Strains of this virus can kill cancer cells by interfering with cell metabolism and is being studied for its immunity boosting characteristics for fighting cancer itself.|
|Vaccinia Virus (Small Pox)||This virus belongs to the pox virus family and has been genetically modified. Studies have indicated significant promise with regards to several areas including vast tumor destruction. As an oncolytic treatment, it is undergoing rigorous clinical trials for use on tumor-related cancers, with special attention to pancreatic cancer. The Vaccinia virus is also showing its ability to stimulate the immune system and thus aiding the efficacy of conjunctive treatment efforts.|
|Measles Virus||A genetically modified strain that may offer a new generation of safer and more effective oncolytic viruses. The measles virus has indicated spontaneous tumor regression occurred during a natural measles infection. Therefore, it is hoped that studies can extract the anti-cancer agents and enhance their efficacy for tumor specific activity and destruction. Current clinical trials are underway for treatment of myeloma patients.|
Clinical application of oncolytic viruses
Currently, the only FDA approved oncolytic viral therapy is talimogene laherparepvec (T-Vec or Imlygic) for use in metastatic melanoma, though there are numerous other viruses being developed pre-clinically and clinically. By 2016, there are reportedly at least eight oncolytic viruses in phase I, nine in phase II, and two in phase III clinical trials. Notably, the therapeutic potential of oncolytic viruses is way beyond melanomas and current studies are ongoing at least in pancreatic and hepatocellular carcinomas. Indeed, a search of all registered clinical trials in 2017 demonstrates 78 interventional trials referencing the usage of an “oncolytic virus” and spanning nearly every solid organ malignancy. This ability for near universal therapeutic impact in cancer makes oncolytic viruses a unique therapeutic tool. While more traditional therapies such as chemotherapy and radiotherapy lack tumor specificity targeting all replicating cells, and other immunotherapies have limited scope by relying on the presence of a specific ligand/receptor, oncolytic viruses are postulated to be both specific to neoplastic cells and have an expansive immunostimulatory latitude. The broad effect of oncolytic viruses is the consequence of using of the host adaptive immune response which is able to sharply distinguish target and non-target cells for precise specificity; while also being able to harness signals ubiquitous to perhaps all malignancies.