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Let's beat cancer sooner

Our researchers are looking at ways to make blood cancer treatments last longer. Flickr/CC BY-NC-ND 2.0

Inside our bodies lives an inbuilt army against disease – the immune system. And it’s not just bugs and germs that it can fight off; immune cells can help tackle tumours too.

That’s why researchers are attempting to rally these cellular troops to treat cancer, and some significant advances have been made over the years.

But there’s room for improvement. And the latest research from our scientists may reveal a new way to tap into the power of this system and boost a type of immunotherapy.

The drug rituximab (Mabthera) lends the immune system a lethal helping hand in destroying certain types of lymphomas and leukaemias, substantially improving the outlook for many patients.

If this could be developed into a treatment for patients, then it might help stop their cancer from returning

– Dr Eleanor Cheadle, University of Manchester

But patients often see their cancer come back, which is why better treatments are needed that can provide longer-lasting effects. A drug called obinutuzumab (Gazyvaro) is a step towards that goal.

Developed from rituximab, this immunotherapy drug has proven to be even more effective than its predecessor and has been approved as a treatment for some leukaemia patients.

Now, a new study led by our researchers at the University of Manchester, may have found a way to make it even better.

The team used a second drug to give the immune systems of mice with lymphoma an extra kick into action. And not only did this boost the effects of obinutuzumab, it also made those effects last longer.

“Combining these two different treatments generated an enhanced and long-term anti-cancer effect,” says Dr Eleanor Cheadle, lead author of the study published in the journal Leukemia.

“So if this could be developed into a treatment for patients, then it might help stop their cancer from returning.”

A common target

Rituximab and obinutuzumab are both a type of treatment called an antibody therapy. Antibodies are molecules produced by the immune system that lock on to a particular target, such as molecules on the surface of viruses or cancer cells. Think of antibodies as the handcuffs to the immune system’s patrolling police force.

When the antibody takes hold of its target, immune cells flood the scene and assist in destroying the target. The cells typically do this either by gobbling up the enemy tumour cell or killing it directly.

Our lab is looking to stimulate these responses to cancer cells so that the disease can’t come back

– Dr Eleanor Cheadle, University of Manchester

In the case of rituximab and obinutuzumab, the target is a molecule called CD20. It’s found on the surface of lymphoma and leukaemia cells that develop when a type of immune cell called a B cell becomes faulty and grows out of control.

Although these drugs can launch an effective attack against the cancer cells, they don’t always stop the disease from returning. That’s largely thought to be because they don’t alert an important group of specialised immune cells called T cells to the scene.

“T cell responses are long-lived and give our bodies memory of prior encounters with harmful cells to prevent future threats to our health,” Cheadle says.

“Our lab is looking to stimulate these responses to cancer cells so that the disease can’t come back.”

Remembering the enemy

For their study, led by Cancer Research UK scientist Professor Tim Illidge, the researchers turned their attention to an immune system molecule called TLR7, which sits inside immune cells.

T cell

T cells are important fighters against disease. Credit: NIAID/NIH (public domain), via Wikimedia Commons

“TLR molecules stick to bits of bacteria and viruses, triggering the activation of immune cells to help get rid of the invader,” explains Cheadle.

“In the case of TLR7, it generates T cell responses that clear the virus but also remember the attack.”

The team wondered whether switching on TLR7 in cancer could help the immune system remember the disease, offering long-term protection.

The team treated mice with lymphoma with either obinutuzumab on its own, a TLR7-activating drug called R848, or the two combined.

While the individual drugs boosted survival, combining them helped the mice live even longer. Importantly, when the researchers gave the treated mice a dose of lymphoma cells at a later stage, those given the duo of drugs didn’t develop cancer.

“The fact that the mice were protected from developing lymphoma again shows that the drugs could produce a memory response,” Cheadle says.

Natural born killers

Looking closer at the immune systems of the mice, the researchers found that the TLR7-activating drug helped switch on 2 different types of T cells, named after the specific molecules found on their surface – CD4 and CD8 cells.

To further probe their roles, the team reduced the levels of these cells while repeating the previous experiments. This revealed that CD4 cells were important in destroying the tumour, but both types of cell were needed to give the lasting ‘memory’ of the cancer.

Going one step further, the researchers also tested how lowering the levels of another type of tumour-attacking immune cell, called a Natural Killer (NK) cell, affected the response. This reduced the anti-tumour effects of the drug combination, suggesting the cells work alongside CD4 cells to fight the cancer.

But how precisely are they doing this?

“We think that R848 is activating NK cells and allowing them to stick to the antibody drug,” says Cheadle.

“When this happens, the NK cells release toxic molecules that kill the tumour cell. R848 seems to be priming the NK cells so that they’re more effective at this process.”

A fighting chance

Pooling these results together, the study suggests it may be possible to generate similar immune memories in patients treated with antibody therapies. Potentially, Cheadle says, not just in leukaemias and lymphomas, but also other types of cancer in which antibody therapies work in a similar way as the CD20-targeting drugs.

But for now that’s a distant goal. R848 can’t be given to patients in the same way as it was given to the mice in this study, because it would cause severe side effects.

Our goal is to develop a treatment that triggers CD8 cells to help clear the tumour, while also creating a lasting memory of the cancer

– Dr Eleanor Cheadle, University of Manchester

That said, drug companies are in the process of developing newer drugs that could also turn TLR7 on, according to Cheadle. If successful, perhaps these could be tested in combination with antibody therapies in cancer patients.

In the meantime, the research group are looking at ways of further boosting CD8 T cells.

“We showed we could activate these cells, but the response wasn’t very strong,” says Cheadle.

And the stronger the response, she explains, the less likely a patient’s disease is to come back.

“So our goal is to develop a treatment that triggers CD8 cells to help clear the tumour, while also creating a lasting memory of the cancer. Because that will give us the best chance of a cure.”

Justine

Cheadle, E. J. et al. (2017). A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells. Leukemia. doi: 10.1038/leu.2016.352

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