Can Viruses Be Our Biggest Allies in the Fight Against Cancer?
Oncolytic Virus Therapy
Note: This is part 4 of my article series on cancer immunotherapy and covers the basic science behind cancer-killing (or oncolytic) viruses and how they might change the immunotherapy space forever.
If you don’t have prior exposure or understanding of how the immune system works or what immune checkpoint blockade therapies are, check out part 1 in the series where I go over the basics of the human immune system, and then come back to continue reading this article! If you want to read more about other immunotherapies, check out part 3 of this series where I cover tumor-infiltrating lymphocytes.
We humans seem to hate viruses quite a bit don’t we? I mean, to be fair one is responsible for the pandemic currently ravaging the world, and there have been countless viruses in the past that have caused similar large scale chaos.
But those viruses make up just a very very tiny fraction of all the viruses that exist on the planet. According to Nature Reviews Microbiology, there are 1 × 10³¹ (10 nonillion) viruses on the planet, which greatly outnumbers the number of stars in the known universe (1 × 10²¹) to the point that 10 BILLION viruses could be assigned to each star. Now, all of these aren’t different types, but there are still millions of species of viruses, out of which only a measly 7000 or so have been fully analyzed and described by humans.
We can simply consider all of these viruses as enemies and leave it at that, developing all sorts of therapeutic agents to kill as many of them as possible. Or… we can try to use these brilliant subcellular killing machines to our advantage and expand medicine far beyond what is currently possible. The correct choice is quite obvious, isn’t it?
Basics of Oncolytic Virus Therapy
One approach taking advantage of viruses that is heavily being researched right now is oncolytic virus therapy (OVT). Oncolytic viruses (OVs) are simply viruses designed to target and kill cancer cells in the body, and they’re being recruited largely because of their host specificity.
Infecting a cell requires that cell to possess the receptors that can bind the proteins on the surface of the virus. So, if a cell does not possess the necessary receptors, the virus is unable to infect it. This is why, for example, the HIV virus can only infect helper T cells, even though the blood has a huge variety of different cell types including red blood cells and other white blood cells.
When developing therapies designed to kill cells, it is crucial to ensure that only cancer cells are killed, whereas healthy cells sustain as little damage as possible. This is the major concern with common cancer therapies today. Even with the care used when administering chemotherapies or radiation therapies, a lot of damage is inflicted to healthy cells around the tumor, and in some cases, this cellular damage can spawn new cancer cells that grow into entirely new tumors.
Now, to understand how exactly the virus is able to eliminate tumors once it has infected cancer cells, we first need to review the life cycle of a virus.
The Viral Life Cycle
The life cycle consists of five main phases: attachment, penetration, biosynthesis, maturation, and release.
During attachment, the virus binds to specific surface receptors on the host cell. For example, the SARS-CoV-2 virus has spike proteins on its surface that bind to ACE2 receptors on respiratory epithelial cells.
Following the binding with the receptor, the virus is taken into the cell via either receptor-mediated endocytosis or by membrane fusion. In receptor-mediated endocytosis, the binding of viral proteins to cell-surface receptors causes the cell membrane to surround the virus and form a bubble (aka vesicle) that then enters the cell. During membrane fusion, on the other hand, the plasma membrane of the virus fuses with the membrane of the cell itself, releasing its contents (the protein capsid with the viral genome) into the cell. This phase is referred to as penetration.
The exact nature of the biosynthesis phase is dependent on the kind of genetic material the virus possesses, which could be double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), double-stranded RNA (dsRNA), or single-stranded RNA (ssRNA). However, at a basic level, this phase consists of copying the genome of the virus as well as producing the proteins encoded by the viral genome which serve as the components of the viral capsid itself.
During maturation, new virions are formed by assembling the proteins into the capsid around the copies of the viral genome. Following this phase, the cell is filled with new, fully assembled virions ready to be released and infect new hosts.
Finally, the lysis phase refers to the bursting of the cell (which could be due to a variety of different processes) that releases all the new virions into the extracellular space, so that they can continue the cycle of infecting new hosts and replicating themselves.
Mechanism of Action
One important mechanism which makes viruses an amazing option for immunotherapy is their method of inducing cell death. Normally, cells can undergo a process of apoptosis, where the cell releases enzymes within its cytoplasm that simply digest the cell, without releasing almost any material into the extracellular space. However, viruses induce what is called immunogenic cell death (ICD), in which the endoplasmic reticulum releases three metabolites, collectively referred to as damage-associated molecular patterns (DAMPs), into the extracellular space. These metabolites are: calreticulin, ATP, and HMGB1. Further, tumor-associated antigens from the cell are also released into the extracellular space.
Dendritic cells (DCs) patrolling in the tissue can recognize these metabolites and antigens, and stimulate an appropriate immune response. Via this mechanism, OVs overcome the mechanisms cancer cells use to become “invisible” to the immune system.
Along with this, as I covered in the article about the basics of the immune system, cytotoxic T-cells also serve the function of protecting against viral infections by finding and killing cells infected with viruses. This process is also recruited as the cancer cells begin to display the foreign antigens of the OV on their surface, leading to the cytotoxic T-cell-mediated tumor cell lysis.
Cancer-Specific Viruses
Getting a virus to proliferate inside the targeted cancer cells isn’t the big challenge, since cancer cells possess weaker protection mechanisms against viral infections. The major challenge of the oncolytic viral therapy arises in developing viruses that replicate & undergo the viral life cycle only in cancer cells, ignoring normal cells of the same type. To achieve this, two strategies have been explored: selecting viruses that are non-virulent in humans & genetically engineering the virus.
Strategy 1: Non-Virulent Viruses
A prime example of the first strategy is Reolysin (aka Pelareorep), which is a reovirus (double-stranded RNA virus). Reolysin is capable of cancer-specific function since it can replicate only in cells that display activated Ras signaling, which is characteristic of many cancers. Phase I studies have demonstrated that it was safe and that it displayed anti-cancer activity in prostate cancer, malignant glioma, metastatic colorectal cancer, multiple myeloma, and other solid cancers. A recent study by Oncolytics Biotech, the company developing Reolysin, also demonstrated that the joint-administration of Reolysin with Kyprolis (a proteosome inhibitor → prevents cancer cells from recycling damaged or misfolded proteins that may be toxic to the cell) elicited a strong inflammatory and anti-cancer response.
In 2015, the FDA granted Reolysin designation as an orphan drug, which means that it targets a medical condition that is so rare that it would not be profitable to produce without government support.
Strategy 2: Genetically Edited Viruses
Genetically editing the virus is a much better strategy to gain strict control of viral replication, limiting it to cancer cells. There are several viruses that fall under this type, and many more are being researched & developed right now. Two such promising viruses, T-Vec & G47Δ, are discussed here.
T-Vec is an HSV-1 virus with deletions in the γ34.5 & α47 genes, and the insertion of the human GM-CSF (granulocyte-macrophage colony-stimulating factor) gene into the γ34.5 locus. γ34.5 prevents the host cell from shutting off protein production when infected, so without a functioning copy of the gene, T-Vec can‘t replicate inside normal host cells. However, many cancer cells lack the shut-off response, so even without γ34.5, T-Vec OVs can still replicate in those tumor cells. Meanwhile, the deletion in the α47 gene allows early expression of the neighboring US11 gene, which enhances viral replication. Finally, the insertion of GM-CSF is supposed to enhance antitumor immunity induction, but whether it does in fact achieve this function is still unknown. In previous clinical studies on breast cancers, head & neck cancers, gastrointestinal cancers, and malignant melanomas, T-Vec has contributed to tumor necrosis in many, and resulted in stable disease progression in others.
G47Δ is an OV derived from G207, a second generation HSV-1 virus that tends to be much safer. Like T-Vec, G47Δ also has mutations in the γ34.5 and α47 genes, but it also has an insertion of the E. coli LacZ gene to inactivate the ICP6 gene. ICP6 encodes the large subunit of a molecule called ribonucleotide reductase (RR) that enhances viral synthesis, so inactivating ICP6 ensures that G47Δ can only replicate in cancer cells that already have sufficient levels of RR expression. G47Δ has shown high efficacy in almost all in vivo solid tumors tested, including glioma, breast cancer, prostate cancer, and colorectal cancer, and also killed cancer stem cells derived from human glioblastoma very efficiently.
Major Limitations
Despite how promising the field is, there are some limitations/disadvantages that OVTs carry and needs to be dealt with to increase its impact on as many cancer patients as possible.
The first: viral specificity. If we are not entirely sure that OVs will only replicate in cancer cells, they become somewhat of a risky bet. I mean, no one wants to use OVs to treat their cancer only to find out that their body is now suffering from a full-fledged viral infection. But, research in this area looks promising, and OVs are becoming increasingly specific to cancer cells.
Another limitation is the fact that not every tissue is accessible/suitable for this therapy. For example, cancers in the brain cannot be targeted using OVT since the blood-brain barrier prevents infiltration by large number of molecules and cells. Similarly, some viruses need to be delivered/injected right at the site of the tumor instead of into the blood, but in many cases, the tumor itself is inaccessible or there may be metastases that are missed. To counteract this, more and more research is being done into viruses that can carry out their function via intravenous (into blood stream) injection. But, this is where we run into another problem.
Neutralizing antibodies circulating in the blood may be able to recognize and neutralize the OVs before they can make their way to the tumor. One strategy to counteract this that is being explored is to extract the host cancer cells, infect them with the virus in vitro, and then once again return the infected host cells into the tumor, where the virus can begin proliferation without ever having to deal with antibodies. But, once again, this can become difficult for tumors that are hard to reach.
There are also a host of other smaller limitations that are currently being tackled, but I have no doubt that all of the limitations, including the major ones above, can be worked around as research in the field advances. And based on the pace of research, the future of OVTs is certainly looking promising.
I previously wrote an article on such a topic where I discussed the use of phage therapy to fight superbugs (bacteria resistant to even the strongest antibiotics), so check it out if you’re interested in reading more about how we can use viruses to our advantage.
But that’s all from me for now! If you’re interested in finding out more about what I’m passionate about and what I’m working on, check out my website and follow me on Twitter. Also, to keep up with my growth and progress, make sure you subscribe to my newsletter here. See you next article!
