Dr Who-Whong WANG Dr Timothy SHUEN Dr See Voon SEOW Dr Emma Kay RICHARDSON Chit Lai CHEE Charmaine TANEvelyn NATHALIA Gui Ping PHANG Hui Shi CHEONG Hui Min CHAI Janice LIM Joelle CHUA Lay Hoon LEE Lip Seng KOH Rebecca BA Rachael CHEONG Sabirah CHEN Siew Kuen HEW Xin LIU
Our laboratory focuses primarily on cancer immunology and immunotherapy for solid tumours, including better understanding their mechanisms of resistance and efficacy. Since the birth of our laboratory in 2001, we have been pursuing ever more efficacious immunotherapies for cancers to answer unmet medical needs, investigating into the underlying immune regulatory mechanisms within tumour microenvironment, and biomarkers for prediction of treatment efficacy. In particularly, our team has clocked over 20 years of cell and gene therapy R&D and clinical experience, establishing Singapore’s first systematic Cell and Cancer Immunotherapy Programme in solid tumours.
More specifically, we have developed clinical cell-based immunotherapeutic strategies, including dendritic cell vaccines and adoptive transfer of Epstein Barr Virus (EBV)-specific T cells, and completed cancer vaccine clinical trials against advanced colorectal cancer and nasopharyngeal carcinoma (NPC). Our phase II clinical trial of autologous EBV-specific T cell therapy following chemotherapy in 38 advanced NPC patients - showed encouraging clinical benefit and survival outcomes. This led to a close partnership with Singapore biotechnology company, Tessa Therapeutics Ltd, to embark on an FDA IND international multi-centre randomised phase III clinical trial in 330 NPC patients across 30 sites in 5 countries. For this pivotal trial, our team led the laying of its operational foundation, as well as providing clinical, scientific and technical guidance. Currently, we are analysing the biosamples collected from this phase III trial to validate the predictive biomarkers and correlative T cell receptor (TCR) clonality we discovered from the completed phase II trial. More recently, we had completed and published a first-in-human phase I trial of Ad-sig-hMUC-1/ecdCD40L cancer vaccine in epithelial cancers. Currently, a highly complex new clinical trial of autologous cancer neoantigen-targeting dendritic cell vaccine in 60 patients with liver cancer or colorectal liver metastasis, followed by comprehensive translational analyses, is underway. Besides this, development of a novel gamma-delta T (T) and other cellular immunotherapy strategies are also in progress. Our translational research area pivots on such immunotherapy clinical projects to identify predictive transcriptomic-based and cellular biomarkers using single-cell transcriptomics (scRNA-Seq), Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq), mass cytometry, spatial transcriptomics, and to investigate the functionality of the immune cells of interest and diversity of TCR using highly multiplexed secretome proteomics and single-cell TCR sequencing, etc.
Another key focus of our laboratory is to study the biology and identify novel treatment strategies against HCC, focusing on gaining a deeper understanding of the interaction between the tumour and the immune microenvironment including the study of novel immune checkpoints. GATA4, is a key transcription gene that we reported as central to oncogenesis when a copy of GATA4 is deleted. Our goal is to elucidate the biological pathways associated with GATA4 and its loss. In collaboration with A*STAR institutions including Genome Institute of Singapore (GIS), Singapore Immunology Network (SIgN), and Institute of Molecular & Cell Biology (IMCB), we have developed novel immunocompetent Gata4-deficiency liver cancer mouse models, novel humanised HCC mouse models, as well as uncovered key metabolic pathways related to HCC tumorigenesis. We have further identified the loss-of-GATA4 related tumour microenvironment changes and the potential mechanisms using combined scRNA-Seq and untargeted metabolomics, followed by comprehensive in vitro characterisation. The rational combination immunotherapy is currently being tested in the established preclinical models. Another focus area is the establishment of in vitro 3D systems including organoids to more deeply interrogate HCC biology and for therapeutic targeting.
In the past 5 years, we have been awarded more than five national grants to establish the in vitro and in vivo liver cancer models to delineate the molecular mechanisms of GATA4, to investigate the transcriptomics and immune heterogeneity in HCC, and to rationally design and test new combination immunotherapies for treatment in HCC. Besides HCC, we are also actively studying EBV-associated epithelial cancers, such as EBV-associated pulmonary lymphoepithelioma-like carcinoma (pLELC), in depth. We have been awarded the NMRC Open Fund – Large Collaborative Grant (OF-LCG) to support our national programme: the Virus-Induced Cancers: Translational Oncology Research and immunologY (VICTORY) consortium, with major emphases on translational biology, immunology and immunotherapy targeting of EBV, HPV, and HBV/HCV-related cancers.
Selected publications
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