Genetic chaos in tumours could predict responses to immunotherapy

Advanced bladder cancers have been shown to respond to a new immunotherapy drug when used as a patient’s first treatment, according to early clinical trial results presented at the world’s largest cancer conference. 

And patients with tumours carrying the most genetic faults may be most likely to benefit.

A similar pattern was also seen for certain bowel cancers that are generally more heavily mutated, researchers told the ASCO conference in Chicago. 

The first trial, run by scientists at New York University Langone Medical Center, offered a new immunotherapy drug called atezolizumab (Tecentriq) to people with advanced bladder cancer as their first treatment. 

A previous study from the team tested the drug in bladder cancer patients who had already had chemotherapy. Based on the findings, the US drug Food and Drugs Administration (FDA) fast-tracked approval of the drug for these patients.

Atezolizumab is part of a growing number of immunotherapy treatments called checkpoint inhibitors. It targets a molecule called PD-L1, which releases the ‘brakes’ on the body’s immune T cells, freeing them to target and kill cancer cells.

In the latest trial, the researchers found the drug shrank tumours in around a quarter of the 129 patients enrolled in the study. 

And 21 of those 28 patients whose tumours responded were still experiencing that benefit at the time the study’s results were analysed.

“Up to half of patients with advanced bladder cancer are too frail to receive the only known survival-prolonging treatment, cisplatin,” said Professor Arjun Vasant Balar, who led the study. “There is really no standard treatment for such patients.” 

“We are encouraged to see that atezolizumab immunotherapy may help address this major unmet need,” he added.

While a small number of patients (10-15%) experienced serious side effects from the drug, the researchers said that in the majority of cases it was ‘well tolerated’. They added that this may even be better than what patients experience with chemotherapy.

“Immunotherapy appears to be much easier to tolerate than chemotherapy, and this is especially important for elderly patients,” said Balar.

The researchers are now planning a larger study to test atezolizumab further as an up-front treatment for bladder cancer.

Dr Alan Worsley, senior science communication officer at Cancer Research UK, said that immunotherapy had ‘proven’ itself in generating striking responses in patients, but more work was needed to find out why some patients respond and others don’t.

“Immunotherapy has proven its great potential in treating, and possibly even curing, cancer patients who previously had very few options,” he said.

“The next challenge is to figure out which patients will benefit from these drugs and why.

“The only way we can address this challenge is to understand the underlying biology of the disease, and how these drugs work,” he added.

In a follow-up analysis to the bladder cancer trial, Dr Jonathan Rosenberg, from the Memorial Sloan Kettering Cancer Center in New York, showed that tumours carrying the most genetic faults – so-called ‘high mutational burden’ – responded best to immunotherapy. 

Rosenberg said that tumours with the most mutations in their DNA may be more likely to produce faulty molecules that the immune system can recognise and target. And this may result in the more favourable responses seen in their trial. 

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A similar pattern emerged from a second study that treated bowel cancer patients with a different immunotherapy drug called pembrolizumab (Keytruda). It targets a different checkpoint molecule called PD1. 

The trial included 53 bowel cancer patients that fell into one of two groups. 

The first included patients with tumours defined by the cells’ inability to repair certain forms of damage to their DNA. As a result of the defects, these bowel tumours have a particularly high mutational burden. 

The other group had tumours that were able to repair damaged DNA, and therefore had a lower mutational burden.

Dr Luis Diaz, from Johns Hopkins University in Baltimore, presented the results of the study showing that the only patients who responded to immunotherapy were those whose tumours carried defects in DNA repair. 

Two years on, almost two thirds of these patients have not seen their disease get any worse. 

Diaz said these responses were so striking that testing tumours for deficiencies in their ability repair damaged DNA could also predict if other types of cancer will respond to immunotherapy too. 

Cancer Research UK’s Dr Worsley said the next step was to test this in larger trials.

“Finding a potential marker that flags which patients are more likely to respond is crucial, and larger studies to test if the genetic chaos inside tumours is that marker are now needed,” he said.