Over several decades, we’ve taken huge strides in the race to cure cancer. Among recent scientific triumphs are immunotherapies—drugs that boost the body’s immune system, unleashing its power to fight tumours.
Still, for many patients with cancer, it’s a roll of the dice whether such treatments work. Of those with hepatocellular carcinoma (HCC)—the commonest form of liver cancer—only some respond well to immune checkpoint inhibitors (ICI), a type of immunotherapy that keeps tumour-killing immune cells from ‘turning off’ too early when fighting cancers.
Researchers still don’t know why people respond differently to ICIs. However, if clinicians had a tool that could at least predict those responses, it could significantly improve outcomes in this vulnerable population, said Julian Goggi, Principal Investigator at A*STAR’s Institute of Bioengineering and Bioimaging (IBB).
“Accurately stratifying patients by their response to ICI treatment is especially important in HCC, where many have existing chronic viral liver infections or scarring,” explained Goggi.
If clinicians can tell early that a patient isn’t responding to an ICI, they can quickly move on to trying other treatments. Unfortunately, many biomarkers that do help predict ICI response in other cancer types—such as microsatellite instability (MSI) and tumour mutational burden (TMB)—don’t work as well for HCC, which suppresses the immune system in a way that interferes with those indicators.
Goggi, who leads the Isotopic Molecular Imaging Laboratory (IMIL), hypothesised that radioactive molecules could help provide an unprecedented look at tumour dynamics in HCC patients. Previous studies had shown immune cells boosted by ICIs often release unique enzymes; if these could be ‘tagged’ with radioactive molecules, they might allow clinicians to ’see’ if the ICIs were successfully taking effect in a patient.
Working with researchers from the National University of Singapore (NUS), Goggi and the IBB team developed a radiolabelled peptide that would attach to granzyme B, an enzyme released by tumour-killing immune cells, as a way of measuring their activity in the liver. Since Granzyme B is only produced by living cells that are actively killing tumours, its presence could be a positive predictor that a patient with HCC would respond to ICI.
Through non-invasive positron emission tomography (PET) imaging, the researchers found that in mice with HCC which were treated with ICIs, the radiolabelled peptides—and therefore, granzyme B—visibly built up in tumours that were heavily infiltrated with immune cells such as natural killer (NK) cells. Mice with higher granzyme B activity also showed better responses to the ICI treatment, which triggered an influx of tumour-suppressing immune cell activity.
According to Goggi, the study’s results point to granzyme B as a promising target for diagnostic tools to stratify ICI responses in patients with HCC. Radiolabelled markers aimed at granzyme B could be also useful for other types of tumours that, like HCC, involve immune-suppressed environments.
“New, improved versions of our granzyme B peptide-based radiopharmaceutical have been discovered and are being developed for first-in-human clinical trials in Singapore,” said Goggi, adding that an invention disclosure has been filed for their work. The team is continuing to explore how the biomarker could be used to improve care for those living with HCC.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Bioengineering and Bioimaging (IBB) and the Singapore Immunology Network (SIgN).
