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Vesicular stomatitis virus

Researchers used a harmless virus to smuggle DNA into the body.

We’ve previously written about immunotherapy– treatments that use the power of a patient’s own immune system to attack their disease.

On paper, immunotherapy looks like a sure-fire way to treat cancer – simply ‘train’ a patient’s immune system to recognise and destroy tumour cells, and nature will do the rest. However, clinical trials of various immunotherapy techniques have shown only modest benefits, with one or two high-profile exceptions.

But a paper from Cancer Research UK scientists and their UK and US colleagues, published in this week’s edition of the journal Nature Medicine, describes a completely new approach that could make a big difference to immunotherapy in the future.

In this case, the team used the technique to treat prostate cancer in mice, but it’s likely that the same technology could be applied to other types of cancer.

Here’s a short interview with one of the paper’s authors, Professor Alan Melcher from the Cancer Research UK Clinical Centre in Leeds, explaining more about the new results:

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Link to transcript

Creating cancer vaccines

At the moment, most immunotherapy techniques work by teaching a patient’s immune system to recognise certain individual molecules found in cancer cells.

One way of doing this is to use a therapeutic cancer vaccine.  Unlike prophylactic vaccines, which prevent you from getting an illness in the first place (such as those given to children or people travelling abroad), cancer vaccines are designed to stimulate a patient’s immune system to seek out and destroy cancerous cells, wherever they may be hiding.

There are several ways of doing this, but Professor Melcher and his colleagues are focusing on DNA vaccines, where a patient is injected with DNA containing the instructions telling cells to make a harmless protein found in cancer cells.

The patient then produces this protein in their body, and their immune system recognises it and starts making antibodies that attack it. But because the protein also exists in cancer cells, the immune system hunts them down too.

What’s so special about this new technique?

Most DNA cancer vaccines train the immune system to recognise either one or just a handful of proteins. But if the patient’s cancer cells aren’t producing any of them, then the vaccine won’t work – a problem for producing a vaccine that’s suitable for large numbers of cancer patients.

To get round this problem, Professor Melcher and his colleagues tried a different approach. Rather than making a vaccine out of DNA instructions for making just one or two proteins, they used thousands.

The researchers started with thousands of DNA fragments taken from normal prostate tissue, each of which was capable of making a single protein. To turn these fragments into a vaccine, the researchers packaged each of them up into a harmless virus called vesicular stomatitis virus (VSV).

Other researchers are currently developing VSV for use as a treatment for cancer, and similar viruses have already been tested in clinical trials, suggesting that it’s safe for use in patients – a head start for any potential treatment.

VSV is a handy way of smuggling DNA into the body, because it tends to infect cancer cells in preference to healthy tissue. And because the immune system is, under most circumstances, very good at recognising and attacking virus-infected cells, this increases the chances that it will be stimulated by the unusual DNA to go on the hunt for cancer cells.

Testing it out

First, the scientists needed to make sure their virus-based vaccine wouldn’t cause the immune system to start attacking healthy prostate tissue – something that would obviously be a bad thing for a potential cancer treatment.

The researchers vaccinated healthy mice and monitored the size of the animals’ prostates over time.  Although initially they saw an increase in prostate size, after several weeks they were the same as prostate glands from untreated animals, suggesting that there wasn’t a major immune response against healthy cells.

Next, they treated mice with prostate cancer with the modified virus and found that they survived longer than mice given normal, unmodified viruses.  And after nine injections of the DNA-packed virus, eight out of ten animals were cured.

The scientists also discovered that viruses packed with DNA from prostate cells didn’t work against skin tumours, showing that the DNA needs to come from the same tissue as the cancer to be effective.

Targeting recurring tumours

Although the vaccine was effective in treating 80 per cent of tumours, this means that it didn’t work for around 20 per cent of cases – in these instances, although the cancers initially shrank, the scientists found that they came back and grew aggressively.

To tackle this problem, the researchers generated a collection of DNA fragments from these resistant tumours, and put it into VSV viruses.  Then they treated mice with prostate tumours first with the virus containing DNA from normal prostate, then with VSV carrying DNA from the recurrent tumours.

The researchers discovered that the tumours recurred much more slowly in mice given the combination of vaccines than those given the normal DNA vaccine alone. And in some cases, the tumours never came back.

What does this mean for cancer patients?

Right now, this vaccine is a long way from being suitable for use in patients with prostate or any other type of cancer. More tests need to be done to confirm that the treatment is safe and effective.

For a start, the scientists don’t know exactly what sort of DNA would work best to stimulate the human immune system. And although the treatment didn’t cause big problems with the immune system attacking healthy tissue in mice, that’s no guarantee it won’t happen in humans.

But given those caveats, this is certainly an exciting piece of research that could change the direction of immunotherapy. Perhaps one day we’ll see ‘off the shelf’ DNA vaccines for many different types of cancer, generated using an approach like this.

We’ll be watching to see how this story develops over the coming years, and hope that it will soon translate into clinical trials and – ultimately – benefits for patients.

Kat

Reference
Kottke T et al (2011). Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nature medicine PMID: 21685898

Comments

Vera June 23, 2011

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