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Cell Therapy and Cancer Vaccine

Research lead:​Prof Han Chong TOH
Research team:

​Dr Who-Whong WANG
Dr Timothy SHUEN
Dr See Voon SEOW
Chit Lai CHEE
Charmaine TAN
Gui Ping PHANG
Hui Min CHAI
Janice LIM
Joelle CHUA
Lay Hoon LEE
Lip Seng KOH
Rebecca BA
Rachael CHEONG
Sabirah CHEN
Siew Kuen HEW

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

  1. Wuestefeld A, Iakovleva V, Yap SXL, Ong ABL, Huang DQ, Shuen TWH, Toh HC, Dan YY, Zender L, Wuestefeld T. A Pro-Regenerative Environment Triggers Premalignant to Malignant Transformation of Senescent Hepatocytes. Cancer Res. 2023 Feb 3;83(3):428-440. doi: 10.1158/0008-5472.CAN-22-1477. PMID: 36449018; PMCID: PMC9896023. 
  2. Tan TJ, Ang WXG, Wang WW, Chong HS, Tan SH, Cheong R, Chia JW, Syn NL, Shuen WH, Ba R, Kaliaperumal N, Au B, Hopkins R, Li X, Tan AC, Seet AOL, Connolly JE, Arkachaisri T, Chew V, Lajam ABM, Guo D, Chew MZW, Wasser M, Kumar P, Albani S, Toh HC. A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma. Nat Commun. 2022 Oct 28;13(1):6453. doi: 10.1038/s41467-022-33834-4. PMID: 36307410; PMCID: PMC9616917. 
  3. Shuen TWH, Alunni-Fabbroni M, Öcal E, Malfertheiner P, Wildgruber M, Schinner R, Pech M, Benckert J, Sangro B, Kuhl C, Gasbarrini A, Chow PKH, Toh HC, Ricke J. Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial. Clin Cancer Res. 2022 Sep 1;28(17):3890-3901. doi: 10.1158/1078-0432.CCR-22-0569. PMID: 35763041; PMCID: PMC9433961. 
  4. Zhu AX, Abbas AR, de Galarreta MR, Guan Y, Lu S, Koeppen H, Zhang W, Hsu CH, He AR, Ryoo BY, Yau T, Kaseb AO, Burgoyne AM, Dayyani F, Spahn J, Verret W, Finn RS, Toh HC, Lujambio A, Wang Y. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 2022 Aug;28(8):1599-1611. doi: 10.1038/s41591-022-01868-2. Epub 2022 Jun 23. PMID: 35739268. 
  5. Nguyen PHD, Wasser M, Tan CT, Lim CJ, Lai HLH, Seow JJW, DasGupta R, Phua CZJ, Ma S, Yang J, Suthen SD, Tam WL, Lim TKH, Yeong J, Leow WQ, Pang YH, Soon G, Loh TJ, Wan WK, Chan CY, Cheow PC, Toh HC, Kow A, Dan YY, Kam JH, Iyer S, Madhavan K, Chung A, Bonney GK, Goh BKP, Fu N, Yu VC, Zhai W, Albani S, Chow PKH, Chew V. Trajectory of immune evasion and cancer progression in hepatocellular carcinoma. Nat Commun. 2022 Mar 17;13(1):1441. doi: 10.1038/s41467-022-29122-w. PMID: 35301339; PMCID: PMC8931110. 
  6. Suthen S, Lim CJ, Nguyen PHD, Dutertre CA, Lai HLH, Wasser M, Chua C, Lim TKH, Leow WQ, Loh TJ, Wan WK, Pang YH, Soon G, Cheow PC, Kam JH, Iyer S, Kow A, Tam WL, Shuen TWH, Toh HC, Dan YY, Bonney GK, Chan CY, Chung A, Goh BKP, Zhai W, Ginhoux F, Chow PKH, Albani S, Chew V. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology. 2022 Nov;76(5):1329-1344. doi: 10.1002/hep.32419. Epub 2022 Mar 17. PMID: 35184329. 
  7. Shuen TWH, Alunni-Fabbroni M, Öcal E, Malfertheiner P, Wildgruber M, Schinner R, Pech M, Benckert J, Sangro B, Kuhl C, Gasbarrini A, Chow PKH, Toh HC, Ricke J. Extracellular Vesicles May Predict Response to Radioembolization and Sorafenib Treatment in Advanced Hepatocellular Carcinoma: An Exploratory Analysis from the SORAMIC Trial. Clin Cancer Res. 2022 Sep 1;28(17):3890-3901. doi: 10.1158/1078-0432.CCR-22-0569. PMID: 35763041; PMCID: PMC9433961. 
  8. Tay RE, Richardson EK, Toh HC. Revisiting the role of CD4+ T cells in cancer immunotherapy-new insights into old paradigms. Cancer Gene Ther. 2021 Feb;28(1-2):5-17. doi: 10.1038/s41417-020-0183-x. Epub 2020 May 27. PMID: 32457487; PMCID: PMC7886651. 
  9. Han S, Shuen T, Wang WW, Nazim E, Toh HC. Tailoring precision immunotherapy: coming to a clinic soon? ESMO Open. 2020;5 Suppl 1(Suppl 1): e000631. doi: 10.1136/esmoopen-2019-000631. Epub 2020 Sep 30. PMID: 33558033; PMCID: PMC7046383. 
  10. Chong YC, Toh TB, Chan Z, Lin QXX, Thng DKH, Hooi L, Ding Z, Shuen T, Toh HC, Dan YY, Bonney GK, Zhou L, Chow P, Wang Y, Benoukraf T, Chow EK, Han W. 2020 Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression. Hepatol Commun. Jul 27;4(9):1362-1381. doi: 10.1002/hep4.1559. PMID: 32923839; PMCID: PMC7471427. 
  11. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745. PMID: 32402160. 
  12. Ding Z, Ericksen RE, Escande-Beillard N, Lee QY, Loh A, Denil S, Steckel M, Haegebarth A, Shuen T, Chow P, Toh HC, Reversade B, Gruenewald S, Han W. 2020. Metabolic pathway analyses identify proline biosynthesis pathway as a promoter of liver tumorigenesis. J Hepatol. 2020 Apr;72(4):725-735. doi: 10.1016/j.jhep.2019.10.026. Epub 2019 Nov 11. PMID: 31726117. 
  13. Hopkins R, Xiang W, Marlier D, Au VB, Ching Q, Wu LX, Guan R, Lee B, Chia WK, Wang WW, Wee J, Ng J, Cheong R, Han S, Chu A, Chee CL, Shuen T, Podinger M, Lezhava A, Toh HC^, Connolly JE^. Monocytic Myeloid-Derived Suppressor Cells Underpin Resistance to Adoptive T Cell Therapy in Nasopharyngeal Carcinoma. Mol Ther. 2021 Feb 3;29(2):734-743. doi: 10.1016/j.ymthe.2020.09.040. Epub 2020 Sep 30. PMID: 33038324; PMCID: PMC7854281. (^co-corresponding authors) 
  14. Ericksen RE, Lim SL, McDonnell E, Shuen T, Vadiveloo M, White PJ, Ding Z, Kwok R, Lee P, Radda GK, Toh HC, Hirschey MD, Han W. 2019. Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression. Cell Metab. 2019 May 7;29(5):1151-1165.e6. doi: 10.1016/j.cmet.2018.12.020. Epub 2019 Jan 17. PMID: 30661928; PMCID: PMC6506390. 
  15. Zhao Y, Shuen T, Toh TB, Chan XY, Liu M, Tan SY, Fan Y, Yang H, Lyer SG, Bonney GK, Loh E, Chang KTE, Tan TC, Zhai W, Chan JKY, Chow EK, Chee CE, Lee GH, Dan YY, Chow PK, Toh HC, Lim SG, Chen Q. 2018. Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy. Gut. 2018 Oct;67(10):1845-1854. doi: 10.1136/gutjnl-2017-315201. Epub 2018 Mar 30. PMID: 29602780; PMCID: PMC6145285. 
  16. Enane FO*, Shuen T*, Gu X, Quteba E, Przychodzen B, Makishima H, Bodo J, Ng J, Chee CL, Ba R, Seng Koh L, Lim J, Cheong R, Teo M, Hu Z, Ng KP, Maciejewski J, Radivoyevitch T, Chung A, Ooi LL, Tan YM, Cheow PC, Chow P, Chan CY, Lim KH, Yerian L, Hsi E, Toh HC^, Saunthararajah Y^. 2017. GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition. J Clin Invest. 2017 Sep 1;127(9):3527-3542. doi: 10.1172/JCI93488. Epub 2017 Jul 31. PMID: 28758902; PMCID: PMC5669578. (*co-first authors, ^co-corresponding authors) 
  17. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC, Gorbunova V, Eskens FA, Qian J, McKee MD, Ricker JL, Carlson DM, El-Nowiem S. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015 Jan 10;33(2):172-9. doi: 10.1200/JCO.2013.54.3298. Epub 2014 Dec 8. Erratum in: J Clin Oncol. 2017 Aug 1;35(22):2590. PMID: 25488963; PMCID: PMC4279237. 
  18. Bard-Chapeau EA, Nguyen AT, Rust AG, Sayadi A, Lee P, Chua BQ, New LS, de Jong J, Ward JM, Chin CK, Chew V, Toh HC, Abastado JP, Benoukraf T, Soong R, Bard FA, Dupuy AJ, Johnson RL, Radda GK, Chan EC, Wessels LF, Adams DJ, Jenkins NA, Copeland NG. Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model. Nat Genet. 2014 Jan;46(1):24-32. doi: 10.1038/ng.2847. Epub 2013 Dec 8. PMID: 24316982; PMCID: PMC4131144. 
  19. Chia WK, Teo M, Wang WW, Lee B, Ang SF, Tai WM, Chee CL, Ng J, Kan R, Lim WT, Tan SH, Ong WS, Cheung YB, Tan EH, Connolly JE, Gottschalk S, Toh HC. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther. 2014 Jan;22(1):132-9. doi: 10.1038/mt.2013.242. Epub 2013 Oct 17. PMID: 24297049; PMCID: PMC3978790. 
  20. Chia WK, Wang WW, Teo M, Tai WM, Lim WT, Tan EH, Leong SS, Sun L, Chen JJ, Gottschalk S, Toh HC. A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. Ann Oncol. 2012 Apr;23(4):997-1005. doi: 10.1093/annonc/mdr341. Epub 2011 Aug 4. PMID: 21821548; PMCID: PMC3314324. 
  21. Chia WK, Ali R, Toh HC. Aspirin as adjuvant therapy for colorectal cancer--reinterpreting paradigms. Nat Rev Clin Oncol. 2012 Oct;9(10):561-70. doi: 10.1038/nrclinonc.2012.137. Epub 2012 Aug 21. PMID: 22910681. 
  22. Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, Loh M, Bolze A, Quek R, Lee VK, Lee KH, Abastado JP, Toh HC^, Nardin A^. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol. 2010 Mar;52(3):370-9. doi: 10.1016/j.jhep.2009.07.013. Epub 2009 Aug 3. PMID: 19720422. (^co-corresponding authors) 
  23. Toh HC, Wang WW, Chia WK, Kvistborg P, Sun L, Teo K, Phoon YP, Soe Y, Tan SH, Hee SW, Foo KF, Ong S, Koo WH, Zocca MB, Claesson MH. Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients. Clin Cancer Res. 2009 Dec 15;15(24):7726-7736. doi: 10.1158/1078-0432.CCR-09-1537. PMID: 19996212.