Epstein-Barr virus and the immune system – are cures in sight?

The fourth post in our Cancer and Infections series is a continuation of the Epstein-Barr virus (EBV) story. From its remarkable discovery 50 years ago, we’ve continued to fund research in this area that has led to pioneering new treatments for some EBV-linked cancers.

In this post we take a look at how scientists untangled the complicated relationship between EBV and our immune system and what happens when the virus goes unchecked. We’ll then delve into how this foundation of knowledge is building towards new ways to tackle EBV-driven cancers.

Stealth tactics

The remarkable thing about EBV, as a virus, is its understated success. Around nine out of 10 adults carry the virus, making it one of the commonest human viral infections around.

If caught as a child, EBV normally causes no symptoms at all. Catching it later in life can also be symptom-free, although some people get quite ill for a short while with glandular fever before the immune system kicks into action.

But the virus has a card up its sleeve.

Unlike most infections, it isn’t conquered by the immune response. Instead it waves a white flag and retreats into hiding, lurking inside B cells – a type of white blood cell in the immune system.

This works to the virus’s advantage in the long run. As long as our immune defences are intact, the virus quietly persists under the radar, spreading from person to person, without us even knowing it’s there.

But there’s a darker side to EBV infection, as we explored in our last post. There are an estimated 200,000 cancers caused by the virus across the world every year, including lymphomas, nasopharyngeal cancers, and some stomach cancers.

After many years of detailed research, scientists are starting to understand why EBV causes cancer in only a small minority of the vast number of infected people, and how it leads to different types of cancers and affects different age groups and populations across the world.

Understanding the way our immune system responds to EBV and keeps the virus at bay has turned out to be a crucial piece of the puzzle, and it’s leading to new ways to tackle these cancers.

And just as the story of the discovery of EBV had a hefty dose of serendipity, a couple of chance medical observations revealed the battle ground between EBV and our immune system.

When our defences are breached

One of the first clues came from some of the earliest people to receive human organ transplants, which became commonplace in the 1960s.

A decade later, doctors noticed that there were a worrying number of patients developing cancer after their transplant – primarily skin cancers, but commonly lymphomas too (coined post-transplant lymphoma).

The link to EBV was founded on a chance encounter in a lift. EBV expert, Dorothy Crawford, overheard a conversation between transplant surgeons discussing how to treat one of their patients who had developed post-transplant lymphoma.

She suspected EBV may be playing a role in the lymphomas and had been searching for samples to test, and suddenly the opportunity fell into her lap. The surgeons agreed to send her a sample from their patient – and, sure enough, all of the tumour cells tested positive for EBV.

Soon more samples were examined, and the link between EBV and post-transplantation lymphomas was confirmed.

The next intriguing piece of the puzzle turned up in the 80s, from within the gay community in San Francisco.

A new sexually transmitted infection had broken out, which we now know to be HIV, leading to AIDS. Many young men were hospitalised with infections such as pneumonia, but some had certain types of cancer including lymphomas that resembled ‘post transplant’ lymphomas.

These cancers were nearly all positive when tested for EBV too.

The discoveries raised big questions. Why were EBV-positive lymphomas so frequently affecting patients receiving organ transplants and young adults with AIDS? And what did these groups of people have in common?

The answer is a huge loss in the strength of their immune system. In the case of people receiving donor organs, they are given powerful drugs to suppress their immune reactions to stop them rejecting the organs.

Patients with AIDS lose a crucial part of their immune system, as the HIV virus destroys important white blood cells called T cells.

The pieces fall into place

Around the same time, scientists in Cambridge made a huge breakthrough.

In 1984 they published the complete DNA sequence of EBV. This meant scientists were able to identify the key proteins made by the virus that pushed B cells to grow out of control and become cancerous.

Combining this knowledge with the new understanding of the role played by our immune system helped untangle the complicated relationships.

EBV-linked cancers develop due to a combination of factors but they share one thing in common – a swing in the delicate balance between the body and the virus. We now know that the ability of our immune defences to keep the virus in check is one of the crucial barriers stopping cancers forming.

The lack of a robust immune defence against EBV (caused by drugs, disease, or small variations in genes that mean immune cells are less able to spot EBV) allows the normally timid virus to run riot. Then the proteins made by the virus instruct cells to keep dividing – the principle cause of cancer.

From knowledge comes treatments

Gathering interesting scientific knowledge is all very well, but what patients want are cures. The next step was to turn this information into new treatments for people with EBV-related cancers.

The idea seemed simple – if gaps in the immune system were causing the cancer to develop, could we turn the tables and use the immune system to strike back at the cancers?

In 1995, pioneering scientist Cliona Rooney working in the US showed that this approach held promise, while she was working at a clinic giving children with leukaemia life-saving bone marrow transplants.

To stop the donor’s bone marrow attacking the child’s tissue, the doctors removed T cells first.

But while the treatment helped to cure their leukaemia, it left the children at high risk of developing EBV-related lymphoma.

To bridge the gap, Rooney and her team rescued the T cells removed from the donor marrow and separated out the ones that could specifically attack EBV. They then grew these ‘EBV killer T cells’ in the lab until they had sufficient numbers to inject into the children following their transplant.

The results were remarkable.

The 10 children she initially treated responded well – none had any problems caused by the donor’s T cells, and the three children whose EBV levels had shot up regained control of their infections.

One child had already developed a post-transplant lymphoma, but the EBV killer cells attacked and destroyed the tumour without needing any other treatment.

As with many early experimental therapies, Rooney’s new treatment had practical drawbacks, principally that it took a lot of time and money to make personalised EBV killer T cells from every individual donor.

The next step came from Cancer Research UK-funded scientist Dorothy Crawford, who first linked EBV with post-transplant lymphomas back in 1980.

She set up a large bank of EBV killer T cells taken from people donating blood and began a large clinical trial matching them to post-transplant patients to see if they could treat the lymphomas caused by EBV. The results were published in 2007, showing that more than half of patients who had developed lymphomas were completely cured.

This pioneering technique is now available for post-transplant patients with EBV-linked lymphomas.

Most patients are successfully treated by lowering the dose of immune suppressing drugs or a therapy that destroys B cells called rituximab. But for those who don’t respond the EBV killer T cells are a crucial avenue of treatment.

There’s much more to come

Following Rooney and Crawford’s ground-breaking research, scientists and doctors are now exploring whether the EBV killer T cells could also be manipulated to treat people with other EBV-linked cancers, such as nasopharyngeal cancer and lymphomas.

And there is another exciting approach in the pipeline – vaccines, both as a treatment and a preventive measure.

Our researchers in Birmingham are leading a clinical trial to find out whether a vaccine designed to boost the anti-EBV immune response of patients with nasopharyngeal cancer is an effective treatment.

The vaccine acts as a sharp reminder to the immune cells that the cancer cells infected with EBV are dangerous and should be destroyed.

So far, early results show that the vaccine is safe and can stimulate the patients’ white blood cells to attack their tumours, so the trial is continuing to the next stage. If it proves successful, the vaccine could also be used to treat people with other types of EBV-linked cancers.

Other Cancer Research UK scientists in Birmingham are working hard in the lab to find out whether a vaccine could be developed as a preventative measure to stop people catching EBV. Vaccinating people at high risk from EBV-linked cancers, such as children in sub-Saharan Africa, to stop them becoming infected in the first place could make a big impact on cancer rates around the world.

Professor Alan Rickinson, a leading expert in EBV research and one of our pioneering team in Birmingham, has seen much of the progress unfold and is optimistic we are working towards cures.

“Looking back over 50 years of research, one thing that really stands out for me is the journey we’ve come on,” he said. “From people’s scepticism of Epstein’s initial discovery that there was a link to Burkitt’s lymphoma, to where we are now – the realisation that EBV plays a key role in several cancers and an understanding of how the virus does this.”

“Thanks to all this research, we’re now moving towards the ultimate goal of being able to prevent EBV infection, potentially stopping many children and adults around the world from developing cancer.”

Despite all the work that’s gone on, the EBV story is far from finished, and we look forward to seeing the fruits of this groundbreaking research making a difference to patients for the next 50 years and more.

Emma

Image credits: Stealth plane image, B cell image, microscopic virus image, T cell image and syringe image all from Wikimedia Commons