Immune cells may become ‘exhausted’ during immunotherapy

​Specialised immune cells can become ‘exhausted’ following immunotherapy to treat cancer, limiting the treatment’s effectiveness in some people, according to a US study.  

Immunotherapies called ‘checkpoint inhibitors’ work by boosting immune cells’ ability to fight tumours and infections like HIV, malaria, and hepatitis C.

The drugs block molecules on the surface of the specialised cells – called T cells – that dampen down immune reactions. 

One of these molecules, called PD-1, normally helps to protect healthy tissue from damage by over-active immune cells. But cancer cells can bypass these molecular ‘brakes’ to hide from the immune system.  

Immunotherapies that block PD-1 cause T cells to attack cancer, but the researchers at the University of Pennsylvania in the US found that this re-invigoration is temporary, and the T cells become exhausted and stop doing their job.

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• What are ‘checkpoint’ immunotherapy drugs?

Dr Santiago Zelenay, an expert in the immune system from the Cancer Research UK Manchester Institute, said: “This study analysing T cells – the immune cells boosted by immunotherapies – may help to explain why some patients fail on these treatments. 

“Understanding why T cells become exhausted could lead to new combination approaches to stop them becoming fatigued in this way.

“Immunotherapies have made a big impact on cancer therapy in recent years. Those based on immune checkpoint blockade are typically to patients given long-term. 

“But, some patients experienced long lasting responses, and even cures, with just a few courses of treatment, so there are still big gaps in our knowledge of how they work.”

There are different types of T cells, each with its own skills. Memory T cells are more long-lasting and can kick-start an effective immune response years later.  

But the study, published in the journal Science, found that immunotherapy did not turn the T cells into memory T cells.

The researchers say the next steps will be finding out if there are ways of combining immunotherapies with other treatments that reprogram the exhausted T cells.

Dr Alison Taylor, a Cancer Research UK expert in immunotherapy from the University of Leeds, said that the combination approach may prove promising, as it has with other cancer drugs.

“A cocktail of different drugs to stimulate an immune attack on cancer might be more potent than giving people single immunotherapies,” she said. 

“The interesting detail in this study is uncovering the precise effect checkpoint inhibitors have on T cells and how long this effect lasts. 

“Studies like this that deepen our understanding of immunotherapies will help scientists discover more effective ways to use these treatments and combine them with other types of therapy.”