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cytotoxic T lymphocytes (CTLs) targeting against this antigen have been shown to exist in the T cell
repertoire, without being peripherally or centrally deleted, which suggests AFP is a promising target antigen
for HCC immunotherapy [24,25] . Human T cell repertoire could effectively respond to the AFP self-antigen in
the context of major histocompatibility complex (MHC) class I or after the administration of AFP peptide-
pulsed DC [26,27] . Previous studies using DCs or T cells pulsed with AFP-derived peptides suggest that AFP-
derived peptides are suitable epitopes as immunotherapy targets. However, because of the self-nature of AFP,
the vaccine-activated immune responses were weak. Thus, not surprisingly, the clinical results were not
satisfactory [27,28] except that a recent phase 1 clinical trial in HLA-A24 patients showed that immunization
with AFP-derived peptides resulted in immune responses in 33% (5 of 15) of patients, of whom one patient
had complete response . To enhance the AFP-specific immune responses, investigators mutated the AFP
[29]
epitope to create epitope-optimized vaccines. They recently found that epitope-optimization of AFP antigen
[30]
together with genetic immunization can activate potent AFP-specific CD8 responses . The activated CD8+
T cells in mice could not only cross-recognize short synthetic wild-type AFP peptides, but also identify
and kill the tumor cells expressing wild-type AFP, which successfully prevents the immunized mice from
developing carcinogen-induced autochthonous HCC. Further studies show that the antitumor effects of
vaccine-activated AFP-specific CD8 T cells are correlated to optimal T cell receptor (TCR) signaling strength
and induction of stem-like memory T cells [31,32] .

Conversely, cancer vaccine development benefits from deep sequencing and rapid identification of neoepitopes
in the tumor lesions , a modern technology has emerged for designing a personalized immunotherapy
[33]
approach by using neoantigens -mutated antigens generated in the tumor mass that are unique to each
patient’s cancer to elevate the immune function and kill cancer cells. The identification of personalized
somatic mutations can be conducted by whole-exome sequencing and matching DNA from normal cell
with tumor cell from each patient. Mutated peptides are then synthesized to create a new vaccine that has
a high likelihood to bind to the autologous human leukocyte antigen (HLA)-A or HLA-B proteins. In a
phase I clinical study for melanoma with neoantigen-based vaccines, 15 (16%) and 58 (60%) of the 97 unique
neoantigens could be targeted by vaccine-induced polyfunctional CD8+ and CD4+ T cells, respectively. No
recurrence of tumor was noticed in 4 of the 6 vaccinated patients for up to 25 months after vaccination.

Vaccination with APC
Antigen presenting cell, including dendritic cells, activated B cells, and peripheral blood mononuclear cells,
have been widely investigated as candidates for tumor vaccine. In the innate immune system, the most
efficient APCs are the DCs [34,35] . They are well-known to be the most potent APCs for inducing antigen-
specific T cell responses. They acquire and present tumor antigens to T lymphocytes, promote the generation
of CTLs and helper T cells , decrease the proportion of CD4+CD25+ regulatory T cells and induce anti-
[37]
[36]
tumor immune response . After the first DC-based vaccine for the treatment for prostate cancer, the study
[38]
of DCs is continuously growing internationally. DC-based therapies are increasingly investigated and used
to treat many kinds of patients with cancer or other diseases. In terms of manufacturing the DC vaccines,
it is important to select proper tumor antigens and choose the appropriate method for loading the tumor
antigens onto the DCs. Tumor antigen-pulsed DC vaccines can effectively develop mature DCs (mDCs) and
enhance T cell stimulation to generate potent CTLs.

There are 3 generations of DC vaccines according to the development of different subsets. First-generation
DC vaccines are not fully matured, consisting of patient-derived natural DCs or monocyte-derived DCs
(mo-DCs). Antigens, such as tumor cell lysates or recombined/synthetic antigenic peptides, are loaded onto
the DCs ex vivo and then reinjected in the patients. The first-generation DC vaccines provided satisfactory
outcomes in terms of safety and feasibility but not of expected clinical efficacy [39-41] . The second-generation DC
vaccines consisted of mo-DCs matured via maturation cocktails. Such vaccines are widely used in the clinics
because of its minimal immunogenic side effects and better clinical responses . Nowadays, the clinical
[42]
progress on DC vaccines has reached a new era: next-generation DC vaccines. Many defined DC subsets