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Chimeric antigen receptor engineered T cells
Unlike TCRs, CARs are formed by a combination of antibody-derived or ligand-derived domains and TCR
domains. Due to engineering specific antigens, CAR-T specifically expresses a receptor to direct the T cells
to target and destroy cancer cells. Therefore, CAR-T therapy represents specific recognition and lethality.
Meanwhile, specificity enhancement of CAR-T cells can make them activate at very low level of target on non-
malignant tissue so that prevent off-tumor toxicity. Based on the different engineered chains of CAR, CAR-T
has developed from the first generation to the second and third generation [83,92] . With the development of
CAR-T therapy, CAR-T cells have longer survival times, better functional properties, and less toxicity. These
characteristics make CARs “living drugs” that exert both immediate and long-term therapeutic benefits. The
third generation of GPC3-CAR-T cells are able to efficiently kill GPC3-positive HCC cells, while suppressing
the growth of HCC xenografts. The cytotoxic effects were positively correlated to the GPC3 expression levels
in the target [93,94] . A phase I clinical trial for anti-GPC3 CAR T has been sponsored in 2015 to evaluate the
safety and effectiveness for patients with relapse or refractory HCC. Thirteen patients were enrolled in this
trial, and the results are eagerly anticipated (NCT02395250). A different CAR-T approach towards HCC was
recently developed by utilizing the antibody against HLA-A2/AFP peptide complex . If successful, this
[95]
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approach may expand CAR-T therapy to the intracellular tumor antigen. T cells expressing ET1402L1-CAR
(AFP-CAR) could selectively lyse liver cancer cells that were HLA-A*02:01 /AFP . Under in vivo conditions,
+
+
both intratumoral infection and intravenous administration of AFP-CAR T cells significantly inhibit
tumor growth in mice. The robust antitumor activity was attempted in an established intraperitoneal liver
cancer xenograft model. The phase I clinical trial of an ET1402L1-CAR started only in 2017 (NCT03349255).
Autologous CAR-modified T cell directed CD133 (CART-133) is another therapy targeting for CD133, which
has developed into a phase I trial for HCC and pancreatic carcinomas and colorectal carcinomas. The results
showed 3 PR and 14 stable disease in all 23 patients. For safety, the reduction of hemoglobin, lymphocytes,
and thrombocytes occurred in nearly all the patients. Lymphopenia presented in all the non-HCC patients
with grade 2-4 and all HCC patients with grade 2 . So far, most clinical results of CAR-T have come
[96]
from the treatment of hematologic diseases. The clinical trial of CAR-T for solid tumors is just beginning.
However, cytokine releasing syndrome and on-target/off-tumor toxicity are still very important side effects
which should be solved in either hematologic diseases or solid tumors.

Due to the complexity of the immune system post-infusion, ACT is more complex than other types of
immunotherapy. For expressing the different antigens and the varied microenvironments in different
patients, several biotechnology companies are turning their efforts to develop personalized approaches. This
is being attempted by screening personalized tumor antigens and expanding personalized lymphocytes in
the individuals. Although multiple commercial models have been proposed, the effectiveness and safety
need further investigation.

SUMMARY AND FUTURE RESEARCH DIRECTION
Although the number of HCC related deaths is high, its prognosis remains poor and available treatment
options are limited. Over the past decades, immunology has evolved from the basic to the clinical realm,
which has contributed to many immunotherapies entering the clinics, which is encouraging and offers new
treatment prospects for HCC. Strategies including immune checkpoint blockers, genetically engineered T
cells (TCR-T and CAR-T) have already secured FDA approval for many types of cancer treatments. The
screening and identification of HCC neoantigens have reinvigorated the relevance of immunotherapy, and
precisely, pushing the personalized treatment into a reality. The progress in the field of cancer treatment
is obvious, yet, tumor is still a dreadful disease with limited options to cure. Making the treatment more
accurate and effective for HCC remains a huge challenge. To better understand tumor, further research
of the tumorigenesis mechanism is needed. With immune suppression in tumor microenvironments,
further research should likely focus on alleviating inhibition of immune suppression and restoring normal
immune functions. Various immune functions also need to be further investigated including tumor antigen