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Page 6 of 12 He et al. Hepatoma Res 2018;4:40 I http://dx.doi.org/10.20517/2394-5079.2018.45

Genetically engineered T cells
As a pivotal role in killing tumor cell, the function of T cells has always been the focus of investigation.
With the development of modern genetic techniques, T cells can be genetically engineered for enhanced
anticancer immune functions. These engineered T cell therapy has been first applied in hematological
malignancy [78,79] and then gradually introduced to treat solid tumors such as glioblastoma , prostate
[80]
cancer and sarcoma . Recent studies on modified T cells expressing engineered TCRs and CARs show
[82]
[81]
encouraging results to advance from basic to clinical research.
TCR engineered T cells
Endogenous TCRs recognize the peptide segments submitted by MHC-I and MHC-II on the cell surface
with a heterodimer consisting α- and β-chains. Each TCR is a heterodimer that determines the TCR antigen-
specificity. TCR-T was genetically modified with TCR chains for targeting specific antigens expressed on
tumor cells to cure specific diseases. As the peptides were processed and submitted by MHC, they present
various antigens as an expanded pool of potential targets. For this reason, TCR-T can target moreantigens
in comparison to CAR-T . It was the first successful application of ACT when 17 patients with metastatic
[83]
melanoma were treated using autologous T cells transduced with TCR recognizing the MART-1 melanoma-
melanocyte differentiation antigen . Although objective cancer regressions were observed in mice and
[84]
expanded clinical trials, severe “on-target, off-tumor” toxicity occurred in the skin, eyes, and ears of patients
because of the expression of antigenic targets in these organs [85,86] . AFP and GPC3 are commonly expressed
in the HCC. These two specific antigens are good targets for engineered T cell therapy. Peptide GPC3 is
367
a predominant peptide identified on HLA-A2 positive hepatoma cells. CD8(+) T cells that express GPC3 -
367
specific T cell receptor can recognize and kill GPC3-positive hepatoma cells and reduce growth of HCC
xenograft tumors in mice . In a recent study, novel AFP-specific murine TCR genes have been identified that
[87]
can redirect human T cells to specifically recognize and kill HCC tumor cells . AFP-specific murine TCR
[32]
genes were identified in another study. These TCR-T cells specifically recognize HLA-A*02:01 /AFP HCC
+
+
tumor cells and produce effector cytokines to kill them in vitro. Adoptive transfer of TCR-T cells prevent
and regress HepG2 tumor outgrowth in NSG mice, irrespective of CD4 or CD8 TCR-T cells. Though tumor
developed in one of the TCR-T-treated mice, it was eradicated 3 weeks after transfer . HBV infection is one
[32]
of the most common causes of HCC tumorigenesis. In one case report, a patient seems to have developed
HCC relapse 10 years after liver transplantation for HBV+ HCC. At the time of HCC relapse, HBsAg (but
not HBV DNA) was detected in the blood analysis, while HBsAg, HBcAg and HBV DNA were negative in
liver biopsies for the transplanted liver. Subsequently, HCC autologous T cells genetically modified to express
an HBsAg specific T cell receptor were transferred to this patient. The results show reduced levels of HBsAg
without exacerbation of liver inflammation or other toxicity, while clinical efficacy could not be established.
This leads to a novel strategy of personalized immunotherapy targeting specific peptides in the treatment of
HBV associated HCC .
[88]

TCR-T therapy has got into clinical trial of multiple myeloma (MM), metastatic melanoma and esophageal
cancer, while the safety reports differ from each other. In a phase I trial of MAGE-A4 T cell receptor gene-
transduced lymphocytes in patients with recurrent esophageal cancer, none of 10 patients experienced any
adverse events for the first 14 days after T cell transfer . However, the safety is not optimistic in other 2
[89]
trials. Seven of 20 patients with MM had SAEs after infusion of NY-ESO-1 specific TCR engineered T cells .
[90]
While 2 of 14 patients had serious adverse events (SAEs) of acute respiratory distress requiring intubation
associated with patchy pulmonary infiltrates within 1 week of cell infusion with MART-1 T cell receptor
transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma . Therefore,
[91]
the toxicity may bring new challenges to the development of TCR-T therapy. Recently, 4 TCR-T therapies in
HCC have started phase I/II clinical trial (NCT02686372, NCT02719782, NCT03441100, NCT03132792). The
safety of these trials needs to be paid significant attention as well as clinical efficacy.