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Lee Cell-mediated immunotherapy for HCC

programmed cell death protein-1, is another checkpoint unresectable HCC. They enrolled 72 patients treated
inhibitor employed in a clinical trial of HCC treatment. by combination of TACE and CIK cells infusion and
In total, 262 patients were enrolled in dose-escalation 74 patient treated by TACE alone. The results showed
and dose-expansion phases. The objective response progression-free survival and overall survival were both
rate was 20%. Complete response rate was 1%, partial improved. The 1- and 2-year survival were 71.9% and
response was 18%, and stable disease was 45%. The 62.4% for combination therapy of TACE and CIK cells
median progression-free survival was 4 months [54] . infusion, compared to 42.8% and 18.8% for therapy
Currently, several clinical trials of checkpoint inhibitor with TACE alone. Su et al. [60] collected 7 randomized
immunotherapy are ongoing. Results will be published controlled trials and one controlled clinical trial to
in the near future. perform a meta-analysis study of comparison between
DC + CIK cells + TACE/RFA treatment for HCC and
T-cell immunotherapy control. A total of 349 patients had DC + CIK cells +
T-cells are direct effector cells to attract cancer cells. TACE/RFA treatment, compared to 344 patients as
control. The results showed that DC + CIK cells + TACE/
Activated T-cells can be applied to treat cancers [55] . RFA treatment improved 1- and 2-year overall survival.
Takayama et al. [56] conducted a randomized clinical
trial by infusion of T-cells to prevent HCC recurrence Tumor neo-antigens
after curative resection of HCC. One hundred and fifty
patients were enrolled and randomized: 76 received A successful DC-based immunotherapy for cancers
adoptive immunotherapy with activated T-cells, and 74 needs specific tumor-associated antigens to promote
anti-cancer immunity. HCC-associated antigens were
patients received no adjuvant treatment. Autologous well reviewed by Hong and Huang [61] and Sun et al. [62] .
lymphocytes were activated by recombinant IL-2 and Among the reported antigens, a-fetoprotein, glypican-3
anti-CD3 antibody and could be expanded more than (GPC3), and multidrug resistance-associated protein-3
1000-fold. Compared to control, the frequency of (MRP-3) were frequently expressed on HCC and were
tumor recurrence was decreased by 18%, and time to employed as tumor antigens to conduct clinical trials.
the first tumor recurrence was longer. However, overall However, the clinical responses were not satisfactory.
survival was not significantly affected. Recently, Aref et al. [63] found HCA519/TPX2 was an
HCC-associated antigen. When DCs were pulsed
Jiang et al. [57] conducted a phase I trial using autologous with this peptide, cytotoxic T-cells could be activated.
tumor-infiltrating lymphocytes (TIL) to prevent tumor Zhu et al. [64] found the levels of cytokeratin (CK) 10 in
recurrence after curative resection for HCC. TIL was HCC cell lines were higher than in normal liver tissue.
obtained from adjacent-tumor tissue and could be CK 10 is a potentially targetable tumor-associated
expanded by IL-2 and anti-CD3 in 15 of 17 patients. antigen. Whether these antigens can be presented
When the expanded TIL was infused back into the by DC to enhance anti-cancer immunity needs to be
patients, only grade 1 flu-like symptoms and malaise proved by clinical trials.
were noted. After a median follow-up of 14 months,
12 patients were tumor-free and 3 patients had tumor CONCLUSION
recurrence. Basically, immunotherapy with expanded
autologous TIL was safe and the toxicity was low. HCC is an aggressive cancer and can recur even when
Future clinical trials may be conducted by the authors. tumors are completely removed. Effective treatments
for advanced stage HCC are still lacking. Cell-mediated
Cytokine-induced killer cell therapy immunotherapy is an attractive therapy for HCC with few
Autologous cytokine-induced killer (CIK) cells were toxicities. However, tumor response rates are only around
also used to provide cell-mediated immunotherapy 20% because immunosuppressive factors or cells interfere
for HCC. Shi et al. [58] conducted a phase I clinical trial with the effects of immunotherapy. The combination of
using CIK cells to treat HCC. CIK cells were expanded increasing immunity and depleting immunosuppressive
from PBMC ex vivo by interferon-g in the first day and factors shows promise for future success in conducting
followed by anti-CD3, IL-1a, and IL-2. After CIK cells cell-mediated immunotherapy for HCC.
were infused, the populations of CD8 cells and DCs
+
were both increased. Tumor volume was decreased in DECLARATIONS
3 of 13 patients. The authors concluded that infusion
of CIK cells was safe and immunological status could Authors’ contributions
be improved. Since CIK cells might show anti-tumor W.C. Lee contributed solely to the paper.
activity for HCC, Hao et al. [59] conducted a randomized
trial to compare the treatment efficacy of combination Financial support and sponsorship
of TACE and CIK cells infusion vs. TACE alone for None.

Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017 247