Imagination and innovation tend to be overlooked when it comes to cancer treatment. Chemotherapy, radiotherapy and surgery are the first line treatments for many cancers and as a result most of the public are only ever exposed to these types of therapies. Others seem to think that cancer treatment is particularly crude, consisting of a recipe as follows: 1) administer toxic chemicals 2) hope for the best and make do with the side effects.

If there’s anything I try to portray through these posts is that cancer treatment is evolving, producing targeted therapies that can hone in on cancer cells and screening methods that are so incredibly specific that they can detect the presence of single proteins in the sea of molecules that is your blood.

So what’s new this time?

Stealthing Up a Virus

Viruses have often been the subject of sci-fi disaster movies, causing outbreaks of disease and ending the human race in a rather grim version of armageddon. Granted, some viruses are incredibly dangerous (the swine flu and bird flu epidemics being the most recent indications of this), however, as I have mentioned in a previous post regarding HIV, viruses have been seen as a potential therapeutic means for decades now as a form of “gene therapy” – targeting the genetic code of a cancer cell directly.

Imagine having the ability to correct a cancer cell by having a virus infect it and insert a gene of your choosing into the cells DNA. You may want to insert a working gene in order to replace a faulty one or perhaps a piece of genetic material that will interfere with the production of a mutated protein. This is essentially what gene therapy aims to do. Because of this, many studies have looked into the way in which viruses interact with cell surfaces, whether they can carry more than just genetic material and, in this case, how to protect viruses on their way to their target cells. The field has been rather stagnant in its progress for the past few years and it is not surprising when you see how much needs to be considered when selecting an appropriate virus, as indicated by the diagram below.

There are many different aspects of viruses that need to be considered before choosing one for gene therapy.
There are many different aspects of viruses that need to be considered before choosing one for gene therapy.

One of the biggest problems to date regarding viruses and cancer treatment is their lengthy list of restrictions. The viruses that are considered usable as potential therapies come in (mainly) 4 forms: retroviruses, adenoviruses, adeno-associated viruses and lentiviruses (a branch of retroviruses). Each have different storage capacities and material restrictions that prove to be advantageous or disadvantageous in certain circumstances.

For example, if you wanted to deliver the gene encoding for the human insulin receptor into a cell, you need to consider that the gene is 315,560 base pairs (~315kb) long. In this instance, it is impossible to use one of the 4 major types of viruses. On the other hand, if you wanted to transport the insulin protein gene itself, the length of the gene is 1,563 base pairs (~15kb) therefore an adenovirus would be the most suitable viral vector to use.

In this case, an adenovirus was used but not to transport a particular gene. The virus in question is an oncolytic virus i.e. one that kills cancer cells through its replication and bursting through the cell membrane.

Making Viruses Invisible

Another major disadvantage of viruses, and a feature that has proven to be the bane of viral therapy up until now, is the ability for viruses to elicit an immune response from its host. Naturally when an individual becomes infected with a virus, a chain of reactions occur within the body to alert the immune system to its presence, eventually leading to the destruction and disposal of the intruder virus. This is obviously a good thing, but in terms of gene therapy, producing an immune response is the LAST thing you want to do.

As the core concept of viral therapy is to deliver genes directly to cells, immunogenicity needs to be at an all time low for this to successfully occur. Certain techniques have tried to work around this issue such as injecting viruses directly into tumours or increasing the amount of viruses injected into a patient. Unfortunately direct injection isn’t always possible for most tumours and increasing the amount of viruses in the blood causes dangerous levels of the structures in the liver.

A recent study looked into the idea of “stealthing” viruses – coating the viruses in polymers to prevent recognition by the immune system. This combined with a radical new approach involving microbubbles resulted in an enhanced efficacy, tumour localisation and multiplication of the virus in breast cancer tumours in mouse models.

The technique relies upon the introduction of ultrasound waves towards the local tumour area(s) which allow the microbubbles to burst and release the virus. This way, only the viruses that have localised to the tumour sites will benefit from the shock waves produced.
The technique relies upon the introduction of ultrasound waves towards the local tumour area(s) which allow the microbubbles to burst and propel the virus further towards, or into, a tumour. This way, only the viruses that have localised to the tumour sites will benefit from the shock waves produced.

Ultrasound waves were used to cause inertial cavitation (bursting to you and me) of the microbubbles administered into the bloodstream along with the viruses in order to propel the viruses towards their tumour targets. As the ultrasound waves were targeted mainly toward tumour sites, the viruses could achieve better penetration into tumour tissue. Once the viruses reached their desired destinations, the acidic environment – which is often a characteristic of tumours – caused the viruses to shed their polymer coats, allowing them to proceed in the infection of tumour cells and subsequent multiplication within the tumour.

Bursting Your Bubble

The results from this study speak for themselves: enhanced circulation of the viruses by >50-fold due to avoidance of liver clearance provided by the polymer coating, increased tumour infection by >30-fold and a significant stunting of tumour growth along with increased survival of mouse models. Results like these show a remarkable effect from using such an unestablished and original idea.

There are some aspects of this treatment that need to be considered before claiming it to be a revolution in cancer treatment. The elimination of the virus once it has done it’s job or the fact that it stops growth of tumours rather than reducing tumour size are both areas that need to be addressed. That being said, there is definite potential in this treatment, especially in the case of metastases. The way in which ultrasound waves enhance viral penetration into tumours suggests it is a brilliant method for preventing growth of remote sites of the disease.

The treatment alone without the addition of ultrasound waves acts almost like standard chemotherapy – moving throughout the body to the furthest possible locations away from the primary tumour(s) in order to fish out any cancer cells that have migrated. Combine this with the ingenious polymer coating method and ultrasound waves and you have a persistent therapy that can infiltrate deep into tumours before its exponential concentration increase through natural replication.

Conclusion

Gene therapy has been suffering as of late through the lack of efficiency shown by the fragile structure of viruses. Although viruses may well strike you as a perfect means to transport something into the body, their lack of targeting potential has been a major disappointment for many scientists. On the other hand, there have been successes. The video below indicates the success of gene therapy in terms of correcting the immune system of individuals.

Whether gene therapy will successfully be used for treating cancer is anyone’s guess, but it is studies such as this one that reinvigorates interest in the method and may well hold the key to unlocking the true potential of viruses in cancer treatment.

Read more:

The viral stealthing article: Carlisle, R et al. “Enhanced Tumor Uptake and Penetration of Virotherapy Using Polymer Stealthing and Focused Ultrasound” (2013) Journal of the National Cancer Institute

Here is a direct link to the results from the experiment for a more in-depth look at the effect that a polymer-coated virus (PC-Ad) had versus that of a virus alone (Ad) on tumours in mice. DO NOT click if you are squeamish or do not want to see images of animals subject to testing.

Advertisements