The immune system is naturally programmed to identify and fight off cancer cells. However, ‘cold’ tumours, such as hepatocellular carcinoma (HCC)—a form of liver cancer—either lack the signals that alert the immune system or create a suppressive environment that inhibits the immune response. This makes such tumours notoriously difficult to treat with therapies that depend on the immune system's natural cancer-fighting abilities.
To deal with the cold tumours seen in HCC, some experts are turning to Y90 radioembolisation: a treatment where radioactive beads are injected into the blood vessels that feed a tumour, with the goal of delivering targeted radiation therapy that avoids healthy liver tissue.
“Y90 radioembolisation can turn a tumour from ‘immune cold’ to ‘immune hot’ so that patients have a higher chance of benefiting from immunotherapy,” said Joe Yeong, a Group Leader at A*STAR’s Institute of Molecular and Cell Biology (IMCB). A recent Phase II clinical trial has corroborated the increased efficacy of this approach in HCC patients, Yeong added.
To spearhead efforts in enhancing the effectiveness of a combined immunotherapy (nivolumab) and Y90 radioembolisation treatment for treating HCC, Yeong worked with colleagues from A*STAR; the National Cancer Centre Singapore; Singapore General Hospital; National University of Singapore; University of Cologne, Germany; and Guangzhou International Bio Island, China.
Aiming to identify the patients that stand to benefit most from this therapeutic strategy, the researchers performed whole exome sequencing, RNA-sequencing and immunoassays on blood samples from 33 patients enrolled in the Phase II trial. They discovered that those with a higher tumour mutation burden and NCOR1 gene mutations, which influence gene regulation, were more likely to respond, as proven by robust inflammatory markers and a proliferation of immune cells such as macrophages.
Conversely, the patients for whom treatment was ineffective frequently showed chromosomal alterations and enhanced cellular growth processes, with many exhibiting Kaya_P2, a molecular signature specific to Asian genomes.
This led the team to hypothesise that the combination therapy's efficacy may vary across ethnicities. “We are working with an oncology group based in Spain to combine data from two clinical trials, allowing us to compare European and Asian cohorts to generate more convincing markers,” Yeong said.
Identifying these predictive markers offers a promising path to refining patient stratification and choosing more appropriate treatments, potentially doubling the response rate from immunotherapy alone to that achieved with the combination therapy.
“The next step is to add in longitudinal immune profiles or other biomarkers as we head towards a multi-omics era for personalised treatments against cancer,” said Yeong.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS), Bioinformatics Institute (BII), Institute of Molecular and Cell Biology (IMCB) and the Singapore Immunology Network (SIgN).
