Colorectal cancer (CRC) is one of the most common
cancers worldwide and represents the second principal cause of
cancer death. The mortality rates due to CRC have been increasing
in recent years and account for 8.5% of total cancer mortality
(1). The World Health
Organization estimated over 1.9 million newly diagnosed CRC cases
globally in 2020 and there were more than 930,000 mortalities due
to CRC. The global incidence of CRC is projected to rise to 3.2
million new cases annually by 2040, indicating a 63% increase and
the number of fatalities is expected to be 1.6 million per year
(1). Within the field of
oncology, immunotherapy is fast becoming recognized as a critical
approach, though with varying degrees of success for CRC. Immune
checkpoint blockade (ICB) therapy, for instance, demonstrates
limited effectiveness in advanced CRC patients with microsatellite
instability-high (MSI-H) tumors (2). This highlights a current limitation
in the broader application of this specific immunotherapy for
CRC.
The Consensus Molecular Subtypes (CMS) provide a
framework for understanding the heterogeneity of CRC and are
categorized into four subtypes: CMS1 (MSI Immune), CMS2
(Canonical), CMS3 (Metabolic) and CMS4 (Mesenchymal) (3). Each subtype presents unique
molecular aberrations and distinct immune profiles that dictate the
choice of antigens that can be exploited for cancer immunotherapy.
Integrating these classifications allows for the identification of
specific tumor microenvironments, ranging from highly immunogenic
to immunosuppressive, that can be more easily targeted through
personalized immunotherapy. CMS1 tumors, for example, are
hypermutated and characterized by strong immune activation and high
infiltration of Th1 and cytotoxic T cells, making them ideal
candidates for vaccines targeting high neoantigen burdens. By
contrast, CMS4 tumors exhibit prominent angiogenesis and stromal
invasion, which often leads to an immunosuppressive environment
that hinders T cell infiltration. This mesenchymal phenotype
provides a strong rationale for the DC vaccines that target
tumor-derived blood vessels to induce anti-angiogenic immunity and
overcome stromal barriers. Meanwhile, 'cold' epithelial subtypes
such as CMS2 and CMS3, which lack significant immune infiltration,
may benefit from DC vaccines designed to initiate de novo
priming and convert these immunologically inactive environments
into 'hot' tumor. The gut microbiome has also emerged as a critical
regulator for cancer immunity, fundamentally influencing the
effectiveness of anticancer immunosurveillance. Evidence suggests
that specific commensal bacteria are essential for the therapeutic
effectiveness of immune-checkpoint inhibitors (ICIs) by modulating
the functional activity of immune cells, including dendritic cells
(DCs) (4,5). Understanding the interactions
between the microbiome, immune cells and CRC is important for
optimizing cancer immunotherapy, as therapeutic efficacy may depend
on a balanced gut microbiota that supports effective systemic
immunity.
Looking to the future and the continued emergence of
immunotherapy approaches for CRC, therapeutic cancer vaccines are
being developed to activate the immune system (6). Therapeutic vaccines are known to
activate DCs and promote infiltration of T lymphocytes into the
cancer microenvironment to elicit immune responses against
tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs)
that are present in cancer cells. The overexpression of TAAs and
TSAs is frequently observed in tumor cells and cancer cells
respectively, as compared with normal cells (6). However, the challenge is to
precisely identify the TAAs and TSAs present in CRC tumors. If the
neoantigens are known, the accurate design of a peptide, DNA- or
mRNA-based cancer vaccine is feasible. In the absence of known
neoantigens from an individual cancer, using whole tumor cell
lysates can elicit broad cytotoxic T-cell responses against
multiple unknown antigens and patient-specific neoantigens from CRC
(2,6).
DCs are crucial in initiating adaptive immunotherapy
for CRC. There are a number of different colon cancer vaccines that
function to stimulate antigen-presenting cells (APCs) (2). DC vaccines specifically utilize DCs
loaded with tumor antigens under ex vivo conditions. This
process activates effector immune cells such as CD4+ and
CD8+ T cells, leading to a strong and long-term
anti-tumor response (2,6). The rationale for utilizing DCs as a
vaccine platform, particularly in the context of CRC immunotherapy,
is rooted in their pivotal role in initiating adaptive immune
responses. DCs are highly effective APCs as they excel at
capturing, processing and presenting tumor antigens to immune cells
such as CD4+ and CD8+ T cells (6). This capability is central to their
function in vaccines. This mechanism is crucial for eliciting a
robust immune response against cancer cells, thereby overcoming the
challenges that conventional treatments often face in preventing
metastasis. Essentially, DCs act as a vital link between
recognizing the tumor and mobilizing the body's specific immune
defense to combat it.
The primary focus for the present review was to
explore the role of DCs as a promising immunotherapeutic tool,
building upon the recognized limitations of conventional CRC
therapies. The present review summarized the current landscape and
mechanisms of DC vaccines specifically tailored for CRC. This
encompasses detailing how DCs are utilized, for instance, by being
loaded with tumor antigens ex vivo and underscoring their
crucial function as APCs. It is also important to elucidate how DC
vaccines are designed to overcome the significant limitations of
conventional CRC therapies. The present review highlighted how
these vaccines aim to combat CRC by activating effector immune
cells, thereby eliciting a potent and long-term anti-tumor
polyclonal response against all tumor antigens. Furthermore, the
present review presented the current outcomes and findings from
relevant clinical trials specifically involving DC vaccines for
CRC, assessing their efficacy, safety and clinical progress. While
this narrative review was focused on CRC, it drew on evidence from
other cancers, including melanoma and glioblastoma, as supporting
context for general DC vaccine principles and generation
strategies.
DCs are a diverse population of leukocytes that
function as the 'sentinels' of the immune system, playing a pivotal
role in orchestrating both innate and adaptive immunity (7). Initially discovered by Paul
Langerhans back in 1868, these cells are responsible for balancing
immunity and tolerance (8).
The general biology of DCs involves their origin
from bone marrow progenitors such as common myeloid progenitors or
common monocyte-DC precursors (MDPs) (9). From the bone marrow, DC precursors
travel through the bloodstream to most non-lymphoid tissues, where
they reside in an immature state. In this immature state, DCs
continuously sample their environment through mechanisms such as
endocytosis, macropinocytosis and phagocytosis (10,11). They have the ability to extend
processes across epithelial tight junctions independent of any
apparent stimulation including infections and inflammatory
triggers. As the most potent type of APCs, DCs are specialized in
capturing and processing antigens, converting proteins into
peptides that are then presented or cross-presented on both major
histocompatibility complex (MHC) class I and II molecules for T
cell recognition (11).
Upon detecting intruders via pattern recognition
receptors (such as Toll-like receptors) and capturing antigens
within the tumor microenvironment (TME), immature DCs undergo
phenotypical and functional maturation (12,13). This critical process leads to
enhanced expression of MHCs and co-stimulatory molecules (such as
CD40, CD80 and CD86), as well as increased secretion of cytokines
such as IL-12, thereby equipping them to more effectively prime
anti-tumor T cell responses (14-17). These mature DCs then migrate to
lymphoid organs, particularly the tumor-draining lymph nodes
(TDLNs) where they present processed antigens to naïve T cells to
fully activate and differentiate them into effector T cells capable
of killing cancer cells as well as supporting the immune response
(18,19). The unique ability to directly and
indirectly target cancer cells is what makes DCs a powerful
platform for generating DC-based cancer vaccines as they
effectively prime and activate T cells for a robust anti-tumor
immune response (Fig. 1)
(20).
The next section explores the biological
characteristics of DC subsets such as conventional, plasmacytoid
and monocyte-derived DCs, as well as their functional roles that
make them an effective and promising approach for cancer vaccine
development. It delves into one particular DC subset derived from
monocytes as a leading candidate for DC-based cancer vaccines to
explore its easy accessibility, antigen-presenting capacity and
ability to induce robust T cell responses.
DCs are a heterogeneous population with varying
functions and they are categorized into three main populations:
Conventional DCs (cDCs), plasmacytoid DCs (pDCs) and
monocyte-derived DCs (MoDCs) (9).
While the primary classification of DCs remains as plasmacytoid and
monocyte-derived, the ever-growing insights into DC biology
continue to reveal a more complex and heterogeneous population,
with more dynamic states and emerging subtypes particularly within
the TME.
cDCs arise from common DC precursors (CDPs) and are
divided into two primary types: Type 1 conventional DCs (cDC1) and
type 2 conventional DCs (cDC2). Type 1 cDCs are defined by their
reliance on transcription factors BATF3 and IRF8 for development
(21,22). Aside from the common expression of
XCR1, CLEC9A, CADM1 (NECL2), BTLA and CD26 found in both species,
mouse cDC1s are found to express CD8α in lymphoid organs and C103
in peripheral tissues, while in humans, they are characterized by
CD141 (BDCA-3), HLA-DRhigh, CD11c and the absence of
lineage markers (23). There are
two major subsets of cDCs present in the TME, cDC1 and cDC2. cDC1s
are highly specialized in cross-presenting exogenous antigens and
activating CD8+ T cells and are critical for inducing
the 'cancer-immune cycle' and anti-tumor immunity, including
responses to ICB and adoptive T cell transfer (18-24). They transport tumor antigens to
draining lymph nodes (LNs) and are the main producers of IL-12 and
chemokines such as CXCL9/CXCL10 in the TME, which attract
CD8+ T cells (25).
The functional roles of cDC1s within the TME may however vary
across different tumor types.
Type 2 cDCs are typically identified by the absence
of cDC1 markers and higher expression of CD11b, CD1c and SIRPα
(CD172α), with IRF4 as a key transcription factor (26,27). In humans, they also express
HLA-DR+, CLEC10A+, CD1c+ and
CD172+ (27). cDC2s
are primarily responsible for presenting endogenous antigens to
CD4+ T cells and shaping their polarization (such as
Th2, Th17, Treg) (28-30). While the functional demarcation
between cDC1 and cDC2 is more pronounced in mice, human cDC2s can
also cross-present antigens and produce high levels of IL-12
(31). cDC2s are also important
for improved CD4+ T cell priming and tumor rejection,
especially when regulatory T cells are absent (19). A previous study reported that
cDC2s can activate CD8+ T cells under certain
conditions, even in the absence of cDC1s (32). Single-cell RNA sequencing studies
have further identified heterogeneity within cDC2s, including cDC2A
(T-bet+) and cDC2B (T-bet−) subtypes
(33,34). Numerous cancers have been found to
exhibit cDC2 infiltration within the TME, particularly those that
have shown no response to cytotoxic T cells (35).
MoDCs are amongst the most extensively studied DCs
and are frequently utilized in clinical studies for cancer therapy,
owing to their relative ease of in vitro generation and
differentiation, as well as the limited availability of cDCs and
pre-DCs (46). Due to their
foundational and well-established role in DC-based cancer
immunotherapy, they provide a viable option for treatment against
CRC. These cells differentiate from Ly6C+ monocytes in
mice or CD14hi monocytes in humans, typically under
inflammatory conditions or exposure to cancer or infection
(21,47). Although Ly6Chi
monocytes typically exhibit immunosuppressive functions within the
TME, their differentiation into inflammatory DCs has been shown to
trigger reactive oxygen species (ROS) production and promote an
anti-tumor response independent of effector T cells (48,49). In mice, the differentiation of
Ly6C+ monocytes into inflammatory MoDCs has been shown
to be dependent on activation by interferon regulatory factor 4
(IRF4) and ETV3 (50-52).
There are two subtypes of MoDCs: MoDC1 that
expresses PD-L1 and MoDC2 that expresses CD155 (53). Their identification has
historically been challenging due to marker overlap with
macrophages and CD11b+ DCs, but some studies use markers
such as Fc receptors (FcγRI, FcεRI), CD11b, CD1c, SIRPα, HLA-DR,
CLEC10A, CD11c and cystatin F (CST7) (53,54). CD14, abundantly expressed in
peripheral blood monocytes, is markedly absent from the expression
profile of mature MoDCs, although it may be retained at low or
variable levels in immature MoDCs (55,56). Upon stimulation, mature MoDCs have
been also shown to express high levels of MHC I, MHC II and
co-stimulatory molecules such as CD40, CD80 and CD86 (53).
Beyond the classical subsets, emerging populations
such as mature regulatory DCs (mregDCs) and DC type 3 (DC3s) have
gained increasing attention for their distinct immunomodulatory
roles within the TME (37).
mregDCs, characterized by their expression of regulatory molecules
and migratory capacity, have been implicated in both immune
activation and tolerance, while DC3s show functional plasticity and
potential in anti-tumor immunity, although their classification is
still under refinement. Understanding the diversity of DC
populations and heterogeneity may help redefine and shape new
approaches in cancer immunotherapy, specifically for CRC. mregDCs
represent a newly characterized subset found in the TME that can
arise from both cDC1 and cDC2 lineages after maturation and tumor
antigen uptake (71,72). They exhibit regulatory activity
toward tumor-responding T cells and are defined by coexisting
maturation, migration and immunoregulatory profiles [such as
PD-L1/PD-L2, indoleamine 2,3-dioxygenase 1 (IDO1), T cell
immunoglobulin and mucin domain-containing protein 3 (TIM-3)]
(71,72). DC3s was recently found to be
another type of human DC that resembles cDC2 (34,73). Several studies have indicated that
DC3s may represent an ontogenetically distinct subset, deriving
from MDPs rather than from CDPs, which give rise to cDCs (74). These cells are able to upregulate
glucocorticoid-induced tumor necrosis factor receptor ligand
(GITRL), thereby potentially sending cues that support T cells
after being primed and also promote resident memory T cell survival
(75,76).
As the main players of immunity, DCs trigger the
immune response by first initiating antigen uptake, processing them
and presenting them for T cell activation. The wide range of
membrane receptors allows the cells to recognize and subsequently
capture and internalize various antigens, using different methods
such as phagocytosis, macropinocytosis, micropinocytosis and
endocytosis (10,11). Some of these diverse receptors
include antibody receptor types I or II (FcγRI or FcγRII),
integrins, glycan-binding proteins (lectin), phosphatidylserine
receptors, phagocytic receptors and scavenger receptors involved in
inflammation (77-80). Phagocytosis is the main process
that allows DCs to capture and engulf large particles such as
microorganisms, foreign materials and necrotic cells (9). The solubility of antigens also
influences antigen uptake and subsequent immune activation, in
which particulate antigens are found to elicit a stronger immune
response than soluble antigens (81,82).
Once antigens are internalized, DCs process them
into peptides for presentation through MHC molecules (83). Presenting these antigens along
with a costimulatory signal allows DCs to fully activate naïve T
cells and shape their differentiation into T effector subsets
(CD8+ and CD4+ T cells). The classical
antigen presentation pathways include the MHC Class I Pathway
(Endogenous Pathway), which typically presents endogenous antigens
(such as from viruses or tumor cells) to CD8+ T cells
(84). The MHC Class II Pathway
(Exogenous Pathway), on the other hand, presents exogenous antigens
from the extracellular environment to CD4+ T cells
(84). In the MHC II pathway,
newly synthesized MHC II molecules are stabilized by binding to the
invariant chain, which is later degraded to allow peptide binding
facilitated by HLA-DM (85).
A unique and critical capability of DCs is
cross-presentation, where they present internalized exogenous
antigens on MHC class I molecules to activate CD8+ T
cells (84). This is especially
important for anti-tumor responses and is particularly significant
with cDC1s, as they are highly specialized in cross-presenting
exogenous antigens and activating CD8+ T cells (86). This specialization is more
pronounced in mice than in humans (87,88). Cross-presentation by cDC1s is
enhanced by type I IFN signaling (89). MoDCs can also cross-present
antigens to prime CD8+ T cell responses, particularly
when triggered under inflammatory or cancerous conditions (90,91). Human cDC2s can also cross-present
antigens and produce high levels of IL-12, though this function is
largely confined to cDC1s in mice (31,92). Upon activation, tumor-infiltrating
CD11b+ cDC2s that express IFN have been shown to present
tumor-derived peptide-MHC I complexes via direct interactions,
subsequently activating CD8+ T cells and promoting
anti-tumor immunity even in the absence of cDC1s (32). There are two principal pathways
for cross-presentation: i) The vacuolar pathway, in which antigens
are processed and loaded onto MHC I molecules in endo/lysosomes and
ii) the endosome-to-cytosol pathway, in which antigens enter the
cytosol to be degraded by the proteasome and subsequently have
their peptides transported to the endoplasmic reticulum (ER) for
MHC I loading (93). WD Repeat-
and FYVE Domain-Containing Protein 4 and SNARE family member SEC22B
proteins are required for efficient cross-presentation (81). Antigen solubility also affects
cross-presentation; soluble antigens are quickly degraded, leading
to poor cross-presentation. By contrast, antigens in larger
vesicles (~500 nm) are found in early endosomes and protected from
complete degradation, resulting in more efficient
cross-presentation when compared with smaller particles (<200
nm) or soluble antigens (94).
DCs also employ a mechanism known as cross-dressing,
where they capture pre-formed peptide-MHC-I complexes from
neighboring cells via trogocytosis, including tumor cells and
present them (95,96). This takes place through plasma
membrane transfer mediated by direct cell-cell contact or by
secretion using membrane vesicles called exosomes (96). This mechanism has been shown to be
sufficient for priming antigen-specific CD8+ T
cells.
The process of DC maturation begins with reduced
antigen uptake activity and increased antigen presentation
activity, which involves an upregulation of MHC molecules and
co-stimulatory markers such as CD80, CD83 and CD86 (14-16). This is also accompanied by higher
cytokine production (TNF-α and IL-12) and an enhanced migration
ability to LNs, largely attributed to higher C-C chemokine receptor
7 (CCR7) expression (17,97). The transition between the two
states is clearly defined, in which immature DCs are specialized
for antigen capture, whereas mature MoDCs become optimized for T
cell activation and immune modulation.
Mature DCs migrate to the draining LNs for T cell
activation and differentiation, a process that requires three
critical signals (98): i) The
first signal (Signal 1) involves the presentation of processed
tumor antigens. DCs present antigens on MHC class I molecules to
naïve CD8+ T cells through cross-presentation (99,100). This cross-presentation is a
dedicated pathway for processing internalized exogenous antigens
and loading them onto MHC class I molecules, which is crucial for
generating de novo cytotoxic T lymphocytes (CTLs).
Simultaneously, DCs present antigens on MHC class II molecules to
naïve CD4+ T cells (101). ii) The second signal (Signal 2)
provides essential co-stimulation, in which DCs express high levels
of costimulatory molecules such as CD80/CD86 and CD40, which
interact with their corresponding ligands (such as CD28) on T cells
(101,102). This co-stimulation is important
for full T cell activation and to prevent clonal anergy (103). iii) A third critical signal
(Signal 3) involves the secretion of cytokines, which further
shapes the T cell response. MoDCs can secrete inflammatory
cytokines (104). Notably, the
production of IL-12p70 is crucial, as it favors the development of
cytotoxic cellular immunity and supports the differentiation of
CD4+ T cells into the Th1 phenotype (61,103). Th1 cells are characterized by
the production of IFN-γ (105).
This cytokine milieu, along with costimulatory signals, guides
naïve T cells to differentiate into specialized helper and effector
T cells, including Th1, Th2 and Th17 phenotypes (102,106). Other important co-stimulatory
pathways include interactions between CD40-CD40L, CD137-CD137L,
OX40-OX40L, GITR-GITRL and CD70-CD27 (107-110). The key cytokines that drive DC
function for T cell effector activity lie in IL-12 and type I IFNs
(111).
The TME can markedly impair DC functionality, often
leading to an immunosuppressive or tolerogenic phenotype (86). Inhibitory signals within the TME,
such as vascular endothelial growth factor (VEGF), IL-10 and TIM-3,
can suppress DC maturation and function (112). Tumors can hinder cDC recruitment
and differentiation by reducing chemoattractants (such as CCL4) or
affecting growth factors such as VEGF and FLT3L (113). Tumor-derived factors such as
PGE2, IL-6 and gangliosides can inhibit DC maturation
and survival (114-116). DCs can also modulate T cell
function by altering the availability of metabolic substrates, for
instance, by depleting L-tryptophan through IDO1, which promotes
regulatory T cells (Tregs) differentiation and suppresses
CD8+ T cell and NK cell functions (117,118). Lipid accumulation and ER stress
in tumor-associated DCs can impair antigen processing and
cross-presentation (119-121).
Lactic acid, a metabolic product of tumor cells, can also impair
MoDC differentiation and activation (122). Furthermore, some pDCs in the TME
are associated with immunosuppression, causing the cells to fail to
produce type I IFN and promoting Treg expansion (123,124).
In the TME, T cell exhaustion and dysfunction are
dominant characteristics of immune responses against cancer
(Fig. 3). Exhausted T cells have
a reduced ability to generate pro-inflammatory cytokines such as
IFN-γ, TNF-α and IL-2 and to kill cancer cells. They have increased
expression of several co-inhibitory receptors, including programmed
cell death protein 1 (PD-1), TIM-3, lymphocyte activation gene 3
(LAG-3) and 2B4 (CD244), which contribute to the immunosuppressive
environment within the TME (133). MoDCs, while having an
established foundation in DC therapy, are considered a double-edged
sword as they can both oppose and contribute to the state of TME,
particularly under conditions of T cell exhaustion.
While under inflammatory conditions such as
exposure to cancer cells, MoDCs become stimulated, enabling them to
induce TNF-α and NO and subsequently enhance the survival of
adoptively transferred T cells (53,57). These stimulated cells, also called
TIP-DCs, are shown to play a crucial role in controlling tumor
growth and might be dependent on activation of the CD40-CD40L
signaling pathway (57). Building
on this, when targeted with agonistic anti-CD40 antibodies, MoDCs
are able to differentiate into inducible nitric oxide synthase
(iNOS)-producing cells and express high levels of costimulatory
molecules that correlate with the presence of effector tumor
infiltrating lymphocytes, thereby enhancing PD-1 ICB therapy
(53). In some contexts, a
combination of MoDCs with adjuvant therapy such as
polyinosinic:polycytidilic acid (Poly(I:C)) was also observed to be
significant in eliciting an anti-tumor response compared with other
DC subsets (134). These
inflammatory MoDCs can foster a microenvironment that not only
exerts direct tumoricidal effects but also sustains the expansion
of tumor-infiltrating T cells, thereby amplifying anti-tumor
immunity.
However, under chronic inflammation or T cell
exhaustion, persistent TNF-α and NO might also contribute to
immunosuppression and tissue damage, limiting therapeutic benefit.
While low/moderate NO could support immune activation, excessive NO
might suppress T cell proliferation and contribute to immune
exhaustion (135,136). Moreover, monocytes as a source
of inflammatory DCs are also known to give rise to myeloid-derived
suppressor cells (MDSCs), further hampering anti-tumor activity and
promoting tumor growth (137).
It is important to acknowledge that while the TME could impair MoDC
function and contribute to T cell dysfunction, strategic targeting
and activation of MoDCs represent a viable therapeutic avenue to
support T cell activity and overcome exhaustion. However, further
research is necessary to specifically identify MoDCs and fully
comprehend their complex roles within the TME, especially given the
challenge of distinguishing them from other DC subsets.
The strategy used to load antigens onto DCs is
pivotal in determining the vaccine efficacy, as it governs both the
breadth of tumor antigen recognition and the specificity of the
resulting T-cell responses (Fig.
4). Whole tumor cell lysates (TCLs) remained among the most
widely employed approaches, since they encompassed the full
repertoire of TAAs and TSAs. This poly-antigenic stimulation
generated polyclonal T-cell populations capable of recognizing
multiple epitopes, thereby reducing the likelihood of immune
evasion through antigen-loss variants (138). Clinical studies in glioblastoma
and ovarian carcinoma demonstrated that lysate-pulsed DCs could
elicit durable CTL responses and long-term immune memory with
acceptable safety profiles (139,140). More recently, the phase-III
DCVax-L trial validated this proof-of-concept at a clinical level,
where the study reported significant prolonged survival in
glioblastoma patients treated with autologous tumor lysate-loaded
DCs compared with control groups with any treatment/interventions
(141). This study firmly
established broad tumor-antigen coverage as a clinically relevant
strategy, though survival benefits were not similar across multiple
different cancers, reflecting the variability of host immune
competence and the heterogeneity of TME.
The manner in which lysates are prepared is now
understood to critically influence vaccine potency. Roufarshbaf
et al (142)
systematically compared four methods of tumor lysate generation:
freeze-thaw, hypochlorous acid (HOCl) oxidation, hyperthermia and
ultraviolet irradiation. The results showed that HOCl-treated
lysates produced superior DC maturation, higher IFN-γ secretion and
reduced IL-10 release. The findings from the study highlighted that
oxidative stress markedly induced immunogenic danger signals that
could polarize T cells toward Th1 immunity. At the same time, the
authors cautioned that excessive oxidation could lead to epitope
degradation, potentially impairing T-cell recognition and further
stated that such methods demand precise laboratory control to
ensure reproducibility. Herzog et al (143) also demonstrated that the use of
trypsin to detach adherent tumor cells prior to lysate generation
resulted in degradation of key surface proteins required for
effective antigen presentation, thereby diminishing the stimulatory
potential of the final DC product. Collectively, these studies
indicate that antigen preparation is not a trivial technical step
but a decisive factor that can determine whether lysates generated
are immunogenic or non-immunogenic.
Heat shock-based TCL preparation was also observed
to provide ample DC stimulation. Heat-shock treatments induced the
expression of stress proteins such as HSP70 and HSP90, which served
as endogenous danger signals that promoted DC maturation and
antigen cross-presentation. Heat-shocked TCLs therefore not only
provide a comprehensive repertoire of TAAs but also incorporated
intrinsic adjuvant activity. Srivastava et al (144) were among the first to identify
the immunogenic potential of heat-shock proteins as carriers of
tumor peptides, showing that HSP-peptide complexes could elicit
protective immunity in mice. Later work by Manjili et al
(145) demonstrated that TCLs
subjected to heat shock enhanced DC activation, leading to stronger
CD8+ T-cell priming and tumor rejection compared with
lysates prepared under standard conditions. DCs pulsed with
heat-shock TCLs generated higher levels of IL-12 and TNF-α,
favoring Th1-polarized immunity (146). The strength of this approach is
that it coupled antigen breadth with innate activation, thus
circumventing the need for external adjuvants. However, the
drawbacks included variability in lysate preparations, the
potential induction of tolerance if maturation signals were
insufficient and difficulty in standardizing clinical-grade
heat-shock protocols.
Beyond conventional lysates, fusion-based vaccines
could offer an alternative means of broad antigen presentation. Kao
et al (147) directly
compared DCs pulsed with TCLs to DC/tumor fusion hybrids in a
murine colon carcinoma model. The authors found that fusion-derived
DC vaccines elicited stronger CTL responses and superior tumor
rejection, a phenomenon that could be attributed to the continuous
endogenous expression of tumor antigens after fusion, which allowed
sustained presentation to T cells. While this approach circumvented
some of the limitations of TCL-derived DC vaccines, the technical
demands of creating fusion cells ex vivo and the challenges
of regulatory standardization across patient-specific samples
remained major hurdles for clinical translation. The immunogenic
potential of lysate-pulsed DCs could also be augmented through
rational combinations with immune modulators. Bakhshivand et
al (148) examined the use
of breast cancer lysate-pulsed DCs in combination with cytotoxic
T-lymphocyte antigen-4 (CTLA-4) blockade. The results demonstrated
markedly enhanced T-cell expansion and improved tumor control
compared with DC vaccination alone. These findings suggested that
checkpoint inhibitors could synergize with DC vaccines by
overcoming tumor-induced tolerance and reinvigorating exhausted
T-cell populations. Nevertheless, the increased risk of
immune-related toxicities and the economic burden of combining two
advanced therapies presented practical barriers to generalized
clinical implementation and therapeutic use. Whole tumor cell (WTC)
vaccines represented another approach to broaden antigen exposure.
As summarized by Pérez-Baños et al (149), WTC vaccines not only delivered a
comprehensive range of antigens but also provided tumor-derived
danger signals that activated innate immune pathways. This dual
mechanism was suggested to enhance both antigen-specific responses
and pro-inflammatory conditioning of the TME. However, this could
also introduce variabilities and complicate the standardization of
vaccine preparations. Furthermore, the presence of self-antigens in
WTC preparations raised the possibility of tolerance rather than
immunity in some patients.
Peptide- and protein-based antigen loading, such as
those using carcinoembryonic antigen (CEA) or mucin 1, allowed
precise targeting and facilitated monitoring of antigen-specific
T-cell responses (150). In the
context of colorectal cancer, these antigens are of particular
clinical relevance; for instance, CEA is overexpressed in ~90% of
CRC cases (151). While
targeting these TAAs had successfully elicited T-cell responses in
early-phase CRC trials, a major hurdle remains their low
immunogenicity in mismatch repair-proficient (pMMR) tumors, which
lack the high mutational burden found in MSI-H cases (152,153). Despite these advantages, they
are restricted by MHC haplotypes and by the narrow antigenic
spectrum they cover, rendering them vulnerable to tumor antigen
heterogeneity. To overcome these issues, investigators began
exploring neoantigen peptide-pulsed DCs. In pancreatic cancer,
Oyama et al (154)
demonstrated the feasibility of loading DCs with patient-specific
neoepitopes identified through sequencing, with early evidence of
improved disease control following surgery.
However, recent evidence underscores that the
clinical benefit of these vaccines depends more on neoantigen
'quality' than 'quantity' (total mutational burden). As
demonstrated by McGranahan et al (155), tumors characterized by a high
burden of clonal neoantigens, mutations present in every tumor
cell, exhibited markedly higher T-cell immunoreactivity and
improved survival outcomes compared with tumors with high subclonal
heterogeneity. This 'quality' model, which focuses on the
best-presented clonal mutation, has proven more predictive of
therapeutic success than the 'quantity' model, which is based on
the total number of neoantigens (156,157). By prioritizing these
high-quality clonal targets, DC vaccines may potentially eliminate
the entire tumor population and minimize the risk of subclonal
immune evasion (158). This
approach allowed highly individualized targeting of mutations, but
its dependence on rapid next-generation sequencing, epitope
prediction, immuno-proteomic validations and complex manufacturing
remained a major limitation.
As an intermediate between lysate breadth and
peptide precision, total tumor RNA (ttRNA) was used to load DCs.
ttRNA ensured endogenous antigen processing across both MHC class I
and II pathways, thereby combining broad coverage with
physiologically relevant presentation. Early-phase trials across
multiple solid tumors indicated that ttRNA-loaded DCs were safe and
immunogenic (154). Yet, RNA
instability and batch-to-batch variability in transcript content
continued to present logistical challenges for multicenter
applications.
In addition to endogenous tumor antigens,
heterologous antigens were also tested as adjuncts. Zhai et
al (159) reported that DCs
pulsed with the mycobacterial antigen Ag85A enhanced immune
responses against colorectal carcinoma in murine models. The use of
Ag85A not only increased the expression of costimulatory molecules
CD80 and CD86 but also promoted IFN-γ secretion and delayed tumor
progression. These results suggested that heterologous microbial
antigens could serve as powerful adjuvants by further activating
innate immunity pathways while augmenting tumor-specific responses.
Whether this indirect elicitation could be a long-term, transient,
or highly case-by-case basis has yet to be studied in depth.
Additionally, concerns also remain regarding the specificity of
such approaches and the potential for off-target or autoimmune
responses in humans.
Nucleic acid-based strategies, including mRNA and
DNA, also provided a new frontier in DC vaccine stimulation and
generation. mRNA-transfected DCs could generate endogenous antigen
expression and present epitopes via both MHC-I and II pathways,
enhancing CD8+ and CD4+ T-cell priming
(160,161). Personalized mRNA neoantigen
vaccines are known to induce immunogenicity in melanoma and
glioblastoma patients, with evidence of durable T-cell activation
(162,163). These approaches bypassed central
tolerance and focused on patient-specific mutations via prior
characterization. However, the substantial costs incurred,
time-consuming production periods and the need for individualized
manufacturing pipelines could lead to a challenging establishment
of personalized mRNA-based vaccines.
Notably, natural microbial products are also
exploited for their capacity to activate DCs. One prominent example
was the use of Saccharomyces cerevisiae (baker's yeast) cell
wall components, particularly β-glucans, which engaged pattern
recognition receptors such as Dectin-1 and TLR2/4 on DCs. This
interaction promoted DC maturation, cytokine secretion and
cross-presentation of TAAs. Experimental cancer vaccines using
recombinant yeast particles expressing TAAs showed the ability to
induce strong CD8+ T-cell responses and tumor regression
in preclinical models (164).
Moreover, β-glucan particles derived from yeast cell walls were
developed as antigen carriers: DCs phagocytosed these hollow glucan
shells and presented encapsulated antigens efficiently to T cells,
achieving potent immunity with minimal toxicity (165). The advantage of this approach
lies in the dual role of β-glucans as both delivery vehicle and
adjuvant, providing intrinsic immunostimulatory signals while
ensuring efficient antigen loading. However, variability in yeast
preparations and the potential for excessive inflammation remained
challenges that required careful optimization. Integrating yeast
cell wall platforms into DC vaccine design illustrates how
naturally occurring microbial ligands could be harnessed to
reinforce both immunogenicity and safety.
Recent advances in nanotechnology have also
transformed antigen-DC stimulation approaches. Prasad et al
(166) encapsulated tumor
lysates in biodegradable poly(lactic-co-glycolic acid; PLGA)
nanoparticles, reporting improved antigen stability, protection
from enzymatic degradation and enhanced cross-presentation to CTLs.
Scheffel et al (167)
demonstrated that calcium phosphate nanoparticles not only improved
antigen delivery but also promoted DC maturation and stronger
CD8+ T-cell responses when compared with soluble
antigens. While the nanoparticle systems reduced systemic toxicity
and prolonged antigen persistence, questions remained regarding
their long-term safety in humans and the reproducibility of their
effects across diverse patient populations. Focusing on the
importance of DC-therapy manufacturing, authors such as Boudousquié
et al (168) established
a current good manufacturing practice (cGMP)-compliant protocol for
generating oxidized tumor lysate-pulsed DCs, demonstrating that
HOCl-treated lysates improved immunogenicity and facilitated
consistent, reproducible production across multiple clinical
centers. Such standardization is essential for large-scale clinical
translation. However, the requirement for specialized
infrastructure and the high cost of GMP operations remain
formidable barriers, particularly in resource-limited healthcare
systems.
Immature DCs capture antigens efficiently but are
poor T-cell stimulators, while mature DCs express co-stimulatory
molecules and secrete cytokines essential for T-cell activation.
TLR ligands such as poly(I:C), lipopolysaccharide (LPS) and CpG
oligonucleotides could drive DC maturation and IL-12 production,
favoring Th1 polarization (169,170). These studies highlighted the
promise of pathogen-associated molecular pattern-based cues in
generating immunogenic DCs, though they also revealed the risk of
overstimulation, leading to DC exhaustion or variable cytokine
responses between patients. The kinetics of maturation were
increasingly recognized as critical. Giermasz et al
(171) and Poženel et al
(172) demonstrated that
short-term stimulation of DCs with IFN-γ and TLR ligands could
generate 'type-1 polarized DCs' that retained IL-12p70 secretion at
the time of T-cell encounter, thereby supporting durable Th1 and
CTL responses. These findings emphasized that not only the presence
but also the time window of maturation signals could be important
in determining the functional capacity of the final DC product.
While type-1 polarized DCs offered superior immunogenicity, their
shorter culture duration might have reduced antigen uptake and the
precise implementation of tightly timed protocols posed challenges
for clinical-scale manufacturing.
Cytokine-based differentiation protocols using
GM-CSF and IL-4, followed by TNF-α or PGE2-based
maturation cocktails, were conventional standards for generating
monocyte-derived DCs (173,174). These methods yielded
reproducible results and remained foundational for clinical-grade
DC vaccines. However, limitations included reduced IL-12 production
with PGE2-based maturation and extended culture times
that reduced GMP-level scalability. Addressing these issues, Nava
et al (175) optimized a
GMP-compliant process for producing DC vaccines for glioblastoma,
demonstrating that careful selection of cytokine cocktails and
standardized monocyte isolation techniques could increase yield and
reproducibility. Although such refinements made clinical
translation feasible, they also increased operational complexity
and final production costs. Alternative differentiation strategies
were also explored. IFN-DCs, generated using IFN-α, displayed
superior cross-presentation ability, higher costimulatory molecule
expression and stronger innate crosstalk compared with IL-4 DCs
(176,177). These features might have made
them particularly suitable for poorly immunogenic tumors.
Nonetheless, their distinct ex vivo culture requirements
complicated large-scale production and might have limited their use
outside of specialized facilities.
Novel immune modulators had further expanded the DC
maturation toolkit. CD40 ligand stimulation augmented
cross-presentation, while STING agonists induced type I IFN
production with enhanced CD8+ T-cell priming (178,179). These strategies provided potent
stimulation approaches but held risks of systemic inflammation and
cytokine-related toxicities due to possible over- or hyperimmune
stimulation. Clinical translation was demonstrated in clinical
trials such as TriMixDC-MEL, which used tumor antigen mRNA
alongside CD70, CD40L and caTLR4 mRNAs to generate a highly
immunogenic DC phenotype. Trials of TriMixDC-MEL against melanoma
confirmed safety and indicated potential improvements in
disease-free survival (180,181). These findings highlighted the
feasibility of inducing stimulatory and maturation signaling
directly into DC vaccine constructs, though the added complexity of
mRNA-based engineering posed practical barriers that might lead to
permanent, transcriptomic-level side effects in patients. Nickles
et al (182) extended
this concept with CD137L-DC-EBV-VAX for nasopharyngeal carcinoma,
engineering DCs to express CD137L and thereby enhance
CD8+ memory T-cell generation against Epstein-Barr
virus. This study demonstrated safety and promising immunological
activity, indicating that targeted receptor-ligand engineering
could fine-tune DC maturation to favor long-lived immunity.
However, such disease-specific tailoring might not generalize
across tumor types.
Optimization of these maturation protocols must
specifically account for the unique barriers of the CRC
microenvironment. A significant challenge is CMS4, which is
characterized by high levels of transforming growth factor-beta
(TGF-β) and VEGF, as reported previously. These factors could
actively suppress DC maturation and promote an 'immune-excluded'
phenotype (186). Furthermore, a
number of CRC tumors exhibit a paucity of infiltrating DCs,
particularly in microsatellite-stable (MSS) lesions, which limits
the initial priming of anti-tumor response (187). Therefore, DC vaccines for CRC
must be engineered not only to present antigens but also to
actively reverse the local tolerance. Strategies that preserved
IL-12 competence, incorporated rational costimulatory engineered
signals, leveraged biomaterials, or harnessed oxidative danger
signals appeared as promising strategies for future DC vaccine
developments.
The route of administration profoundly influences
the distribution and immunological activity of DC vaccines that in
turn have an effect on the OS of treated patients. Intradermal and
subcutaneous injections are the most commonly used, capitalizing on
the abundance of skin-resident APCs and efficient access to
draining LNs. Clinical imaging studies confirmed that intradermal
delivery promoted greater DC migration to lymphoid tissues compared
with intravenous administration, where cells were often sequestered
in non-lymphoid organs such as the liver and lungs (150,188). While intradermal delivery
enhanced lymph node access, variability between patients persisted
and repeated injections might be required to maintain immunity.
Subcutaneous administration, though slower in kinetics, was simpler
and more easily tolerated (189). Intravenous delivery was tested
in metastatic disease settings to exploit systemic distribution
(161), but lymph node targeting
remained inefficient.
Imaging technologies have also refined delivery
approaches. Bulte and Daldrup-Link (193), Bulte and Shakeri-Zadeh (194) and Zhang et al (195) developed MRI and PET/SPECT-based
cell-tracking methods to visualize DC migration in vivo,
allowing investigators to identify whether vaccines reached
draining LNs and to troubleshoot failures in targeted cell
trafficking. These techniques served as excellent in vivo
quality-control tools for clinical trials but added complexity and
cost. In parallel, Grippin et al (196) and Fink et al (197) demonstrated that magnetic
nanoparticles could guide DC migration toward LNs, further
improving homing efficiency. These advances pointed toward delivery
systems that were actively controlled and monitored in real time,
rather than based on blind assumptions. This technical optimization
is vital for addressing the clinical disparities observed in CRC
immunotherapy. Currently, although MSI-H CRC patients show
encouraging responses, the vast majority of patients have MSS
tumors, in which the objective response rates to DC vaccines remain
suboptimal, often ranging from 5-10% (186). By using targeted delivery
systems, such as scaffolds or nanoparticles, to concentrate
antigens and adjuvants within TDLNs, researchers aim to bridge this
gap and induce meaningful responses in the 'cold' MSS CRC
population (187).
Clinical translation required attention not only to
delivery routes but also to manufacturing logistics. Boudousquié
et al (168) demonstrated
that oxidized lysate-pulsed DCs could be reliably produced for
multicenter use, while Nava et al (175) developed large-scale protocols
that balanced yield and quality. These examples underscored that
effective delivery could not be divorced from reproducibility and
scalability. An optimized DC vaccine framework, combining the
aspects of broad or specific antigen loading, IL-competent
maturation, lymph node-targeted delivery and integration with
rational checkpoint or cytokine adjunct therapies, might lead to an
improved avenue of therapeutic potency (202). The clinical feasibility of DC
vaccination was definitively demonstrated by the FDA approval of
Sipuleucel-T (Provenge) in 2010 for mCRPC. The findings from a
Phase III clinical trial of Sipuleucel-T have highlighted one of
the key advantages of DC vaccines, the capacity to extend survival
through immune modulation even when conventional
chemotherapy/radiotherapy responses were absent (70). However, Sipuleucel-T also
highlighted challenges that permeated the field. The therapy
required highly individualized manufacturing, multiple
leukapheresis sessions and complex logistics, contributing to high
costs and limiting widespread adoption. Furthermore, the vaccine's
clinical benefit could be improved via combinations with checkpoint
inhibitors or other immunomodulators. Sipuleucel-T thus occupies a
milestone place in the history of cancer vaccinations via DC
vaccines, establishing regulatory precedent and validating
feasibility, while also revealing the economic and logistical
barriers that should be overcome for broader clinical
implementation.
DC-based therapeutic cancer vaccines have been
intensively investigated with the aim of inducing adaptive,
cell-mediated immune responses in cancer patients, thereby
converting the immunologically 'cold tumors' into 'hot tumors' that
are more susceptible to cancer therapy (203-205). In general, DC-based cancer
vaccines are generated by pulsing a patient's DCs with TSAs and
TAAs derived from the patient's tumor tissue, in the form of
recombinant proteins, mRNA, peptides, total RNA, or tumor cell
lysate (TCL) (206,207). The first FDA-approved autologous
DC-based vaccine, Sipuleucel-T (APC-8015), has been marketed since
2010, at a cost of US$ 93,000-100,000 for a complete course of
treatment (70,208,209). Sipuleucel-T was developed by
Dendreon Pharmaceuticals LLC in the US as a therapeutic cancer
vaccine against mCRPC. It stimulates the patient's immune cells to
specifically target and destroy prostate cancer cells without
harming healthy cells. Sipuleucel-T cancer vaccine consists of
autologous monocyte-derived DCs that are ex vivo-activated
with a recombinant fusion protein containing prostatic acid
phosphatase fused to GM-CSF (70). The antigen-loaded DCs are
incorporated into Dendreon's proprietary Antigen Delivery Cassette
and re-infused into the patient via three intravenous (IV)
infusions at 2-week intervals for one month. Based on the latest
multicenter, retrospective study spanning 14 years (2010-2024) in
the US that evaluated the efficacy of Sipuleucel-T treatment in men
with mCRPC, the cohort treated with Sipuleucel-T (n=5,281) had a
median OS of 44 months, while the non-treated cohort (n=5,984) had
a median OS of only 24 months (210). In the cohort treated with
Sipuleucel-T, 28% of the patients were alive at 5 years, with a
median OS of 97 months.
Furthermore, recent and ongoing clinical trials
using autologous DCs pulsed with autologous TCL that were prepared
from patients' tumor have shown promising clinical outcomes in
treating metastatic melanoma, glioblastoma (GBM) and CRC, as well
as in prolonging the median OS, progression-free survival (PFS)
and/or disease-free survival (DFS) of cancer patients (141,211-217). Moreover, these TCL-pulsed DC
vaccines have been consistently shown to be safe and well tolerated
across clinical studies. In particular, a Phase III multicenter
clinical trial of DCVax-L consisting of autologous DCs pulsed with
TCL for the treatment of GBM (NCT00045968), demonstrated that the
addition of DCVax-L to standard-of-care (SOC) temozolomide (TMZ)
was associated with a clinically meaningful and statistically
significant extension of OS in patients with both newly diagnosed
and recurrent GBM, when compared with the control group who
received SOC alone (141). The
DCVax-L-treated cohort of 232 patients with newly diagnosed GBM had
a median OS of 19.3 months, with a 2-fold increase in the survival
rate at 5 years (13%) compared with the control group (5.7%). The
DCVax-L treatment was also found to extend the median OS of 64
patients with recurrent GBM by 5.4 months when compared with the
control group, which had a median OS of 7.8 months from relapse.
The survival rate of these patients was also increased by 2-fold,
reaching 20.7% at 2 years and 11.1% at 2.5 years.
In addition, a randomized Phase II trial
(NCT00948480) of an autologous TCL-pulsed DC vaccine was found to
markedly prolong the survival of 42 patients with metastatic
melanoma by 22.9 months, with a median OS of 43.4 months and
reduced mortality risk by 70% (211). In addition, the safety and
effectiveness of an autologous TCL-pulsed DC vaccine (DCvax) in
patients with unresectable malignant melanoma (stage III or IV)
have been demonstrated in a completed Phase II clinical trial,
ABSIDE (EudraCT 2012-001410-41), in which a median OS of 20.7
months in seven treated-patients was observed (216). This clinical study also showed
that monotherapy with DCvax alone was associated with an improved
OS and a higher immune-related disease control rate of 57% compared
with the combined immunotherapies of DCvax with radiotherapy, IFN-α
or both. The efficacy and safety of this DC-based vaccine approach
were further evaluated in patients with GBM in an ongoing
monocentric Phase II clinical trial, Combi G-vax (EudraCT
2020-003755-15). This trial was conducted in combination with the
standard therapy consisting of concurrent radiotherapy and
temozolomide chemotherapy, known as the Stupp regimen, followed by
a maintenance phase using TMZ alone. Vaccination with autologous
TCL-pulsed DCs in nine patients with GBM was well tolerated and
safe, resulting in a median OS of 23.1 months and a median PFS of
11.3 months (215).
Early Phase I and Phase II clinical trials of an
allogeneic melanoma TCL vaccine (Melacine), which was prepared from
two melanoma cell lines and co-administered with the adjuvant
Detox, demonstrated limited anti-tumor responses in patients with
stage IV melanoma (218,219). Subsequently, in a randomized
Phase III trial conducted by the Southwest Oncology Group (SWOG;
SWOG-9035), Melacine did not improve DFS and OS in the overall
cohort of 300 patients with resected intermediate-thickness,
node-negative melanoma (T3N0M0), in which a 5-year DFS rate of 65%
was observed in the vaccinated patients (220). The survival benefit of Melacine
was restricted to patients with HLA class I antigens A2 and/or
HLA-C3, limiting its broader application. A total of 178
Melacine-treated patients with HLA-A2 and/or HLA-Cw3 serotype had a
markedly improved relapse-free survival (RFS) and OS, with 5-year
RFS of 78% and 5-year OS of 90% (221).
In addition, a Phase I clinical trial (NCT06556004)
of direct vaccination with allogeneic heat-shocked melanoma cell
lysate prepared from three human melanoma cell lines (TRIMELVax) in
combination with mollusk-derived hemocyanin as an adjuvant, showed
moderate preliminary clinical outcomes, with a median OS of 11.6
months and PFS of 4.5 months in 17 nivolumab-refractory patients
with unresectable stage III or IV melanoma (222). Although TRIMELVax vaccination
presented an acceptable safety profile, further studies are needed
to determine the effectiveness of this vaccine that did not use
ex vivo-generated DCs. These early clinical trials of
allogeneic TCL vaccines provided foundational evidence supporting
the immunologic and clinical potential of lysate-based active
immunotherapy. However, their limited clinical outcomes highlighted
the need to use DCs that are ex vivo-activated with TCLs to
achieve greater clinical benefits in cancer treatment. Moreover,
ex vivo loading of DCs with TAAs has been shown to
outperform irradiated autologous tumor cell-based vaccine, as
evidenced in a Phase II trial (NCT00948480) (211).
In clinical trials, DC-based vaccines have been
applied as both stand-alone and complementary therapeutic therapies
for various types of cancers with solid tumors, with the primary
aim of stimulating a tumor-specific cell-mediated immune response
against cancer cells. As a complementary approach, DC vaccines are
often combined with other established treatments such as
chemotherapy, radiotherapy or newer immunotherapies, such as ICB to
enhance overall cancer treatment efficacy. Notably, pMMR or MSS
metastatic CRC accounts for ~95% of CRC cases (223). pMMR/MSS CRC typically results in
a 'cold' TME characterized by limited infiltration of T cells into
the tumors, making it resistant to standard ICB immunotherapy alone
(223-225). By contrast, metastatic CRC with
mismatch repair-deficiency (dMMR) or MSI-H has been shown to be
susceptible to ICB immunotherapy using pembrolizumab, a humanized
monoclonal IgG1 antibody targeting PD-1 in a Phase III clinical
trial, Keynote-177 (NCT02563002), resulting in a significant median
PFS of 16.5 months and overall response rate of 43.8% in 153
patients (226). Apart from
pembrolizumab, nivolumab in combination with ipilimumab has
recently been approved by the FDA following significant clinical
outcomes in a Phase III CheckMate 8HW trial (NCT04008030) for the
treatment of patients with dMMR/MSI-H metastatic CRC (227,228). Nevertheless, as most CRC cases
belong to pMMR/MSS and are not susceptible to ICB immunotherapy
(223), DC vaccines remain a
promising alternative immunotherapy for pMMR/MSS metastatic CRC.
Hence, the efficacy of DC-based vaccines against metastatic CRC has
been evaluated in combination with ICB treatment in recent clinical
trials (214).
An earlier Phase II randomized clinical trial
(NCT01413295) using autologous TCL-pulsed DCs to treat 28 patients
with progressive metastatic CRC showed no clinical benefit for OS
and PFS, although this DC vaccine induced a tumor-specific T-cell
response in 84% of patients (21/25) (229). This vaccine treatment only
extended the median OS by 1.5 months and median PFS by 0.4 months
compared with untreated-patients, who had a median OS of 4.7 months
and median PFS of 2.3 months (Table
I). As no clinical benefit in OS and PFS was observed in this
trial, this DC-based vaccine was not advanced to a Phase III trial
as monotherapy. Following that, the efficacy of this DC vaccine was
assessed in combination with ICB therapy using avelumab (an
anti-PD-L1 monoclonal antibody) against mismatch repair-proficient
metastatic CRC in a Phase I/II multicenter clinical trial, GEMCAD
1602 (NCT03152565) (214). This
clinical study demonstrated a median OS and PFS of 12.2 months and
3.1 months, respectively; however, no objective responses were
observed and only 2 out of 19 patients (11%) were disease-free at 6
months. These two clinical trials were recommended for early
termination following interim analyses due to the lack of efficacy
of the DC vaccine.
Furthermore, DC-based vaccines have demonstrated
potential benefits in metastatic CRC patients with resectable liver
metastases, an unmet clinical need due to the high risk of
recurrence. In a Phase II randomized clinical trial (NCT01348256),
autologous TCL-pulsed DC vaccine was shown to prolong median DFS by
15.73 months in metastatic CRC patients with liver metastases,
compared with untreated patients who had a median DFS of 9.53
months (Table I) (212). Additionally, DC vaccines have
been applied as adjuvant immunotherapy on metastatic CRC patients
following complete surgical resection of metastases, aiming to
prevent CRC recurrence. A previous clinical study demonstrated a
marked improvement of RFS in 15 of 24 patients with metastases of
metastatic CRC. This was achieved through the induction of a
tumor-specific T-cell proliferative response by the autologous
TCL-pulsed DC vaccine, in which a significant 45% increase in the
5-year RFS rate (63%) was observed relative to nonresponders
(230). In this clinical study,
out of 24 patients, eight remained alive and disease-free and four
remained alive with recurrent disease for at least 5.5 years after
DC vaccine treatment.
In addition, the efficacy of autologous DCs pulsed
with allogeneic melanoma cell lysate was evaluated in 20 patients
with advanced CRC expressing at least one of six MAGE-A
genes (231). This Phase II
clinical trial demonstrated a clinical benefit response rate of
40%; however, no complete responses were observed (Table II). The trial reported a median
OS of 7.4 months and median PFS of 2.4 months. Among the patients
with partial response (n=1) and stable disease (n=7), a median OS
of 18.1 months was observed. Notably, this allogeneic melanoma cell
lysate-pulsed DC vaccine prolonged the PFS of 25% of the patients
(5/20) for more than 6 months, with two of these patients remained
progression-free for over 27 and 37 months, respectively (231).
Apart from conventional stand-alone DCs, a
combination immunotherapy consisting of an autologous TCL-pulsed DC
vaccine and cytokine-induced killer cells (DC-CIK) was shown to
markedly improve the survival of 27 patients with CRC, with a
5-year OS rate of 75% and a 5-year DFS rate of 66%, when compared
with patients in the control group with a 5-year OS rate of 15% and
5-year DFS rate of 8% (232).
This DC-CIK immunotherapy also resulted in a significant reduction
in the risk of postoperative disease progression in CRC patients.
Furthermore, autologous DC-CIK therapy combined with standard
chemotherapy has been shown to be more effective than the control
group (receiving standard chemotherapy alone) in markedly
increasing the median OS by 4.5 and 5.13 months in refractory
metastatic CRC patients without and with liver or extra-regional
lymph node metastases, respectively (14.23 and 11.87 months in
controls) and achieving a median PFS of 7.63 months (Table II) (233).
A recent ongoing Phase II multicenter clinical
trial (NCT06522919) is evaluating the clinical efficacy of an
innovative combination immunotherapy involving an TCL-pulsed DC
vaccine in combination with ICB using pembrolizumab, followed by a
maintenance chemotherapy with Trifluridine/Tipiracil and
bevacizumab (known as CombiCoR-Vax) in treating refractory pMMR or
MSS metastatic CRC. The innovative strategy of CombiCoR-Vax was
inspired by a Phase III clinical trial (NCT04737187), which
reported a significant improvement in OS and PFS in patients with
refractory metastatic CRC after chemotherapy treatment with
Trifluridine/Tipiracil plus bevacizumab (FTD/TPI + BEV) (234). In addition, an ongoing Phase II
monocentric clinical trial (NCT02919644) is assessing the safety
and immunological efficacy of an autologous TCL-pulsed DC vaccine
(COREVAX-1), followed by a subcutaneous injection of IL-2 in
patients with stage IV CRC after curative resection. A Phase III
clinical trial on the safety and efficacy of an autologous DC
vaccine loaded with autologous TCL in combination with a modified
chemotherapy regimen of Oxaliplatin, 5-Fluorouracil and Leucovorin
(mFOLFOX-6) has been proposed (NCT02503150), yet its current status
remains unknown, with the last known update indicating that no
participants had been recruited.
The immunogenicity, safety and efficacy of
autologous DC vaccines pulsed with TAAs in the form of peptides
have been evaluated in several early-phase clinical studies. CEA
has been primarily targeted as a TAA in this peptide-pulsed DC
vaccine because of its overexpression in the serum of ~70% of CRC
patients (235). Although CEA is
the most commonly used tumor biomarker for CRC diagnosis, it is not
specific to CRC as elevated CEA levels can result from other
cancers such as pancreatic, breast, lung, liver, prostate and
ovarian cancers, or non-cancerous conditions including
pancreatitis, hepatitis, obstructive pulmonary disease,
hypothyroidism, chronic kidney disease, smoking, chronic renal
failure, Alzheimer's disease and ulcerative colitis (236,237).
Most clinical trials of CEA peptide-pulsed DC
vaccines in advanced CRC were early-phase, focusing on safety and
immunogenicity of the vaccines (Table II). These vaccines were safe and
capable of stimulating potent CEA-specific T-cell responses in at
least 70% of vaccinated patients (238-240). In a Phase I trial (NCT00228189),
the immunogenicity of CEA mRNA-transfected DC vaccine in patients
with resectable liver metastases of CRC was not found to be
superior to DC vaccine pulsed with CEA peptide, in which no
CEA-specific T-cell responses were observed in all five patients
vaccinated with CEA mRNA-electroporated DCs (240). The efficacy of the CEA
mRNA-pulsed DC vaccine treatment in metastatic CRC patients with
liver metastases was also shown in a Phase II clinical study
(241). Although the vaccination
was well tolerated, out of 13 patients, nine patients experienced
recurrence with a median time to recurrence (TTR) of 122 days and
three patients remained disease-free for at least 16.7 months.
Among other TAAs, Wilms' tumor 1 (WT1) has been
used to prime DCs against CRC. In a Phase I clinical study, WT1
peptide-pulsed DC vaccine induced durable WT1-specific cytotoxic
T-cell responses lasting for at least two years in three patients
with advanced CRC, with a calculated median DFS of 24.5 months and
a median OS of 43.6 months (242). Furthermore, vaccination with
autologous DCs pulsed with recombinant human CEA protein in
combination with tetanus toxoid adjuvant and subsequent IL-2
treatment in a Phase I clinical trial (NCT00154713), showed a safe
profile but limited clinical benefits in 12 patients with
metastatic CRC (243). Similar
modest clinical efficacy was also observed in a Phase I/II clinical
study of autologous DCs loaded with CEA peptide in eight patients
with stage IV CRC (244). Taken
together, it appears likely that pulsing DCs with TAA in the form
of peptides provides improved antigen-specific T-cell responses
than mRNA- or protein-based approaches; however, further clinical
studies are necessary to clarify the clinical impact of
peptide-pulsed DC vaccines in CRC.
A practical clinical trial framework for assessing
the effectiveness of DC vaccines in humans is of utmost importance.
It would be ideal to evaluate the safety and efficacy of autologous
with TCL-pulsed DC vaccine in an early-phase clinical trial
involving patients with metastatic CRC after complete resection of
metastases or patients with high-risk stage III CRC following
standard adjuvant chemotherapy. This allows the effectiveness of DC
vaccines to be assessed among cancer patients with minimal residual
disease or clinically disease-free after standard adjuvant
chemotherapy, thereby creating a condition that is favored for
immunotherapy and where any benefits from the DC vaccine treatment
would be adjunctive to standard chemotherapy. In particular, a
single-arm, open-label Phase I/II trial can be conducted to assess
safety, feasibility and preliminary efficacy, with safety as the
primary endpoint and OS and PFS as secondary endpoints.
Furthermore, utilization of autologous TCL as an antigen to prime
DCs represents a promising strategy for the generation of potent DC
vaccines (245). Pulsing DCs
with autologous TCL prepared from fresh tumor tissues as soon as
possible (typically within a few hours) after surgical resection is
preferred, as this preserves optimal antigen quality.
Additionally, it is worthwhile to evaluate the
efficacy of TCL-pulsed DC vaccines in combination with other
immunotherapies, especially ICB therapy using the combination of
nivolumab and ipilimumab, which has been approved by FDA following
evidence of significant clinical benefits (227,228). The efficacy of DC vaccines in
combination therapy warrants assessment in a multi-arm, randomized,
controlled Phase II trial, with DFS as the primary endpoint and OS
as the secondary endpoint. Overall, the clinical trial framework
shall be carefully designed and conducted in accordance to the
study objectives, in order to achieve appropriate patient selection
with a clearly defined inclusion and exclusion criteria of the
targeted population, clinically meaningful primary and secondary
endpoints and standardized protocols in DC vaccines preparation to
ensure reliable and consistent clinical outcomes.
The immunogenicity and safety of DC-based vaccines
in treating CRC have been evidenced in numerous clinical studies;
however, their clinical outcomes, especially when applied as
monotherapy, remain suboptimal in the majority of patients. These
limitations can be ascribed to several major challenges associated
with DC-based vaccines for CRC, including tumor heterogeneity, an
immunosuppressive TME and suboptimal T-cell activation. Tumor
heterogeneity in CRC remains a major challenge that limits the
effectiveness of DC vaccines, particularly when the antigen loaded
onto the DCs is a neoantigen, such as TAA or TSA, which is
delivered in the form of a recombinant protein or peptide.
Neoantigen-based DC vaccines are currently considered one of the
most promising approaches for cancer therapy as demonstrated by the
success of Sipuleucel-T, the first FDA-approved DC-based vaccine
for mCRPC. However, the identification of immunogenic neoantigens
that are uniformly expressed across all tumor cells is laborious,
as it requires deeper sequencing such as single-cell sequencing and
Ribo-seq (246-248) and advanced bioinformatics,
including the use of deep learning algorithms for enhancing the
precision of in silico neoantigen prediction (249,250), to address the high
false-positive rate of candidate neoantigens and low accuracy
related with current prediction tools. Additionally,
proteogenomics, which integrates genomic data with advanced mass
spectrometry-based proteomics, has emerged as a promising novel
strategy for discovering and identifying neoantigens in solid
tumors (251,252).
The TME in CRC can suppress anti-tumor immune
responses by inhibiting the proper maturation and function of DCs
through immunosuppressive mediators, including the secretion of
soluble factors such as VEGF, TGF-β, IL-6, IL-10 and
PGE2, the production of β-catenin and ROS and the
induction of immune checkpoint expression of PD-L1 on DCs (187). As well as this, the metabolic
composition of the TME, such as lipid peroxide byproducts, can lead
to lipid accumulation in DCs that blocks antigen
cross-presentation, thus reducing T-cell activation by DCs
(118). In the CRC TME, cancer
cells actively recruit and promote the activity of
immune-suppressing cells such as Tregs, especially those with high
expression levels of forkhead box P3 and MDSCs, which further
promote immunosuppression within the TME and thus allow cancer
cells to evade immune surveillance (187,253). Furthermore, cancer cells can
downregulate or lose MHC class I molecules to avoid recognition by
tumor antigens presented by MHC class I molecules, thus inhibiting
T cell-mediated immune response (254).
In the TME, upregulated expression of immune
checkpoint molecule PD-L1 on tumor cells and DCs, especially the
type I cDCs upon antigen uptake, can dampen the anti-tumor response
of PD-1-positive T cells and thus prevent tumor cells from being
killed by CTLs (255). The CRC
TME can induce immune-tolerant mature DCs enriched in
immunoregulatory molecules (mregDCs), a novel DC subset found in
the TME (256), via the
expression of the TAM family receptor tyrosine kinases such as
TYRO3, AXL and MER on apoptotic tumor cells following phagocytosis
by cDCs, thus leading to tumor immune escape (187). Previous studies have shown that
high-mobility group box 1 protein (HMGB1) and mucin 2 produced by
CRC cells could induce apoptosis of DCs (257,258), causing the suppression of
anti-tumor immunity and immune evasion due to the substantial loss
of DCs in the TME.
Another challenge in DC-based vaccine application
lies in the technical limitations of DC-based vaccine production.
These include generating monocyte-derived DCs at optimal amounts,
achieving optimal loading of tumor antigens on DCs and ensuring
efficient delivery of antigen-loaded DCs to the targeted tumor
cells. Scaling up the production of personalized DC-based vaccines
from laboratory research to large-scale manufacturing remains a
major obstacle, as the ex vivo generation and culture of
autologous antigen-loaded DC vaccines are operationally complex,
costly and require GMP-compliant facilities, constituting one of
the limitations to their widespread clinical use in cancer
treatment.
In view of the immunosuppression on the function of
DCs and the limited number of activated DCs in the CRC TME,
DC-based vaccines could be an ideal approach to overcome this
challenge through the ex vivo generation of activated DCs
loaded with tumor antigens at higher cell numbers. The
antigen-loaded DCs, which lack PD-L1 expression on their cell
surface, are then re-infused into the patient to train and activate
T cells to specifically target and destroy cancer cells. Pulsing
DCs with TCL derived from a patient's own tumor is an advantageous
strategy to address the challenge of tumor heterogeneity, as the
DCs will be loaded with a broad repertoire of TAAs, including
patient-specific TSAs, which is crucial given CRC's heterogeneity.
This, in turn, allows for comprehensive immune activation, leading
to improved tumor recognition and immune targeting. To promote
enhanced tumor-specific immunity via pulsing DCs with TAAs, other
potential tumor biomarkers for CRC, such as carbohydrate antigen,
tissue polypeptide-specific antigen and tumor-associated
glycoprotein 72, can be targeted as single or multiple TAAs,
particularly in the form of peptides (235,262). Nevertheless, artificial
intelligence (AI)-driven identification of efficacious neoantigens
for CRC from experimental and in silico data can streamline
the design of personalized, potent DC-based vaccine immunotherapy
(263,264).
As the TAAs released from immunogenic cell death of
tumor cells are rapidly cleared by efferocytosis mediated by MER
proto-oncogene tyrosine kinase (MerTK) recognition of
phosphatidylserine on apoptotic tumor cells, nanovaccines mU@OMVs,
consisting of the MerTK inhibitor UNC2025 encapsulated within
bacterial outer-membrane vesicles (OMVs), have been applied to
overcome this issue (266).
Phagocytosis of mU@OMVs by tumor-associated macrophages (TAMs)
subsequently inhibited MerTK phosphorylation, thus delaying the
clearance of apoptotic tumor cells. The inhibition of MerTK
signaling led to tumor cell apoptosis and secondary necrosis, that
further increased the abundance of TAAs and created in situ
'antigen libraries' that were then captured by the maleimide groups
attached to the surface of mU@OMVs. This localized TAA enrichment
enhanced the activation of DCs and provoked robust anti-tumor
T-cell responses. The application of biomimetic nanovaccines using
tumor cell membrane-coated nanoparticles has been shown to
effectively induce intense anti-tumor immune responses through
enhanced broad antigen repertoire presentation to DCs (267,268). Additionally, biomimetic
nanovaccines coated with cancer cell membrane have been
demonstrated to synergistically potentiate more effective
anti-tumor immunity when combined with an ICB cocktail consisting
of anti-CTLA4 and anti-PD1 (269).
DC-based vaccines can be combined with other cancer
therapies, especially ICB immunotherapy using FDA-approved
monoclonal antibodies such as pembrolizumab, nivolumab and
ipilimumab (228), to achieve
enhanced cell-mediated immune responses and optimal clinical
benefits in cancer therapy. Additionally, emerging next-generation
nanotechnology, including the use of nanoparticles and potential
future nanorobots, can markedly enhance the efficacy of DC-based
cancer vaccines by improving antigen delivery, promoting DC
maturation and migration to LNs and delivering adjuvants that
create a stronger anti-tumor immune response, leading to more
effective T-cell activation and improved therapeutic outcomes
(270). Although the limited
number of activated DCs in the TDLNs is still sufficient to induce
antigen-specific anti-tumor responses (259), augmenting DC numbers in the
TDLNs to an optimal level is essential for enhancing anti-tumor
immune responses. Nanorobots within a specific size range of 20-45
nm, such as DNA origami-based constructs, can efficiently drain to
LNs (271,272). Thus, nanorobots represent a
promising application to promote the migration of antigen-loaded
DCs to LNs, where DCs can interact with T cells and initiate the
immune response more effectively.
The unique ability of DC-based cancer vaccines in
initiating and shaping tumor-specific cell-mediated immune
responses makes them a compelling avenue for CRC immunotherapy.
Despite the safety, feasibility and immunogenic potential of
DC-based vaccines for advanced CRC, their clinical efficacies have
been inconsistent and generally modest when applied as monotherapy.
Hence, further clinical research to determine the optimal
combination therapies with DC-based vaccines is warranted to
improve the effectiveness of DC vaccines against CRC. While the
challenges in generating an effective DC-based CRC vaccine remain,
addressed partly through combination immunotherapy with ICBs, the
additional integration of emerging nanotechnology as well as the
application of AI in neoantigen selection pave the way for
development of more potent DC-based cancer vaccines for advanced
CRC, transforming them from experimental therapy to clinically
viable therapeutic cancer vaccines in the era of precision
medicine.
Not applicable.
CLP and SKT conceptualized the review manuscript.
LYP and SAH conducted literature search. LYP and SAH drafted the
original manuscript. LYP, SAH, CLP, SKT, RM, CYW and KSP reviewed
and edited the manuscript. CLP and SKT supervised this work. Data
authentication is not applicable. All authors read and approved the
final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
During the preparation of this work, AI tools were
used to enhance the readability and language of the manuscript and
to generate some images. The authors revised and edited all
AI-assisted content and take full responsibility for the final
version.
Not applicable.
No funding was received.
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