Singapore, 17 May 2022 – A research team from Singapore has identified novel biomarkers that not only predict a patient’s response to immunotherapy, but also the adverse events they may experience from the same immunotherapy used to treat primary liver cancer hepatocellular carcinoma (HCC). These findings, published in the Journal of Hepatology in April 2022, should enable more effective and individualised treatment of HCC patients, with fewer side effects.
Liver cancer is highly prevalent in Asian populations, especially in Southeast Asia, China, Korea and Japan. In Singapore, it is the fourth most common cancer and the third leading cause of cancer mortality for men. With the high incidence of this disease in the region, finding effective treatments for HCC is an urgent need. Personalised medicine is a promising approach for HCC treatment, matching specific therapies to patients to ensure effective treatment with minimal toxicity. Biomarkers, which are unique mutated nucleic acid sequences or proteins associated with a particular cancer type, can indicate the likelihood of developing cancer, diagnose the cancer, predict therapeutic benefit and prognosticate cancer development in a patient.
Using a personalised medicine approach, a team of researchers and clinicians from the National Cancer Centre Singapore (NCCS) and SingHealth’s Translational Immunology Institute (TII) uncovered mechanisms of response and adverse events from the type of immunotherapy known as immune checkpoint blockade used to treat HCC patients. Recent phase III clinical trials of the anti-PD-1 immune checkpoint blockade nivolumab and pembrolizumab achieved a respective 15% or 18.3% overall response rate for patients with advanced HCC. However, about 20% of these patients experienced treatment-induced immune-related adverse events such as skin toxicities, hepatitis, thyroid dysfunction and colitis. Additional studies showed that combining anti-PD-1 and another immune checkpoint blockade, anti-CTLA4 or an anti-angiogenesis drug, anti-VEGF, improved response by up to 31% but with an increased incidence of adverse events.
To improve and predict response rates to immune checkpoint blockade therapy, the team studied 61 HCC patients from NCCS and Asan Medical Center in South Korea who received anti-PD-1 immune checkpoint blockade – intravenous nivolumab or pembrolizumab. The patients’ blood samples were collected at baseline, before the study began, and during treatment. Samples were analysed using advanced single-cell analyses such as Cytometry by time of flight (CyTOF) and single-cell RNA sequencing.
From the analysis, the team identified two novel biomarkers: CD11c+HLADRhi antigen-presenting cells (APCs) and CXCR3+CD8+ effector memory T cells (TEM) that could predict response to the anti-PD1 immune checkpoint blockade. In addition to the initial discovery, the team discovered that one of the novel biomarkers (CXCR3+CD8+ TEM cells), contributed both to patients’ response and the incidence of adverse events from immune checkpoint blockade. This provides valuable insight into the interface between a patient’s response and side effects to the therapy.
“While other studies have explored biomarkers for response to immune checkpoint blockade, ours is the first that found a biomarker that contributed to both the responses and adverse events resulting from the immunotherapy,” said Dr Valerie Chew, a principal investigator in TII and co-senior author of the study. "This allowed us to examine this biomarker further and determine if there was a way to enhance therapeutic response and, at the same time, prevent adverse events.”
Based on their findings, the team proposed and tested a new immunotherapy combination for HCC in a preclinical mouse model. This novel treatment combined anti-PD-1 and anti-TNFR2, blocking a communication pathway that uncoupled the response from adverse events. This allowed enhanced response to immune checkpoint blockade without aggravating adverse events.
“We are excited that our findings have presented a novel treatment pathway, and are now exploring this combination and aim to bring this new therapy to patients with primary liver cancer,” said Clinical Associate Professor David Tai, Senior Consultant, Division of Medical Oncology, NCCS and co-senior author of this study.
This study is supported by the National Research Foundation, Singapore (NRF) under its Open Fund – Large Collaborative Grant (NMRC/OFLCG/003/2018) and Translational and Clinical Research (TCR) Flagship Programme (NMRC/TCR/015-NCC/2016), which are administered by the Singapore Ministry of Health (MOH)'s National Medical Research Council (NMRC). It is also supported by MOH’s NMRC under its Singapore Translational Research Investigator Award (NMRC/STaR/0020/2014) and Clinician Scientist Award (NMRC/CSA-SI/0013/2017 & NMRC/CSA-SI/0018/2017).
Study citation: Chuah, S., Lee, J., Song, Y., Kim, H.-D., Wasser, M., Kaya, N. A., Bang, K., Lee, Y. J., Jeon, S. H., Suthen, S., A'Azman, S., Gien, G., Lim, C. J., Chua, C., Hazirah, S. N., Lee, H. K., Lim, J. Q., Lim, T. K. H., Yeong, J., … Chew, V. (2022). Uncoupling immune trajectories of response and adverse events from anti-PD-1 Immunotherapy in hepatocellular carcinoma. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2022.03.039
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About the National Cancer Centre Singapore
The National Cancer Centre Singapore (NCCS) is a leading national and regional tertiary cancer centre with specialists who are experts in treating cancer. NCCS attends to the majority of cancer cases in Singapore's public healthcare sector. In addition to offering holistic and multidisciplinary oncology care, our clinicians and scientists collaborate with local and international partners to conduct robust, cutting-edge clinical and translational research. To achieve the vision of being a global leading cancer centre, NCCS offers world-class care and shares its depth of experience and expertise by training local and overseas medical professionals.
To meet growing needs, the new NCCS building will be completed in 2022 with increased capacity and expanded facilities dedicated to cancer care, rehabilitation, research and education. To give patients the best treatment outcomes, NCCS will offer access to advanced and innovative treatment such as proton therapy at the new Goh Cheng Liang Proton Therapy Centre.
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