Why some cancer drugs don't always work

Checkpoint Inhibitor Drugs

The body's immune system is constantly tracking down the presence of tumour cells and tissue. This is normal anti-tumour activity. In around two thirds of patients there is a poor response to the cancer drugs known as immunotherapy 'checkpoint inhibitors' and until recently the cause has been unknown. However, a team from the Technical University of Munich (TUM) have now identified an inactive receptor in cancer cells, which prevents the drugs from reactivating the immune system.

Reactivating the Immune System

Immunotherapies would normally enable the immune system to fight the cancer, but the inactive receptor prevents this from happening. The team explain how an overactive immune system can be nearly as dangerous as an inactive one if the subsequent inflammation attacks normal as well as cancer tissue. To counter this, the normal immune system has what are known as 'checkpoint molecules', which, when switched on, act like a brake on the immune system. However, cancer cells can exploit this mechanism: by switching on their checkpoint molecules, they are able to elude attacks by the immune system. The weakened immune response that results is then no longer robust enough to fight off the cancer cells.

A new approach to cancer therapy therefore involves the use of drugs known as checkpoint inhibitors. These substances release the “brake” applied by cancer cells, thus restoring the immune system’s ability to combat cancer. Checkpoint inhibitors are already being used successfully in skin cancer and many other malignancies.

The RIG-I receptor is a key factor

Dr. Simon Heidegger explains, “Unfortunately, checkpoint inhibitors aren’t effective in all patients. Thanks to our recent study, we now understand why that is the case in some forms of cancer, and using experimental approaches, we have even been able to reverse the situation,” says researcher in Medical Unit III at TUM’s university hospital rechts der Isar and lead author of the paper published in Science Immunology.

Human skin cancer samples confirm the findings

The team studied around 450 tissue samples from skin cancer patients to retroactively determine what effect RIG-I activity in the patients’ cancer cells had on their survival. In cases where RIG-I was active, the patients lived significantly longer despite their cancer. The team showed in 20 tested individuals that such patients also responded better to treatment with checkpoint inhibitors.

The researchers now plan to confirm their findings in large-scale trials on patients. “We hope to be able to use RIG-I as a marker as well for predicting how well a patient is likely to respond to therapy. This would avoid unnecessary treatments,” says Heidegger. In addition, they plan to test drugs that activate the RIG-I signal pathway in other mouse models and to investigate the effects of additionally administered checkpoint inhibitors.

Picture Credit (top) © Andreas Heddergott / TU Muenchen

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