Writer: Chengzu Maxwell Xiang

Cancer is a disease that kills hundreds of thousands of people every single year, killing 240 people a day in Canada alone. Cancer was first discovered in 1840 by Rudolf Virchow, who made fundamental observations on cancer cells, describing them as autonomous cells derived from previous cells, suggesting that they resembled cells in the tissue from which they were found. The next key insight in cancer research was the discovery of DNA by James Watson and Francis Crick. This discovery later led to the modern understanding of cancer, which states that cancer is a disease of DNA, and that DNA mutations lead to the loss of control of cell proliferation. Cancer has become increasingly common in the modern age thanks to improved medical technologies and lengthened lifespan, with people in their 80s shown to have vastly increased likelihood of developing cancer compared to those in their 40s, and with more and more of the world population now expected to live into their 70s, cancer rates will only continue to rise. So what is cancer, and what do oncolytic viruses have to do with it?

Malignant tumors, or cancers, are masses of cells that divide uncontrollably due to abnormalities in several signaling proteins and pathways. Cancer cells uncontrollably divide due to a multitude of reasons, and can begin almost anywhere in the human body. Benign tumors are not considered cancerous. Benign tumors do not spread into surrounding tissues, and when removed, they usually stay removed, unlike malignant tumors.

Cancer begins with cells that grow in the absence of signals telling them to grow, and ignore apoptosis, or organized cell death. This is caused through errors during cell division, also known as mitosis, but can also be caused by damage to the DNA through harmful substances in the environment known as carcinogens. A cancer cell will also develop the ability to avoid or protect itself against the immune system, allowing it to grow into a tumor. As the newly developed tumor grows, it requires more nutrients, so it sends signals to the body, connecting blood vessels to the tumor. This is called angiogenesis, and is an important reason why tumors can grow in size and spread across the body. As the cancerous tumors spread into nearby tissue, they begin to have the potential to travel to distant places in the body, forming new tumors, a process known as metastasis. Metastasis depends on the type, size, and location of the primary tumor, and occurs in several ways. Cancer cells can directly grow into surrounding tissue, travel through the bloodstream to other organs or even the bones, or move through the lymphatic system to nearby or distant lymph nodes. Almost all cancers have the potential to metastasize, and when it begins to happen, this is known as Stage IV cancer. Metastasis can be triggered by a multitude of factors, including a weakened immune system, hypoxia, lactic acidosis, and autophagy.

Even when a cancer is thought to be eradicated, it may return years after treatment. This is called a recurrence. This happens due to cancer’s tenacious nature to cling to life and multiply no matter what. Even if a single cell is left behind, it can grow and divide to become a new tumor. These tumors can appear in the same area of the body where the cancer first occurred, or it may have spread through the blood or lymphatic system to a new location, where it becomes a tumor again. And while many cancers can be cured with treatment, doctors prefer to use the term remission, which means that there are fewer signs and symptoms of the cancer, or that the symptoms have disappeared entirely. However, treatment that has previously been effective may stop working due to cancer cells developing resistance to the method used to kill them. This happens through gene mutations within the tumor.

So how do oncolytic viruses change this? Oncolytic viruses (OVs) have the potential to revolutionize cancer treatment, being viruses that selectively kill cancer cells without infecting normal ones. OVs are from a diverse family of viruses, but naturally occurring OVs have been genetically engineered due to their limitations in therapeutic application.

There are two main types of OVs: natural viruses and genetically modified virus strains. Naturally occurring strains of weak viruses, such as parvoviruses and Newcastle disease viruses, can selectively reproduce in tumor cells without any genetic modifications. However, genetically modified strains such as adenoviruses, measles viruses, HSV, and vaccinia viruses, have been altered to enhance their tumor-specific targeting and reduce their pathogenic effects. An example of a naturally occurring virus that already shows promise in clinical environments would be Reovirus, a double-stranded RNA virus that indicates a notable affinity for replicating in RAS mutant cells. As a non-engineered wild-type virus, it possesses an inherent ability to destroy RAS-transformed cells. RAS genes are some of the most commonly mutated oncogenes in cancer. It encodes Ras proteins, which are small guanine nucleotide-binding proteins that regulate various cellular processes, including cell growth, replication, angiogenesis, and apoptosis. When RAS proteins are triggered by epidermal growth factor receptor (EGFR), they switch into an active state, which is normally tightly regulated, but in cancer cells, mutations in the RAS genes or their regulators render RAS proteins persistently active.

The preferential targeting and replication of viruses within cells exhibiting RAS activation appears to involve the activation of the protein kinase (PKR). In the case of reovirus, it can specifically target tumor cells that overexpress EGFR. The activation of EGFR triggers the RAS signaling pathway, which subsequently leads to the release of phospholipase. This enzyme counters the actions of PKR, thereby facilitating viral replication. Reolysin is the wild-type reovirus derived from the T3D strain and has been utilized for therapeutic purposes. When administered intravenously, Roelysun targets tumor cells by exploiting the loss of PKR activity in these cells, ensuring continued viral replication and subsequent oncolysis (destruction of cancer cells). Beyond its cytotoxic effects, the virus also stimulates an anti-tumor immune response, further enhancing its therapeutic potential.

Other viruses that show potential in future therapeutic uses include the measles virus, canine distemper virus (CDV), Newcastle disease virus, herpes simplex virus, vaccinia virus, and adenoviruses. The measles virus and CDV both contain a single-stranded RNA genome and belong to the Paramyxoviridae family. They are classified as morbilliviruses and share several similarities, including causing profound immune suppression and lymphopenia in affected individuals. CDV specifically binds to a cellular receptor called CD150. It has been observed that canine lymphoid cell lines derived from dogs with lymphoma express these CD150 receptors. CDV has been examined for its ability to destroy cancer cells in lymphoma, and was successful in infecting and causing apoptosis in these cells. Modifying the measles virus can produce the tumor-associated marker peptide carcinoembryonic antigen, making it possible to monitor viral gene activity in tumors in real time.

The Newcastle disease virus demonstrates a significant negative relationship between the susceptibility to infection and the expression of antiviral genes. The activation of gene expression can enable healthy cells to resist viral infection, while a diminished expression of antiviral genes rendered tumor cells highly susceptible. Consequently, the Newcastle disease virus can proliferate extensively within tumor cells and selectively eliminate them, all while leaving normal cells untouched. A recombinant Newcastle disease virus, generated using the reverse genetics technique, can express an external factor that eliminates tumors, demonstrating remarkable oncolytic effect, resulting in successful therapeutic outcomes. Certain tests suggest that the recombinant Newcastle disease virus could become a new potential vector for the clinical transformation of immunotherapy for HCC, in addition, the virus is capable of effectively inhibiting liver cancer without apparent toxicity.

The herpes simplex virus is a commonly found pathogen that causes herpes of all kinds, and it is divided into 2 kinds, the HSV-1, and the HSV-2. Cells with nectin-1, the herpes virus entrance mediator, and heparan sulfate receptors are the main targets of HSV-1 infection, which differs from HSV-2, which uses nectin-1 and nectin-2 receptors for entry. In the field of oncolytic therapy, HSV-1 based viruses are widely utilized. Unlike many viruses that require specific receptors to enter host cells, HSV enters the host cell by directly fusing with the host’s lipid membrane, releasing its genome into the host cytoplasm. Additionally, HSV possesses desirable qualities for cancer treatment due to the following factors: They can infect a wide variety of cells, efficiently eliminating tumor cells even at low levels of infection; They are not affected by antibodies present in the bloodstream, allowing for repeated injections without diminishing effectiveness; Herpes simplex viruses also possess a well-characterized and large genome of 152 kb, they contain numerous nonessential genes that can be substituted with multiple therapeutic transgenes. These are the reasons why HSV is considered the most suitable virus for oncolytic virotherapy, along with its ability to persist long enough to target and kill cancer cells.

The first oncolytic virus HSV approved for melanoma treatment, T-VEC, has been engineered to lack the y34.5 neurovirulence factor, allowing the virus to replicate in tumor cells, which lack robust antiviral defense, ensuring that the T-VEC specifically targets and kills cancer cells. Another modified HSV strain, G47△, is undergoing Phase I/II clinical trials for solid tumors. G47△ has been further modified with multiple gene deletions to reduce its susceptibility to the host’s immune system.

Another oncolytic virus is the vaccinia virus, which belongs to the poxvirus family. These viruses posses a double stranded DNA genome that exhibits remarkable effectiveness in accommodating and accurately expressing a large number of inserted genes. One notable feature of the vaccinia virus is that it encodes the thymidine kinase (TK) enzyme, which is critical for its replication. The TK expression is low in normal cells and often overexpressed in cancer cells, making them ideal targets for the virus. To enhance tumor specificity, the vaccinia virus has been engineered to lack the TK enzyme, which prevents its replication in normal cells, and encourages replication in cancer cells where TK is overexpressed. The vaccinia strain JX-594 developed by Jennerex Biotherapeutics exemplifies this approach of lacking the TK gene, making it a suitable candidate for targeting cancer cells with elevated TK levels.

The final virus is the adenovirus, which is known for its ability to infect a wide variety of cells across animals, making it well-suited for oncolytic therapy in humans. Adenovirus receptors are expressed on many tumor cell surfaces, and extensive clinical research has been conducted to improve the adenovirus’s tumor selectivity in binding with these receptors. Currently, the primary approach to enhance adenovirus tumor targeting and transfection efficiency involves leveraging certain anomalous characteristics exhibited by tumor biology. The first recombinant adenovirus approved for oncolytic therapy is Adenovirus-H101, which has been shown to be effective when combined with chemotherapy. The other most commonly utilized types for therapy are Ad2 and Ad5, which are genetically modified by inducing mutations in the E1B and E2B genes, ensuring they preferentially infect and replicate within tumor cells while minimizing replication in normal cells.

In conclusion, oncolytic viruses are a novel and promising approach to cancer treatment. These are viruses that can be found in the wild or genetically engineered to target and kill cancer cells without damaging healthy tissue, making them a promising candidate for a new field of cancer treatment. Some of the major oncolytic viruses used in cancer treatment include: Adenoviruses, measles viruses, the herpes simplex virus, and vaccinia viruses. Oncolytic viruses function through different mechanisms, ranging from direct killing of tumor cells, immunological activation, and remodeling of the tumor microenvironment. Modern advancements in genetic engineering make oncolytic viruses a new and powerful anti-cancer tool by enhancing their tumor-specific targeting, reducing their pathogenic effects, and enabling viruses to be used as vectors for expressing various therapeutic transgenes. Despite this promise, challenges such as tumor heterogeneity, physical barriers, immune clearance, and the immunosuppressive tumor environment can limit their effectiveness. And so further research remains necessary before further application of oncolytic viruses in clinical settings.

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