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Antonio Bertoletti

Professor

Email

Contact: 66013574

Bio Research Publications

Antonio Bertoletti, MD is an expert in the field of viral hepatitis, with a specific interest in the immunopathogenesis of HBV infection. He began working in viral hepatitis as a medical student at the University of Parma (Italy). During his MD specialization (1991) in Infectious Diseases he spent two years at The Scripps Research Institute (La Jolla) characterizing for the first time the Hepatitis B virus (HBV) specific cytotoxic T cell response in man. He returned to the University of Parma, where he worked in the Department of Infectious Diseases as a Clinical Scientist continuing his study of human HBV specific T cells. Dr. Bertoletti then joined (1995) the MRC Unit in the Gambia, as Senior Immunologist, to study HIV-2 specific T cell Immunity before accepting a position of Senior Lecturer at “The UCL Institute of Hepatology” at University College of London (UK) (1997). 

In 2006 he moved to Singapore where he was the Director of Infection and Immunity Program at the Singapore Institute for Clinical Sciences (A*STAR) until 2013 before moving, as Full Professor, at the Emerging Viral Disease Program at Duke-NUS Medical School. He also maintains an Adjunct Position at the Singapore Immunology Network, (A*STAR). He won for two consecutive terms the Singapore Translational Research Awards (2013 and 2018).

In 2015 he founded Lion TCR Pte (http://liontcr.com), a biotech company developing immune-based treatments for virus-related cancers (HBV-HCC and EBV related malignancies) and chronic viral infections. This immune therapy utilizes T cell receptors engineered T cells targeting viral antigens express in cancer cells. The company has been the first to initiate and run clinical trials (Phase I and II) for the treatment of HBV-related HCC relapses in liver transplant patients and in primary HCC in Singapore and China. At present he is Chairman of the Board and major shareholder.

His current research is focus on the development of new immunological based therapies (TCR-redirected T cells) for the treatment of HBV chronic infection and Hepatocellular carcinoma and on the characterization of antiviral Immunity in chronic HBV patients. In the last 2 years, after the start of the COVID-19  pandemic, his laboratory has been actively involved in the characterization of SARS-COV2 specific T cell immune response (Le Bert et al, Nature 2020, 584: 457-62)  in COVID-19 and SARS convalescent and healthy individuals. 

 

Our laboratory focuses on understanding how HBV infection evades or triggers the host-immunity that causes viral control and/or liver inflammation.

These immune mechanisms are preferentially studied in patient’s samples directly (peripheral blood and liver biopsies), obtained with active collaborations with different clinical groups. We also utilize human-chimeric SCID mouse reconstituted with human hepatocytes and immune cells that mimics HBV infection.

Our major projects are focused on:

  • Adoptive T-cell Therapy
    • This focuses on TCR-redirected T cells that can recognize and target Hepatitis B virus in order to reconstitute HBV-specific Immunity in patients with chronic Hepatitis B or Hepatocellular Carcinoma (HCC). We are also working on ways to improve the efficacy of these engineered cells and the selection of the correct TCR for personalized treatment of HBV-related HCC patients. Understanding the liver microenvironment and how it affects the behavior of T-cell receptor engineered T cells is crucial in order for adoptive cell therapy approaches to be successful in the treatment of chronic HBV infection or related hepatocellular carcinoma. We have developed an imaging-based 3-dimensional microdevice assay in collaboration as a pre-clinical test bench to evaluate the functionality of engineered T cells in environments similar to that encountered during actual adoptive therapy.
  • 3-Dimensional Microfluidics Platform 
    • Adaptive immune response in HBV infection and how it might evolve and mature over time; this includes the humoral compartment in which the role of B-cells in HBV infection is relatively poorly understood, and cell-mediated immunity in which T-cells are important for anti-viral control. Understanding the mechanism of HBV vertical infection (mother to child) and the impact that HBV infection exert on the maturation of the host immune system.
  • Adaptive immune response in HBV infection and how it might evolve and mature over time; this includes the humoral compartment in which the role of B-cells in HBV infection is relatively poorly understood, and cell-mediated immunity in which T-cells are important for anti-viral control.
  • Understanding the mechanism of HBV vertical infection (mother to child) and the impact that HBV infection exert on the maturation of the host immune system

Selected Recent Publications (2020-22)


Challenges of CAR- and TCR-T cell-based therapy for chronic infections.
Bertoletti A, Tan AT . J Exp Med. 2020 May 4; 217(5):e20191663. doi: 10.1084/jem.20191663.PMID: 32163104 . Review.

Effects of Hepatitis B Surface Antigen on Virus-specific and Global T Cells in Patients With Chronic HBV infection. Le Bert N, Gill US, Hong M, Kunasegaran K, Tan DZM, Ahmad R, Cheng Y, Dutertre CA, Heinecke A, Rivino L, Tan A, Hansi NK, Zhang M, Xi S, Chong Y, Pflanz S, Newell EW, Kennedy PTF, Bertoletti A .Gastroenterology 2020 Apr 14:S0016-5085(20)30492-3. doi: 10.1053/j.gastro.2020.04.019.

SARS-CoV-2-specific T cell immunity in cases of Covid-19 and SARS, and uninfected controls.  Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng MHY, Lin M, Tan N, Linster M, Chia WN, Chen MI, Wang LF, Ooi EE, Kalimuddin S, Tambyah PA, Low JG, Tan YJ, Bertoletti A Nature. 2020 Jul 15. doi: 10.1038/s41586-020-2550.

Hepatitis Delta virus acts as an immunogenic adjuvant in Hepatitis B virus infected hepatocytes.  Tham CYL, Kah J, Tan AT, Volz T, Chia A, Giersch K , Ladiges Y, Loglio A, Borghi M, Sureau C,  Lampertico P,  Lütgehetmann M, Dandri M, Bertoletti A. Cell Rep Medicine, 2020; 1: 100060.

Immunosuppressive Drug Resistant Armored TCR T cells for immune-therapy of HCC in liver transplant patients. Hafezi M, Lin M, Chia A, Chua A, Ho ZZ, Fam R, Tan D, Aw J, Pavesi A, Krishnamoorthy TL, Chow WC, Chen W, Zhang Q, Wai LE, Koh S, Tan AT, Bertoletti A. Hepatology. 2020 Nov 29. doi: 10.1002/hep.31662.

Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients.  Tan AT, Linster M, Tan CW, Le Bert N, Chia WN, Kunasegaran K, Zhuang Y, Tham CYL, Chia A, Smith GJD, Young B, Kalimuddin S, Low JGH, Lye D, Wang LF, Bertoletti A. Cell Rep. 2021 Feb 9;34(6):108728. doi: 10.1016/j.celrep.2021.108728

Highly functional virus-specific cellular immune response in asymptomatic SARS- CoV-2 infection. Le Bert N, Clapham HE, Tan AT, Chia WN, Tham CYL, Lim JM, Kunasegaran K, Tan LWL, Dutertre CA, Shankar N, Lim JME, Sun LJ, Zahari M, Tun ZM, Kumar V, Lim BL, Lim SH, Chia A, Tan YJ, Tambyah PA, Kalimuddin S, Lye D, Low JGH, Wang LF, Wan WY, Hsu LY, Bertoletti A, Tam CC.  J Exp Med. 2021, 218. doi:10.1084/jem.20202617

Rapid measurement of SARS-CoV-2 spike T cells in whole blood from vaccinated and naturally infected individuals.Tan AT, Lim JME, Le Bert N, Kunasegaran K, ChiaA, Qui M, Tan N, Chia WN, de Alwis R, Ying D, Sim JXY, Ooi EE, Wang LF, Chen MC, Young BE, Hsu LY, Low JGH, Lye DC, Bertoletti A. J.Clin. Invest. 2021131(17).

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.  Swadling L, Diniz MO, Schmidt NM, Amin OE, Chandran A, Shaw E, Pade C, Gibbons JM, Le Bert N, Tan AT, Jeffery-Smith A, Tan C, Tham CYL, Kucykowicz S, Aidoo-Micah G, J Rosenheim J, Davies J, Johnson M, Jensen MP, Joy G, McCoy LE, Valdes AM, Chain BM, Goldblatt D, Altmann DM, Boyton RJ, Manisty C, Treibel TA, Moon JC, van Dorp L, Balloux F, McKnight A, Noursadeghi M, Bertoletti A, Maini MK. Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2. Nature 2021,601: 110-117.

Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC. Tan A, Meng F, Jin J, Zhang JH, Wang S-Y, Shim, Shi L, Li Y, Xie Y, Liu L-M, Zhou C-B, Chau A, Luan J, Zhao J, Li J, Wai L-E, Koh S, Wang T, Bertoletti A, Wang F-S. Hepatol. Commun 2021 doi: 10.1002/hep4.1857.

Differential immunogenicity of homologous versus heterologous boost in Ad26.COV2.S vaccine recipients, Khoo NKH, *Lim JME, Gill US, de Alwis R, Tan N, Toh JZN, Ooi EE, Low JGH, Le Bert N, Kennedy PTF, Bertoletti A.  Med 2022 3, 104-118.

Favorable vaccine-induced SARS-CoV-2 specific T cell response profile in patients undergoing immune-modifying therapies.  Qui M, Le Bert N , Chan WPC, Tan M, HangS K, Hariharaputran S, Sim JY, Low JH, , Ng W, Wan WY, Ang TL, Bertoletti A, Salazar E.  J.Clin. Invest. 2022, DOI 10.1172/JCI159500. 

Enhanced BNT162b2 vaccine-induced cellular immunity in anti-CD19 CAR T cell treated patients. Oh BLZ, Tan N, de Alwis R, Kunasegaran K,Chen Z, Poon M,Chan E, Low JGH, Yeoh AEJ, Bertoletti A, Le Bert N. Blood 2022, doi.org/10.1182/blood.2022016166