Friendly Infections: An Introduction to Oncolytic Viruses
Cancer is one of the hardest diseases to treat - mostly because it has a special ability. Over time, a tumour will develop and grow into blood vessels. After gaining access to veins and arteries, cancer cells now have access to the most important highway in the human body: the circulatory system.
A malignant cell will ride through the circulatory system and park itself in an area with typically slower blood flow (such as an organ). After stopping, it will then plant itself and grow as a secondary tumour. The worst part is that this process occurs multiple times- over and over.
This is known as metastasis.
When a patient’s imaging results show signs of metastases, their cancer is staged as Stage 4.
The reason why it’s so hard to treat is that tracking and removing metastases is near impossible right now. Even if visible tumours are targeted, there could be dozens of travelling malignant cells in the human body, some of which may have already seeded in another organ.
It’s difficult to target something you can’t see- and this is where traditional cancer treatment fails.
How Cancer is Normally Treated
Chemotherapy and radiation are known to be the ‘nuclear missiles’ of cancer treatment. Types of chemotherapy such as alkylating agents are effective as they inhibit cell division in typically faster dividing cells (such as malignant ones). Chemotherapy doesn’t have a GPS of any kind installed. This means they target ALL fast-dividing cells including cells in bone marrow, and causes hair to fall.
While it gets the job done and shrinks cancer efficiently it damages other healthy cells. Damaging the cells in the bone marrow can also cause leukaemia, bringing in a new problem while trying to treat a different one.
It is for this reason that scientists are working to hone targeted therapies such as CAR-T cell therapy which would only attack malignant cells, not healthy ones. These antibodies are the police officers of the human body, they hunt down the cancerous cells (the bad guys!!)
One of the newest forms of targeted therapies being researched is oncolytic viruses, which infect and kill only tumour cells. If CAR-T cell therapy represents the police force of the body, then these viruses are much like capos hunting down people that owe their boss money.
The Basics of a Virus
Viruses are very very small — and are made of proteins and one nucleic acid. They cannot replicate on their own because they lack the other necessary organelles such as ribosomes and mitochondria to create ATP. Their strategy? Get someone else to do the work for them.
The most aggressive form of viral replication is the lytic cycle.
1: The virion (an individual infectious particle) enters a host cell, by either injecting itself into the cell, tricking the cell membrane into letting it in, or fusing with the membrane. This depends on the virus.
2: The virion hijacks the cell's organelles and gets the ribosomes, mitochondria, and other parts to start creating parts for the virus- not other cells. The individual parts will be made and left to float around within the cell.
3: The individual parts of the virions will self assemble to create a new, fully functional copy of the original virus.
4: This process within the cell continues until it cannot hold the virus particles and bursts in a process known as lysis- which releases the inner parts of the cell as well as more copies of the virus.
Key point: Lytic viruses destroy the cells they infect in the process of self-replication.
Fighting Cancer
Your cells have MHC class 1 molecule inside them that bind to any foreign proteins and express them on the surface for T-Cells to recognize and kill. These molecules are underexpressed in cancer molecules- which allows it to hide in plain sight from the immune system. Luckily, there is another way to get the body to fight cancer- by causing the cells to burst open in the process of lysis.
When a cancer cell bursts due to viral replication, it releases its inner contents including antigens. These act as markers that tell the immune system that the body has been infected and that something doesn’t belong- such as malignant cells.
When a B-Cell with the right randomly generated receptor finds this stray antigen and binds to it, it then absorbs it and presents it on its surface on an MHC 2 molecule to a CD4(+) T-Cell, waiting for one with a compatible receptor to find it.
When one is found and binding happens, both lymphocytes are activated and the memory B and T cells produce more lymphocytes with the compatible receptor to the antigen to stay in your body forever in case the same infection occurs again.
Additionally, the T-Cells will signal for more effector T-Cells to rush to the site and destroy any other cells displaying the antigen on their surface.
This process means that viruses would fight tumours in two ways:
- By causing tumour cells to lyse, slowly shrinking the tumour. As more virions are released, more cells are infected, therefore more of them lyse.
- By activating the immune system, and getting T-Cells to actively hunt any malignant cells displaying antigens on their surface- including metastatic cells! While the immune system will also fight the virus, it attracts attention to the antigens from the malignant cells as well and starts working to fight off tumours as well.
Controlling Viruses/ Becoming a Mafia Boss
We now know how viruses work, and how they can effectively fight cancer cells. We just need to know how to get them to work FOR US and target only cancer cells.
Normally, viruses replicate uncontrollably, destroying cells until the immune system kicks in and releases cytotoxic factors to kill the virions and any infected cells.
The goal of targeted therapy is to harm only cancer cells and leave healthy ones alone. To get a virus to replicate solely within malignant cells, scientists use genetic engineering.
The Food and Drug Administration approved the first oncolytic virus treatment Talimogene Laherparepvec (T-VEC) which is a modified strain of the herpes simplex virus (HSV-1)- which was chosen for its lytic properties and a large amount of space in its genome for deletions and insertions.
Editing HSV-1
In 2018, scientists at the University of Alabama detailed the specific genes they edited to result in the T-VEC treatment:
- To eliminate the viruses ability to cause disease to the nervous system (neurovirulence), both copies of the y134.5 gene was deleted. Without the gene, HSV can no longer replicate in healthy cells- but can do so in cancer cells as cancer cells’ mutations decrease their ability to guard against infection.
- The ICP47 gene is deleted to increase the loading on interior antigens onto MHC class 1 molecule which allows antigens to be presented on the surface of the cancer cell (including those of the tumour!!!). This step also makes sure the virus itself cannot evade the immune system.
- Inserting two copies of the GM-CSF gene, which produces a glycoprotein that stimulates stem cells to produce more white blood cells to increase the immune system response and inflammation
These three edits, plus a few more primed the HSV virus to target only cancer cells, and do so effectively. They also rendered the herpes simplex virus unharmful. Scientists are now looking into using polio and other viruses with large genomes as well.
Herpes was favourable not only because of its large genome and lytic properties but also because of its response to antiviral medication- which makes it a safer option to experiment with and test on people.
A Weapon for Good
The most interesting part about oncolytic viruses is its wide range of applications.
Glioblastomas are one of the most deadly tumours- with most patients only surviving for only an average of 15 months after diagnoses. Most treatment options such as radiation and surgery are ineffective as they damage other cells in the brain as well- reducing a person’s quality of life permanently.
Imagine treating a brain tumour without even touching it 🤯.
The use of oncolytic viruses in patients with glioblastomas would mean healthy brain cells would be left unharmed and only cancer cells would be targeted and lysed. Additionally, the immune system would also help in shrinking the tumour as well without causing long term brain damage.
The viruses could also infect metastasized cells! As the virus circulates through the body, it would also encounter and infect other malignant cells regardless of location. This could change the face of late-stage cancer.
The T-VEC treatment is already used to treat late-stage melanoma- but could be applied to a range of other cancers to improve remission rates and possibly even prevent cancers from returning!
Quick Recap
💡 Metastasis is one of the hardest issues to tackle- it complicates cancer treatments and reduces survival rates.
💥 Cancer treatments such as chemotherapy harm healthy cells as well! Treatments that are targeted will improve patient quality of life and recovery!!
🧬 Viruses can be genetically edited to target only cancer cells, and to decrease harmful effects on humans.
🔑 Oncolytic viruses fight cancer by causing individual malignant cells to burst, and also stimulates an immune response against the tumour antigens.
🦠 Oncolytic viruses show promise in patient trials, and the FDA has already released T-VEC to treat late-stage melanoma. However, it could also be used to treat other solid tumours.
Hi! I’m a 16-year-old who loves learning about stem cells, cancer, and other biology-related topics! I’d love to talk: okanlomotatyana@gmail.com
