Lung cancer

Tumour aneuploidy guides personalised RT and ICI cancer therapy

Dr Sean Pitroda

Tumour aneuploidy is the key to successful combined treatment with radiation therapy (RT) and immune checkpoint inhibitors (ICI) in non-small cell lung cancer, a US study suggests.

In a Nature Cancer paper (link), University of Chicago researchers have proposed tumour aneuploidy as a biomarker and therapeutic target in personalising treatment because it predicts response to the radiation therapy and ICI treatment combination.

In a study involving 37 patients with metastatic NSCLC, those with high tumour aneuploidy were found to have significantly better survival if RT was added to ICI. By contrast, there was no survival benefit for patients with low aneuploidy when adding RT to ICI treatment.

The researchers, led by Dr Sean Pitroda, Assistant Professor of Radiation and Cellular Oncology at UChicago Medicine, also showed that benefits were achieved in patients who received concurrent radiotherapy and ICI, but not in those who received sequential therapies.

Dr Pitroda said analysis of tumour tissue before and during treatment showed radiation therapy alone was less effective in tumour cell elimination as compared to simultaneous radiation and immunotherapy.

“Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response,” the study authors said.

Radiation therapy alone decreased intratumoural cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICI upregulated key immune pathways.

Combined therapy also improved elimination of tumour cells that led to positive survival outcomes in metastatic NSCLC patients.

“By giving immunotherapy with radiation, we believe that radiation becomes more effective at killing tumour cells by helping immune cells find the damaged tumour that’s dying off,” he said.

“Our findings highlight that radiation therapy alone is not enough to trigger a localised immune response in mNSCLC and the timing of radiation and immunotherapy is critical to this process,” said Dr Pitroda.

The research team previously developed an algorithm that quantifies the degree of aneuploidy in patients’ tumours when they undergo DNA sequencing. They then developed the hypothesis that perhaps aneuploidy could be useful in determining which tumours might respond better to immunotherapy.

Based on their initial findings, the team further tested whether aneuploidy could have utility as a biomarker for predicting survival in another study published in Nature Genetics, (link) where a larger cohort consisting of 1,660 patients with a wide range of cancer types who have been treated with immune checkpoint blockers were re-analysed.

Tumours with a high degree of aneuploidy had a worse prognosis because these patients did not respond to immunotherapy alone. In addition, tumour aneuploidy complemented tumour mutational burden (TMB) – an established biomarker across many cancers for immunotherapy response. Patients with high TMB often respond well to immunotherapy, and patients with low TMB usually do not.

“We have the first method to personalise therapy – to choose the right therapy for the right patient at the right time – employing radiation and immunotherapy,” said Dr Pitroda.

“For low TMB tumours, you look for another biomarker, like aneuploidy, to improve your prediction of immunotherapy response. The ones that have the worst survival after immunotherapy are the ones that have low TMB and high aneuploidy scores and those are probably the patients that need something more than immunotherapy, like radiation, to improve their treatment response and outcomes,” he said.

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