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the existence of HBV-host chimeric proteins in HCC [47-49] , where only short fragments of HBV DNA are
integrated into the host genome. In such situations, serological assays will fail to detect the presence of HBV
antigens and the patient would be deemed unsuitable for TCR-T immunotherapy. However, these chimeric
proteins could potentially be processed and presented on the HCC cell surface, rendering the tumours
recognizable by TCR-T cells. These integrations could only be detected through genetic means. As such,
to have better patient selection, it is essential to develop new genetic based assays for the rapid detection of
short HBV integrations and determine whether the appropriate HBV T-cell epitopes could be potentially
produced by HBV-HCC cells.

Lastly, it is also necessary to understand how the basal biochemical parameters of HBV-HCC patients could
influence the function of TCR-T cells. It is common to have HBV-HCC patients with, elevated serum alpha-
fetoprotein levels, to be treated with multi-kinase inhibitors or with immunosuppressive agents if they have
been liver transplanted. The effects of such variables have remained largely unexplored in the context of
TCR-T cell immunotherapy, but it could have important impacts on the treatment efficacy.

CONCLUSION
In this short review, we have discussed the need for new treatment strategies against HBV-HCC, the
scientific rationale that guides the development of HBV-specific TCR-T cell immunotherapy and some
practical considerations surrounding its use in patients. It is in our opinion that many unknowns still
remain. At the moment, dosing and infusion frequencies are still determined arbitrarily, or extrapolated
from T-cell immunotherapies for other cancers, while the accessibility of tumours at different anatomical
locations, and even the function of TCR-T cells in different tumour microenvironments remains a subject of
continuous investigation. We are however confident that the promising potential of T-cell immunotherapy
will stimulate further research and development making its use in the treatment of HBV-HCC a reality.

DECLARATIONS
Authors’ contributions
Hafezi M, Bertoletti A and Tan AT wrote the manuscript.

Financial support and sponsorship
This work was supported by a Singapore Translational Research (STaR) Investigator Award (NMRC/
STaR/013/2012) to Bertoletti A.

Conflicts of interest
Bertoletti A participates in Advisory Boards on hepatitis B virus immune therapy for Gilead, Janssen,
Medimmune and is a co-founder of Lion TCR Private Limited, a biotech company developing T cell
receptors for treatment of virus-related cancers and chronic viral diseases. Tan AT is a consultant of Lion
TCR Private Limited. Hafezi M discloses no conflicts.

Patient consent
Not applicable.

Ethics approval
Not applicable.

Copyright
© The Author(s) 2018.