Oncolytic viruses to Treat Cancer. How oncolytic viruses kill cancer cells. Future of Biotech Keynote Speaker

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Oncolytic viruses could turn out to be the most important advance in cancer treatment for 30 years.  What are oncolytic viruses?  How do oncolytic viruses work?  How do oncolytic viruses kill cancer cells?  What is the future of oncolytic virus research?

Why use a virus to cure cancer?

Viruses are intelligent robots which can be taught to infect and control specific types of cells, while leaving the rest of the body untouched.

Most people think that viruses are living organisms like bacteria, but they are really just machines, each of which carries a small piece of genetic code. Genes are the language used to control the actions of every living cell, so when you add new genes to a cell, new things often start to happen.

If you have heard about nanotech, which is the science of building things from individual atoms, you could say that a virus is the ultimate nanobot, or microscopic robot.

How scientists discovered oncolytic viruses

Over 50 years ago, scientists noticed that people with some viral infections were sometimes cured of cancer in surprising ways.  They discovered that the viruses were able to kill cancer cells. These were called oncolytic viruses – onco means cancer, lytic means that cells burst open and die.

All these oncolytic viruses made people ill, so scientists tried to make new types of virus that would be less harmful to normal cells.

Then they made an extraordinary discovery:  almost all cancer cells in solid tumours work in similar ways.  They grow in an uncontrolled manner and lack all kinds of normal functions.  What if we could make a damaged virus, with useless genetic code, where the code only works if activated inside a cancer cell?

Today there are many different types of oncolytic viruses that have been altered from natural viruses in the laboratory, so that they kill cancer cells, while not damaging (many) normal cells.

To those who are outside the field, this simple fact is so shocking that it seems hard to believe, but it is absolutely true.

How do viruses work?

Every virus has three main structures (see picture), which assemble into something similar to a lunar landing craft.

1) Legs to attach to cells
2) Outer wall to protect the virus
3) Inner core containing genetic code

Viruses drift passively around the body, bumping into the surface of cells.  If the legs of the virus manage to latch onto the surface of a cell, the virus injects its payload of genetic code into the cell.

All the virus machinery, legs, outer wall and other elements, are then destroyed. Once inside the cell, the new genetic code is activated, and hijacks the normal function of the cell, turning it into a virus factory.

Eventually the cell becomes so full of viruses that it bursts, releasing hundreds or thousands of new viruses, each of which can then infect another cell.

Designing viruses to control cells

We can design viruses to deliver all kinds of different genes.  For example, we can make a virus that does not have any instructions to make new viruses, but simply inserts a missing gene into cells to correct a genetic defect.

Micro-dose radiotherapy

The trouble with traditional cancer treatments is that they tend to kill healthy dividing cells such as hair cells, gut lining and bone marrow, causing many side effects.  But there is a better way, in addition to the normal mechanism by which oncolytic viruses kill cancer cells.

We can teach cancer cells new tricks to kill them. For example, we can command them to extract a protein from the blood that has been made using radioactive iodine, so that each cell is killed by a tiny dose radiation, delivered inside the cell itself.  

As the cell dies, the iodine is released into the rest of the tumour, killing nearby cells that may not yet have been infected by the oncolytic virus.

Radioactive iodine is a safe treatment, with virtually no side effects, and has been used for many years for thyroid cancer cells, which naturally take up iodine.

Only a very small dose of Iodine needs to be injected, and the radioactivity halves every 8 days.  Most of it is rapidly lost from the body.  The treatment is designed to be harmless to normal tissue.

Micro-dose chemo

As most people with cancer know, chemotherapy is a very blunt instrument to kill cancer cells, whether given as a tablet, or as an injection or infusion.  Once in the blood, chemo hits all kinds of healthy cells as well.

But we can teach cancer cells how to release a tiny dose of powerful chemo agent inside each cell itself.

First we have to make a drug in two parts which is completely harmless until split open – a “pro-drug”.  Then we have to create a virus which infects only cancer cells and tells them to split open any pro-drug that enters the cell.

As soon as cancer cells have been infected with the new virus, the person is given a dose of pro-drug, which is carried around the body without any side effects, until it ends up inside cancer cells.  The pro-drug is split into two, toxic chemo is released, and the cell dies, releasing the chemo to kill nearby cancer cells as well.

Using white cells filled with virus to hit cancer growths

We can go further:  scientists have found ways to extract white cells from the blood, called macrophages, and to use them as delivery vehicles to take virus directly into the heart of tumour growths.

One problem with large cancers is that the centre of the cancer growth is often decaying, with poor blood supply, many tightly packed cancer cells, and low oxygen levels.  In these places, many cancer cells become very sleepy, so are not dividing very well.  Unfortunately that means they may escape being killed by radiotherapy or chemotherapy, since these only work when cells are actively dividing.

The good news is that macrophages are specially designed by the body to go and clean up dead or decaying tissue.  They are programmed to hunt for areas of low oxygen.  

Researchers can inject a person’s own macrophages back into their body after loading them up with virus.  The virus hides inside these white cells until the cells arrive at the heart of the cancer.  The viruses are then released right into the tumour.  This means we can :

1) Inject smaller doses of viruses into the blood
2) Protect them from being rapidly destroyed by the immune system
3) Deliver a concentrated dose into the tumour

Changing legs of viruses to latch onto specific cancer cells

Scientists can also change the legs of oncolytic viruses so that they are an exact fit to the surface of particular cells – for example breast cells, or prostate cells.  

Each cell has unique surface coatings, which can be recognized by viruses.  That is why, for example, a cold virus attacks nose cells and not bone cells, or why polio virus attacks nerve cells but not kidney cells.

The better the targeting, the fewer virus particles you have to inject into the blood to overcome and destroy the tumour, the lower the risk of an immune reaction which destroys the virus in the blood, and the lower the risk of side effects.

Using a range of viruses to prevent cancer or treat recurrence

If oncolytic viruses can be shown to be effective against a wide variety of cancer cells, when injected into a vein, with little or no side effects, then it raises the possibility that people with a very high risk of cancer could be injected on a regular, routine basis, to mop up any new cancer cells that may be in early stages of developing into a tumor mass.

It is likely that whatever virus was used would generate some kind of immune response after repeated injections, even if they only happened once or twice a year, which is one reason why many experts believe that doctors will need an armoury of many different types of oncolytic viruses.

Why use HSV type viruses to cure cancer – rather than others?

There are many different kinds of oncolytic viruses. How do you know which one to choose for research? Ideally it needs to have the following properties:

- Reproduces rapidly

Curing cancer is all about speed. Every treatment is a race against time: killing cells faster than they can reproduce.  So the faster a virus bursts cancer cells, the more likely the person will be cured.  HSV is one of the fastest to reproduce, with cells bursting just 18 hours after infection.

- Kills effectively

HSV is highly efficient at killing the cells it infects.

- Easy to work with

HSV is a very large virus – it has a big capsule, and is relatively easy to reprogramme.

- Easy to make

In expert hands, HSV can be made rapidly and easily in huge amounts.  Researchers can make enough Seprehvir (HSV-1716) to treat 20 million people in less than 4 weeks, in a laboratory the size of a Portacabin, with a manufacturing cost of less than £1 a dose.  Once made, HSV-1716 can be stored indefinitely at -80 degrees centigrade.

- High ratio of active to damaged viruses

HSV-1716 can be made very efficiently. Treatment vials may contain up to 1000 times more active viruses than with some other types of HSV used by other companies. That means less risk of immune reactions, less risk of side effects, more likely that treatments can be repeated.

- Large spare memory capacity

HSV has 30 kilobytes of spare “data storage”.  It contains long sequences of genetic code, which do not appear to have any useful function.  Scientists have been able to insert a wide variety of extra genes into this 30 kilobytes space without damaging the ability of the virus to infect cancer cells and replicate.

- Relatively harmless to humans

Around 80% of the population has been exposed in the past to HSV as part of normal living, of which a significant proportion carry active infection.  HSV produces cold sores, and is not dangerous in normal situations.

- Effective antiviral therapy exists

For many years, doctors have successfully used antivirals to treat HSV, so that in the very unlikely event that there was some kind of infection of normal cells, therapy is available.

- Long history of use of new types of HSV as oncolytics

HSV-1716 (Seprehvir) was the first oncolytic HSV to be used, and was first created over 30 years ago.  The first human trials were conducted over 12 years ago, which resulted in the first cures of cancer in humans anywhere in the world, using oncolytic viruses.

- No significant side effects seen so far

In all clinical studies so far there has not been a single “dose-limiting event” in any person.  This is extraordinary when you consider how serious side effects have stopped most new chemotherapy trials from continuing. Over 80 people have safely received various doses of HSV-1716.  The worst side effect we have seen in one or two people (which may possibly be related to the virus) is mild flu-like symptoms for about 24 hours.

- Considered safe to inject directly into a vein

Cancer specialists need a “magic bullet” which can be injected into a vein in a clinic or at home, rather than injecting direct into a tumour using highly technical equipment in an operating theatre.

HSV-1716 can be injected into veins. How safe is this? It is one thing to inject a small amount of virus directly into a cancer in an adult.  Quite another to inject a larger number of viruses directly into the bloodstream of a child with cancer.  The FDA in America is renowned for being one of the strictest regulators in the world in drug safety, and has approved intravenous injections of children with cancer, with HSV-1716, after reviewing all the results of different safety studies over the last 12 years

- Can be combined with chemotherapy

The ideal oncolytic virus can be combined with other treatments, whether radiotherapy or chemo, so that the patient can chose to try to gain an additional benefit, hopefully a simple treatment without any side effects for them, without the risk of missing out on benefits from existing treatment options.

HSV-1716 has been tested in the laboratory against a very wide range of commonly used chemotherapies, and a number of the most promising new chemotherapies likely to reach the market soon.  In many cases the impact on the cancer is greater than the impact of either chemo or of virus alone.  Indeed, scientists have often seen an amplifying effect or synergy.  

In simple terms an additive effect is where 1+1 = 2.  Synergy or amplification is where 1+1 = >2 .

"The oncolytic virus story sounds too good to be true"

It is right to view any claims for progress in cancer treatment with the utmost caution.  Large numbers of such claims have been debunked over the last 30 years, with many drugs failing to produce promised results in large scale clinical trials, or turning out to be too dangerous to use.

However, set against that is the fact that the genetic revolution is upon us.  While the digital revolution has the power to change how we communicate, the genetic revolution has the power to change the very nature of life itself.

It took many billions of dollars to decode the first person’s entire genetic code.  Yet just a few years later, scientists have developed a process that is likely to do the same for less than $10,000 in less than a day.

Scientists are able to cut and paste gene fragments from one organism into another in an automated process that is becoming as routine as cutting and pasting text using Microsoft Word.

Researches have been able to map hundreds of human genes to different risks of disease, and the number of new avenues for gene-based medical research is growing dramatically every year.

In the light of all this, many gene experts would say that the real surprise looking back over the last decade or two, is how long it has taken for new gene-based treatments to really change health care.  While knowledge has doubled every 12 months, patient benefits have been few so far.

Parallel with how monoclonal antibodies developed

In the 1980s, many experts said that health care was entering a new age.  Scientists were learning rapidly about the immune system, how many illnesses were caused by our own immune defences, and how stimulating the immune system can help us stay well, or cure disease.

A key discovery was how to make huge quantities of antibodies in the laboratory, that could be injected into patients to attack infections or cancers.  It was a touch road with many disappointments over 20 years.  But today, up to 30% of all revenues of pharma companies in cancer therapy are from monoclonal antibodies, and their use has become a major part of cancer treatment.

Why this is a critical time for oncolytic viruses

Many oncolytic virus trials are now taking place, and safety data is looking good.  We have not yet seen a trial where side effects have been seen that required the trial to stop.  This is extraordinarily rare in any type of drug development and therefore very encouraging.

We need to remember that almost all research using oncolytics, is on patients with very advanced cancer, who have otherwise lost all hope of cure, and for whom some side effects is usually a small price to pay if the result is many months of extra symptom-free life.  So even if some significant side effects are found, it is very likely that oncolytics will still be used in cancer treatment if there is a significant effect on tumour growth.

Clinical trials have to go through three stages before a treatment can be approved for normal use.  Phase I is to look at safety.  Phase II is to see if there is evidence of impact.  Phase III is to show that in larger numbers of patients, there is clear benefit without undue risks.  For each kind of tumour, each Phase has to be conducted.

Many oncolytic viruses have completed successful Phase I and early Phase II trials in a growing number of different tumour types.  In all cases they have passed safety tests in Phase I, and in almost all cases where Phase II trials have been carried out, early results have shown that oncolytic viruses reproduce in the cancer being tested, with cancer cells being killed.

In January 2011, Amgen paid $1bn to buy an oncolytic virus (£0.5bn in cash, £0.5bn to come if successfully reaches market), after being impressed by response rates in people with melanoma. Research showed that after injecting a single melanoma nodule, all the other nodules shrank or disappeared in the same person.

In 2005, a weakly active oncolytic virus was approved for use to treat cancer patients in China.  In December 2012, Rheolysin was shown in early Phase III trials to increase response to chemotherapy by 28% in the first 6 weeks after treatment – in patients with head and neck cancers which are notoriously difficult to treat.

Amgen is due to report results on Phase III in melanoma in 2013.

At the same time, lab-based innovation in oncolytics is accelerating, with new research papers published every week showing important and encouraging new data on different types of virus, new additional genes, more animals cured of even wider range of cancer types.

"Why have I not heard about this before?"

While we are seeing increased numbers of media stories about oncolytic viruses, the fact is that most doctors, nurses and journalist have never heard of them.  And when they first hear about them, many can be tempted to dismiss the story because it sounds to them improbable, because of so many false hopes in the past.  They may also have a built in prejudice against the very idea of injecting a virus into people to cure cancer, when so many other types of viruse cause cancer.

Have live viruses been used successfully in medicine before?

Live viruses have been used by doctors to save lives for over 100 years.  Edward Jenner discovered in the 19th Century that farmers who milked cows were often protected against fatal epidemics of smallpox.  He soon realized that they had all suffered a mild illness previously called cowpox, which they caught because of their close contact with sick cows.  The outside coating of both viruses is so similar that immunity against cowpox is strong enough to prevent an attack of smallpox.

That is how vaccination was born – something we take for granted today.  Live cowpox virus has saved the lives of millions of people.  Another example is vaccine against polio.  Few people realize that the vaccine is highly infectious, as an altered version of natural polo virus.  Indeed, if you vaccinate 7 out of 10 children in a school, you will find that many of the other children will also become vaccinated as the vaccine virus spreads around the classroom.

What are media saying?

Journalists are waking up to oncolytic viruses – with regular reports on the BBC and other respected media including the Daily Telegraph and many others.

Trojan-horse therapy 'completely eliminates' (prostate) cancer in mice – BBC News 21/12/2012 citing: Macrophage Delivery of an Oncolytic Virus Abolishes Tumor Regrowth and Metastasis After Chemotherapy or Irradiation – Cancer Research Journal 11/2012 – UK research using Seprehvir

US HOT STOCKS: Oncolytics Biotech, Restoration Hardware, SolarCity – Wall Street Journal 13/12/2012

Small pox virus to treat breast cancer? - Times Of India 12/10/2012

Oncolytic Viruses in the Treatment of Bladder Cancer – Advances in Urology 29/07/2012

'Hitchhiking' anti-cancer viruses ride blood cells – BBC news 13/06/2012

Science goes viral – small step in fighting cancer is giant leap for mankind.  Financial Times 31/08/2012

A virus that kills cancer: the cure that's waiting – Daily Telegraph 31/08/2012

Viruses Recruited as Killers of Tumors – New York Times 19/03/2012

'Anti-cancer virus' shows promise – BBC News 31/08/2011

Possible new weapon in battle against brain tumours – Wall Street Journal 15/11/2011

Oncolytic Viruses: An Approved Product on the Horizon? Molecular Therapy (2010) 18 2, 233–234

Herpes virus used to treat cancer – BBC News 2/08/2010

Fighting cancer with oncolytic viruses – British Medical Journal 19/01/2006

Who is investing in oncolytics?

Most innovation in biotechnology is not happening in big pharma companies, but is being carried out in very small biotech startups.  And the same is true in oncolytics research.  Investors tend to be high net worth individuals, small investment funds, research foundations, academic institutions and venture capital companies.  Very few oncolytic companies are listed publicly.

For more on oncolytic virus research: 

http://en.wikipedia.org/wiki/Oncolytic_virus

http://www.virttu.com

List of published research papers on oncolytic virus HSV-1716 (Seprehvir)

Declaration of interest: after writing this article, the author became Chairman of Virttu Biologics Ltd.  The company was subsequently bought by Sorrento Therapeutics Inc in 2017.

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