Page 20 - Read Online

Page 4 of 8 Hafezi et al. Hepatoma Res 2018;4:16 I http://dx.doi.org/10.20517/2394-5079.2018.55

[29]
responses and a fatal outcome . Targeting overexpressed self-antigens in tumours might not be ideal due to
potential off-tumour responses against normal cells [29,32] .

Recently, the discovery of altered self-antigens in highly mutated tumours have sparked an interest in their
[33]
use as a TAA for T-cell immunotherapy . The continuous evolution and accumulation of mutations in
tumours can result in the modification of self-antigens to an extent where they are no longer perceived
as self-antigens, and hence become immunogenic. These neoantigens have been reported to be capable of
inducing a robust T-cell response which mediates an anti-tumour effect. Since neoantigens are sufficiently
different from self-antigens, this makes them a better TAA with far lower risks of on-target off-tumour
responses observed when targeting classical TAAs. However, the generation of neoantigens involves the
accumulation of random mutations which differs between tumour nodules and patients, making their
[34]
discovery and characterization difficult and cumbersome .
A possible alternative approach is to target HBV antigens as a TAA. In the natural history of chronic HBV
infection, the virus integrates itself into the human genome, hence the HCC cells that eventually develop
from chronically infected hepatocytes will carry these integrations and can be targeted by HBV-specific TCR
T-cells [32,35] . This integration results in either the expression of whole HBV antigens when the complete open
reading frame is integrated, or the production of chimeric HBV-host proteins when only short fragments
[36]
of HBV are integrated . In any case, the integration process inadvertently marks the HBV-HCC cells with
[32]
a foreign antigen through a mechanism that is highly hepatotropic as dictated by the infectivity of HBV .
This liver-specific marking would mean that the on-target off-tumour adverse events is largely predictable
[29]
and would primarily be limited to the liver compartment, with little or no involvement of other organs .
However, since HBV-specific TCR-T cells are unable to discriminate between HBV-infected hepatocytes and
HBV-HCC cells, the risk of on-target off-tumour lysis of infected hepatocytes is also of concern. At present,
this issue can be circumvented by treating only HBV-HCC patients with tumour recurrence post liver
transplantation and by selecting HBV-specific TCRs restricted by HLA molecules present on the patient cells
and not on the donor liver. Extending this approach to HBV-HCC patients without liver transplantation will
have to be properly evaluated after more clinical data and experience have been accumulated. In addition to
the desirable safety considerations above, targeting HBV antigens would also provide a commonality across
multiple tumour nodules and patients, unlike the diverse and somewhat random nature of neoantigens,
making it less complicated to use in clinics.

It is also important to note that the targeting of HBV antigens for HBV-HCC treatment comes with its own
restrictions due to the natural virological characteristics of chronic HBV infection. In chronic HBV patients,
microgram quantities of HBV envelope antigens are circulating in the serum. These soluble HBV antigens
can interfere with the function of HBV-envelope specific CAR-T cells by either blocking and sequestering
of the cell surface CARs, or by the inappropriate activation of the CAR-T cells [32,37,38] . However, the obligate
requirement for HLA presentation of T cell epitopes to TCRs would render the TCR-T cells insensitive
[39]
to soluble HBV antigens in the serum . To capitalise on the better safety considerations associated with
targeting HBV antigens, one would have to employ the use of HBV-specific TCRs and not CARs recognizing
HBV antigens for HBV-HCC T-cell immunotherapy.

FIRST-IN-MAN PROOF-OF-CONCEPT TCR-T CELL IMMUNOTHERAPY OF HBV-HCC
The feasibility of using HBV-specific TCR-T cells for the treatment of HBV-HCC was first demonstrated
in a compassionate therapy of a chronic HBV patient who has widespread extrahepatic HCC metastasis
[40]
post-liver transplantation . The combination of several clinical features of the patient makes him an
ideal candidate for the first-in-man proof-of-concept therapy where an emphasis on safety is essential.
First, the patient had undergone liver transplantation. This means that the main bulk of HBV infected