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1011
Review
IS SN 175 0 -743X10.2217/IMT.12.108 © 2012 Future Medicine Ltd Immunotherapy (2012) 4(10), 1011–1022
Dendritic cell-based immunotherapy in
mesothelioma
Asbestos was named by the ancient Greeks, its
name meaning ‘inextinguishable’. It has been
said that the Greeks also noted its harmful
effects in the first century AD: “sickness of the
lungs” was described in asbestos quarry slaves
or slaves who wove asbestos into cloth, leading
to a recommendation not to buy these slaves as
they often “died young” [ 20 1] . The use of asbestos
declined during the Middle Ages, but it regained
popularity during the Industrial Revolution in
the late 1800s. At the turn of the 20th century,
researchers began to notice a large number of
deaths and lung problems in people living in
asbestos mining towns and during the first dec-
ades of that century, an expanding number of
articles appeared in medical journals [1 –3] , and
some authors suggested a link between inhala-
tion of asbestos fibers and carcino genesis [4 ,5] .
The term ‘mesothelioma’ entered the medical
literature in 1931 when Klemperer and Rabin
described the distinct features of these dif-
fuse pleural neoplasms [6 ]. It was, however, not
until 1960 that the link between asbestos fib-
ers and mesothelioma became incontrovertible
with an article published in The Lancet entitled
“Primary malignant mesothelioma of the pleura”
by Eisenstadt and Wilson [7] . Over the last dec-
ades, the association between asbestos exposure
and subsequent development of mesothelioma
has been extensively studied in multiple ani-
mal species via inhalation of, or subcutaneous,
intrapleural and intra peritoneal inoculation
with, asbestos fibers [8–11] . Inhaled asbestos
fibers within the lung cause infiltration of cir-
culating macrophages into the pleural space,
where the macrophages try to phagocytose the
inhaled foreign bodies [12 ] . In the effort to clear
these asbestos fibers, reactive oxygen species
are generated, causing DNA damage to nearby
cells. Subsequently, inflammatory cytokines
and recruitment of immune cells to sites of
inflammation within the pleura are induced
[13 –1 6] . Given the large size of the asbestos fib-
ers, macrophages fail to clear the asbestos fib-
ers, resulting in continued generation of reactive
oxygen species and secretion of proinflammatory
cytokines [1 6] , a process often called ‘frustrated
phagocytosis’ [17] . In addition to this procarci-
nogenic and proinflammatory substance release,
asbestos fibers can sometimes directly penetrate
the cells and damage chromosomes. Also, the
retained asbestos fibers may adsorb other car-
cinogens on their surface [1 8– 2 2] . As a result,
DNA alterations occur, such as in activation of
p16INK4a/p14ARF, NF2/Merlin and L ATS2,
and the activation of YAP [2 3, 24] .
In contrast to the increase in knowledge of
the etiology of mesothelioma, the treatment
options for mesothelioma are still scarce and
prognosis is poor, with a median survival of only
9–12 months after diagnosis.
Surgery for mesothelioma is a very contro-
versial subject, with the number of randomized
controlled trials being small. Most thoracic
surgeons would agree that a complete resec-
tion for mesothelioma is only possible in a
Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce
and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several
studies have investigated immunotherapeutic strategies to improve the prognosis of patients with
mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to
attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be
unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a
promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an
update and provides a future perspective in which immunotherapy may improve the outcome of
mesothelioma therapy.
KEYWORDS: dendritic cell n immature dendritic cell n immunotherapy
n mesothelioma n myeloid-derived suppressor cell n regulatory T cell
n tumor-associated macrophage
Robin Cornelissen*1,
Lysanne A Lievense1,
Marlies E Heuvers1,
Alexander P Maat2,
Rudi W Hendriks1,
Henk C Hoogsteden1,
Joost P Hegmans1
& Joachim G Aerts1
1Depart ment of Pulmon ary Medic ine,
Erasmus MC, S V-125, PO-B ox 2040,
3000C ARoerda m,TheNether lands
2DepartmentofThora cicSurger y,
Erasmus Medic al Center – Daniel den
Hoed Cancer Center, University
MedicalCe nter,Roerdam,
TheNetherlands
*Authorforcorre spondenc e:
r.cornelissen@erasmusmc.nl
part of
part of
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Dendritic cell-based immunotherapy in mesothelioma ReviewReview Cornelissen, Lievense, Heuvers et al.
limited number of patients. Whether there is
a role for surgery in the other patients is not
known. Also, conflicting opinions regarding
the optimal surgical procedure exist; in effect,
extrapleural pneumonectomy or various forms
of pleurectomy/decortication, with the current
trend towards more localized resections [2 5, 26 ] .
Chemotherapy was the only treatment that
improved survival in randomized controlled tri-
als in mesothelioma patients. This is based on
a study by Vogelzang and colleagues in 2003,
in which they compared cisplatin alone with a
combination of cisplatin and pemetrexed that
resulted in a survival advantage of over 3 months
for the combination therapy arm [27] . This led to
the approval of the combination of cisplatin and
pemetrexed as ‘standard of care’ for the treat-
ment of patients with ‘unresectable’ mesothe-
lioma. It should be noted that similar outcomes
were reached with cisplatin and raltitrexed
compared with cisplatin alone, confirming that
a combination of cisplatin and an antifolate is
superior to cisplatin alone in patients with mes-
othelioma [28]. Whether the antifolate/cisplatin
combination is the most effective chemothera-
peutic option remains uncertain, since no head-
to-head chemotherapeutic comparison has been
performed in mesothelioma. For example, the
comparison between the current standard regi-
men of cisplatin plus pemetrexed versus gemcit-
abine plus cisplatin, mitomycin, vin desine plus
cisplatin or vinorelbine. However, for every
individual agent previously studied, the survival
improvement was modest.
Several targeted agents have been extensively
studied in mesothelioma. EGF receptor (EGFR)
inhibitors were thought to be a promising target
for mesothelioma therapy since studies showed
that EGFR was highly expressed in malignant
mesothelioma [29,30]. However, most likely due
to absence of sensitizing mutations in the EGFR
tyrosine kinase domain, the results of these clini-
cal trials were disappointing [31 ,32]. Remarkably,
in peritoneal mesothelioma, there were reports of
novel EGFR mutations with a possible sensitivity
to erlotinib [33] , but these have been contradicted
by others [34 ]. A mong the anti-angiogenic agents,
thalidomide is the most extensively studied drug.
After numerous previous trials, the Phase III
trial NVALT 5/MATES with thalidomide as
switch maintenance in nonprogressive patients
after first-line pemetrexed chemotherapy could
unfortunately not prove a survival advantage [35] .
Phase II clinical trials of VEGF tyrosine kinase
inhibitors have shown, at best, modest activity in
mesothelioma [36, 37] . Bevacizumab, a humanized
anti-VEGF antibody, is currently being studied
for use in mesothelioma in addition to chemo-
therapy in France and Belgium in a Phase III
trial [2 02] , following several Phase II trials with
variable results [38] . An increasing amount of
preclinical data highlighting the effectiveness of
histone deacetylase inhibitors in mesothelioma
cell lines and mouse xenograft models has led to
a number of early-phase clinical trials in patients
with mesothelioma [39] . The results of these
efforts have led to a multicenter, randomized,
placebo-controlled Phase III study of the histone
deacetylase inhibitor vorinostat in patients with
advanced mesothelioma, which did not improve
survival compared with placebo as second-line
therapy for mesothelioma [4 0] . In conclusion,
there are no promising chemotherapeutic or
targeted agents on the horizon for patients with
mesothelioma. Clearly, there is a need for new
approaches in the treatment of mesothelioma.
Sporadically, a mesothelioma patient has
a tumor that regresses spontaneously. This
observation is ascribed to the immune system,
which may invoke a clinical response in mes-
othelioma patients under some circumstances
[41–43] . Mesothelioma is indeed an immunogenic
cancer and can induce immune recognition,
immune cell infiltration and immune-mediated
killing, the extent of which may define disease
prog nosis. As early as 1982, the impact of T-cell
infiltration on survival in mesothelioma patients
was demonstrated, showing a positive correla-
tion between T cells and increased survival [4 4] .
More recently, subtyping of T cells showed that
high frequencies of CD8+ tumor-infiltrating
T cells had a positive effect on progression-free
and overall survival, while increased frequencies
of CD4+CD25+ Tregs and CD45RO+ memory
T cells tended to be negative prognostic indica-
tors [45]. Higher frequencies of infiltrating CD3+
T cells correlated with worse overall survival in
patients having mesothelioma with sarcoma-
toid or biphasic histology [4 6] . In addition to
the immunogenic characteristics of the tumor,
exposure to asbestos fibers also has significant
negative direct effects on several components of
the immune system [47] . These findings indicate
that people exposed to asbestos fibers possess
reduced tumor immunity, making them more
sensitive to cancer development.
In summary, understanding the immune sys-
tem and developing mechanisms to activate it or
to overcome immune suppression could prove
beneficial to the patient; a therapeutic strategy
called immunotherapy. In this review, we discuss
the progress of immunotherapy in meso thelioma
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over the years and focus on DC-based immuno-
therapy, since the stimulation of these powerful
APCs appears to be a very effective method of
inducing an antitumor response.
Immunotherapy in mesothelioma
The first attempts to activate the immune sys-
tem in mesothelioma were published 30 years
ago with the BCG vaccine trial that favored a
nonspecific activation of the immune response
[48 ,49] . The use of IL-2 to stimulate the immune
response was investigated more than 10 years
later [5 0 ,51] , and other activators of the immune
response, such as GM-CSF, IFN-g and IFN-a2a,
followed [52 –5 4] . However, these therapeutic
approaches have been abandoned owing to lack
of efficacy or unacceptable toxicity.
Due to its location in the pleural cavity, the
possibility of local vector administration to
apply immunotherapy via gene transfer appears
to be an attractive strategy in mesothelioma. In
a recently published pilot and feasibility trial
using an adenovirus vector expressing a homo-
logous type 1 human interferon gene (IFN‑a2b),
antitumor humoral immune responses against
mesothelioma cell lines were seen in seven of the
eight subjects evaluated. Furthermore, evidence
of disease stability or tumor regression was seen
in the remaining five patients, including one
partial tumor regression at sites not contiguous
with vector infusion [55] .
Preclinical studies targeting mesothelin,
a differentiation antigen present on normal
mesothelial cells and overexpressed in several
human tumors including mesothelioma, as
well as ovarian and pancreatic adeno carcinoma
[56 ] , with immunotoxins CAT-5001 (formerly
SS1P) and amatuximab (previously known
as MORab-009) were promising [5 6 –58 ] .
Unfortunately, in clinical trials CAT-5001
showed only modest clinical responses in meso-
thelioma patients [5 7,5 8] , and amatuximab failed
to demonstrate any radio logical responses in a
Phase I trial in meso thelioma and other cancer
types [5 9] . Preclinical studies demonstrated sig-
nificant antitumor efficacy using a combination
of amatuximab and chemotherapy treatment
[60] , justifying a multicenter Phase II clinical trial
utilizing cisplatin/pemetrexed with amatuximab
in meso thelioma patients. The preliminary out-
comes of this trial were recently presented and
showed that amatuximab in combination with
chemotherapy resulted in 90% of patients hav-
ing an objective tumor response or stable disease
[61] . However, progression-free survival was not
significantly different from historical results of
patients treated with chemotherapy only. More
recently, a Phase I study of SS1(dsFv)PE38, a
recombinant antimesothelin immunotoxin, was
commenced, which is ongoing at the time of
writing [203].
In addition to the agents mentioned above, it
is also possible to use immune cells for immu-
notherapy in mesothelioma. One approach is
to make use of lentiviral or retroviral vectors to
transduce T cells with modified T-cell receptors
engineered to attack specific tumor antigens [62] .
Preclinical results of this method are promising
[63] and this approach will proceed to a clinical
trial at the University of Pennsylvania (USA).
Adoptive transfer of lymphocytes with tumori-
cidal properties can, in theory, bypass the daunt-
ing task of breaking tolerance to tumor antigens
and generating a high frequency of high-avidity
effector T cells. In a preclinical mesothelioma
model, tumor-reactive T cells expressing chi-
meric antigen receptors were found to mediate
regression of the tumor [64] .
Another approach is to stimulate the APCs,
which in turn can induce a specific T-cell anti-
tumor response. In this field, dendritic cell
(DC)-based therapy has proven itself very prom-
ising. The present authors have recently pub-
lished the results of a clinical trial with dendritic
cell-based immunotherapy in mesothelioma [65] .
DCs
DCs were first described by Steinman, a discov-
ery for which he was awarded the Nobel Prize in
2011 [6 6] . These cells are widely acknowledged
as the central surveillance cell type and play
a pivotal role in the initiation and program-
ming of tumor-specific T-cell responses [66–69].
DCs are the most potent APCs specialized in
inducing activation and proliferation of CD8+
cytotoxic T lymphocytes (CTLs) and helper
CD4+ lymphocytes. DCs originate from bone
marrow precursors and migrate to peripheral
tissues, where they differentiate into immature
DCs. Immature DCs capture tumor-associated
antigens (TAAs) and start migrating via lym-
phatic vessels to regional lymphoid organs. This
migration is coordinated by chemokines and
their receptors, matrix molecules and adhesion
molecules on DCs, as well as the surrounding
tissues. DCs mature en route; activating their
ability to convert antigens to 10–15-mer pep-
tides bound to MHC class I and II molecules.
Mature DCs upregulate production of sur-
face costimulatory molecules (e.g., CD80 and
CD86) and cytokines needed to stimulate lym-
phocytes in the tumor-draining lymph nodes.
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DCs present tumor antigens to naive CTLs,
among other cells [70 –73] , inducing antitumor
immune responses.
However, tumors induce a microenvironment
that interferes with the natural development and
function of DCs by a number of mechanisms
(Figu re 1)
.
A growing tumor may outgrow its blood sup-
ply, leaving portions of the tumor milieu
deprived of adequate oxygen supply (hypoxia).
Under these conditions the expression of
matrix metalloproteases and the migratory
activity of DCs is suppressed [74, 75] ;
Tumor metabolites, such as lactic acid, arach-
idonic acid metabolites (prostanoids) and
gangliosides, contribute to DC dysfunction
[76–7 8];
The list of tumor-derived cytokines and
chemo kines is constantly growing and
includes, but is not limited to, IL-1, IL-2,
IL-4, IL-6, IL-8, IL-10, IL-15, VEGF, TFG-b,
TNF-a, EGF, FGF, HGF and MIP [79] , of
which IL-10 and TGF-b seem to be the best
characterized tumor-derived cytokines with
well-defined immunosuppressive function;
Besides the induction of defective DC func-
tion, tumor-induced factors can also skew the
differentiation of monocytes/DCs toward
alternatively activated macrophages and
endothelial-like cells [80– 82] ;
Tregs – immune cells that are abundantly pre-
sent in the tumor microenvironment – can
impede DC function.
Cumulatively, these mechanisms result in
DCs that express substantially lower levels of
MHC class II molecules, adhesion molecules
and costimulatory molecules than under nor-
mal conditions, and that are consistent with the
phenotype of nonactivated DCs [83 ,8 4] . These
tolerogenic DCs are impaired in their ability
to phagocytose antigens and stimulate T cells.
They also contribute to the recruitment, expan-
sion and function of Tregs, leading to a defective
induction of antitumor responses [85,86].
mDC
mDC
tDC
FB
FB
In larger tumors, competent
DCs can become
phenotypically and functionally
defective by a number
of mechanisms:
- Hypoxia
- Tumor metabolites
- Cytokines/chemokines
- Skewing of differentiation towards
macrophages and endothelial cells
- Inhibition by regulatory T cells
These impaired DCs secrete immunosuppressive cytokines
and upregulate the cell surface expression of T-cell
suppressive molecules.
Tumor regression
Tumor progression
Figure 1. Impairment of dendritic cell number and activity by tumor environment. mDCs are
capable of inducing an antitumor response in small tumors. However, when tumors grow and
establish a tumor microenvironment, several factors impair the functions of the tDCs.
DC: Dendritic cell; FB: Fibroblast; mDC: Mature dendritic cell; tDC: Tolerogenic dendritic cell.
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First preclinical DC-based
immunotherapy
In 2004, the research group of Gregoire pub-
lished a pioneering article in which they used
DC-based immunotherapy in a human mesothe-
lioma model [87] . By using dead cells (necrotic or
apoptotic lysate) for the loading of DCs, the cells
were exposed to a full array of antigenic peptides
that rapidly gain access to both MHC class I
(cross-presentation) and II pathways, therefore
leading to a diversified immune response involv-
ing CTLs as well as CD4+ T-helper cells. In their
paper, the authors successfully demonstrated
in vitro culture and antigen loading of DCs in a
human mesothelioma model, resulting in a spe-
cific cytotoxic T-cell response. Heat shocking
the tumor cells before apoptosis induction was
required to induce potent cross-priming of CTLs
with antitumor activity.
In 2005, the present authors’ group published
the first trial on DC-based immunotherapy of
mesothelioma in a murine model [88] . This was
a peritoneal tumor model using the AB-1 tumor
cell line. DCs were cultured and loaded with
tumor lysate and vaccinations were given at dif-
ferent time points in relation to tumor inocula-
tion. Immunization with tumor lysate-pulsed
DCs before a lethal tumor implantation pre-
vented mesothelioma outgrowth; mice receiv-
ing tumor lysate-pulsed DCs were protected for
months and even resisted a secondary challenge
with tumor, illustrating the induction of long-
lived immunity by using DC-based immuno-
therapy. Also, immunization with tumor lysate-
pulsed DCs after tumor implantation reduced
mesothelioma growth, depending on the method
of DC maturation and tumor load. In contrast
with the curative effect when tumor lysate-
pulsed DCs were given before or 1 and 8 days
after tumor challenge, immunization with tumor
lysate-pulsed DCs on the day of tumor implan-
tation promoted mesothelioma outgrowth and
poor prognosis occurred. The observation of a
paradoxical tumor-enhancing effect of simul-
taneous administration of DCs may be caused
by several factors. First, high levels of cytokines
or soluble mediators produced by mesotheli-
oma cells could downregulate cellular immune
responses induced by DCs. Next, tumor cells
might cluster with DCs, which, through their
highly motile nature, might lead to more wide-
spread dissemination and attachment of cancer
cells to the mesothelial surface. Finally, if DCs
are mixed with tumor cells in vivo, it has been
shown that DCs can transform into endothe-
lial cells, thus enhancing tumor vasculogenesis
and tumor growth [89] . Successful tumor lysate-
pulsed DC immunotherapy was associated with
cytotoxic T-cell induction and even transfer of
splenocytes or CD8+ T cells from surviving mice
receiving DC immunotherapy transfers tumor
protection for tumor-bearing mice. DC vacci-
nations had a better outcome when DCs were
injected early in tumor development, indicating
that tumor load played an important role in sur-
vival. Although the potency of immunotherapy
treatment decreased when DCs were injected
later, mice still showed an improved prognosis
compared with mice receiving no treatment,
but eventually tumors escaped immune surveil-
lance and all of the mice died. It is now well
established that larger tumor mass is associated
with an immuno suppressive milieu that has the
capacity to suppress the effector arm of the anti-
tumoral immune response (CTL response inside
the tumor) and the inductive arm of the immune
response (i.e., the potential of antigen-presenting
DCs to induce CTL responses) [90] .
First clinical trial
The research group of Robinson published a
trial in 2006 in which they used an autologous
tumor lysate vaccine that was manufactured
from surgically resected tumor and adminis-
tered subcutaneously together with GM-CSF
[91]. GM-CSF stimulates APCs in vivo, which in
turn present TAAs and thereby generate tumor-
specific immunity. A total of 22 patients were
enrolled in the trial. Of these, five developed
positive delayed type hypersensitivity skin tests
and five showed evidence of altered antibody
specificities by western blotting, proving that
tumor lysate plus GM-CSF could induce tumor-
specific immunity, both cellular and humoral.
Of the patients, 32% developed at least one
type of immune response against mesothelioma
[91]. In vivo stimulation of APCs is an attrac-
tive method; however, it remains important to
determine whether the activation signals might
actually polarize the DCs in the desired manner.
For example, engaging DC asialoglycoprotein
receptor [92] induces DCs to secrete IL-10, which
polarizes T cells into IL-10-secreting suppressor
T cells, which in turn might negatively affect
tumor-specific effector T cells. Furthermore,
the tumor microenvironment interferes with
the stimulation of DCs, as is discussed above.
Therefore, ex vivo culture and antigen-loading of
DCs, while demanding more labor, seems pref-
erable. In this way DCs can be cultured and
matured in vitro without the immunosuppres-
sive effect of the tumor. Also, the loading of the
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TAAs can be performed in a controlled situation
to make use of the full potential of these cells.
On the basis of their preclinical animal stud-
ies, the present authors have performed the first
clinical trial in which autologous tumor lysate-
pulsed DCs were administered to mesothelioma
patients [65] . In this clinical trial, patients were
eligible for the study when sufficient tumor
cells could be obtained from pleural effusion
or tumor biopsy material at the time of diag-
nosis. DC-based immunotherapy was planned
after completion of the cytoreductive therapy
provided that no major side effects occurred
during chemotherapy and there was no progres-
sive disease. DCs were obtained using concen-
trated leukocyte fractions that were generated
through peripheral blood leukapheresis [93] .
Large numbers of DCs were generated ex vivo,
in the absence of the suppressing tumor milieu,
and subsequently loaded with a preparation of
autologous tumor antigens and keyhole limpet
hemocyanin as positive control. Mature DCs
were injected three-times with a 2-week inter-
val both intravenously (distribution to the liver,
spleen and bone marrow) and intradermally
from where they migrate to the regional lymph
nodes
(Fi gur e 2)
. In this way, they maximally
stimulate the cytotoxic T cells, B cells, NK cells
and NKT cells that are essential for tumor lysis.
Overall, the vaccination regimen with loaded
DCs was well tolerated in all patients and no
common toxicity criteria grade 3 or 4 toxicities
were reported. A local skin rash occurred at the
site of the intradermal injection after the first vac-
cination in eight of the ten patients. Subsequent
vaccinations (second and third) gave a quicker
and increased induration and erythema in all
patients suggesting that some form of immunity
was induced. Most patients developed mild-to-
severe flu-like symptoms after the vaccination,
particularly fever, muscle aches, chills and tired-
ness; however, these symptoms normalized after
1 day. Since this was a proof-of-principle study,
no conclusions can be drawn regarding improve-
ment of the progression-free survival or overall
survival. To assess the T-cell capacity for cell lysis,
flow cytometric detection of CD3+CD8+ T cells
expressing granzyme B was used. Nine patients
showed a significantly increased percentage of
granzyme B + CD8+ T cells after vaccination and
granzyme B expression per CD8+ cell increased
in most patients. Furthermore, radioactive chro-
mium release assays were performed in six of ten
patients from whom pleural fluid was obtained.
In four patients, a clear induction of cytotoxicity
against autologous tumor cells was measured.
The cytotoxicity levels of one patient increased
after every vaccination; for the other three
patients three vaccinations were necessary to
induce cytotoxicity. In addition, serum samples
from all patients showed a significant increase of
antibodies reactive to keyhole limpet hemocya-
nin post vaccination, both of the IgG and IgM
isotype. The response remained at the same level
for several months after the last DC injection
and gradually decreased after 6–12 months. This
proves that a successful immunoreaction was
induced by the DC vaccinations. In conclusion,
administration of DCs loaded with autologous
tumor cell lysate to patients was safe and feasible,
and no significant adverse effects were observed.
Future developments in DC-based
immunotherapy
There is still room for improvement in DC pro-
duction, either ex vivo or in vivo. The most com-
monly used approach to harvest DCs for immu-
notherapy is to use the differentiated DCs from
peripheral blood mononuclear cells obtained
from whole blood or by a leukapheresis pro-
cedure. However, DCs can also be propagated
from CD34+ precursors. CD34+ precursors are
first mobilized from the bone marrow by treat-
ment of patients with GM-CSF prior to leuka-
pheresis procedures [94] . In addition, DCs can
also be directly isolated from circulating DCs.
Circulating DC subsets comprise less than 1%
of peripheral blood mononuclear cells. In vivo
expansion of these rare cells can be achieved by
administration of hemopoietic growth factors
such as Flt3L followed by leukapheresis [95] . For
a more elaborate description of DC subsets, the
review by Liu and Nussenzweig is recommended
[96] . All of these methods for gener ating DCs are
currently used in clinical trials, but there is no
consensus on the optimal method of generating
DCs for immunotherapy use [9 7, 98] .
A novel strategy for loading antigens involves
the direct targeting of antigens to DCs in vivo
to induce tumor-specific immune responses [9 9] .
Although the limitations have been mentioned
above, in vivo targeting of DCs represents an
option for DC immunotherapy as it bypasses the
expensive and labor-intensive ex vivo DC gen-
eration process. Vaccines may be produced on a
larger scale and at a lower cost than an ex vivo
cultured DC vaccine. In vivo targeting also
allows for the stimulation of natural DC sub-
sets at multiple sites in vivo. Newer approaches
involve the targeting of DC-specific molecules.
Candidate receptors for stimulation and matu-
ration of DCs include Fc receptors, CD40 and
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C-type lectin receptors [97] . However, further
studies are still required to translate this new
strategy to clinical applications in humans.
Improving maturation of DCs also has the
potential to improve the efficacy of the immuno-
response; recently, it has been shown that in vitro
sequential DC maturation can be beneficial [10 0] .
This method tries to mimic the in vivo situa-
tion in which DCs exposed at the periphery to
maturation stimuli migrate to lymph nodes,
where they receive secondary signals from CD4+
T-helper cells. It was shown that a sequential
activation with activated CD4+ T cells dramati-
cally increased the maturation of DCs in terms
of their phenotype and cytokine secretion com-
pared with DCs activated with maturation stim-
uli delivered simultaneously [10 0 ] . Furthermore,
this sequential maturation led to the induction
of CTLs with long-term effector and central
memory phenotypes.
Either ex vivo or in vivo, the most optimal
method of DC production has to be established;
the question remains whether efficacy will be
enhanced due to optimization of this method,
because immunomonitoring of the present
authors’ clinical trial and those using other DC
vaccines has demonstrated that these cells are
now sufficiently powerful to be used in clinical
trials [101 ] .
Besides DC production, the method of antigen
loading is one of great debate; the ideal target for
cancer immunotherapy would be a TAA that is
exclusively expressed in all tumor cells but not in
normal tissues in order to avoid potential induc-
tion of autoimmunity. In addition, the TAA
should be important for tumor growth and sur-
vival, so that down regulation to escape the immu-
notherapeutic effect of the vaccine is impossible.
Most TAAs are self-derived proteins and thus,
in vivo, poorly immunogenic, certainly keeping
in mind the concept of the immuno suppressive
environment of the tumor. Nevertheless, DCs
loaded with these antigens can be used to initiate
antigen-specific T-cell responses. In recent years,
a large number of strategies have been developed
to deliver TAAs to DCs, using defined epitopes,
specific TAAs, apoptotic whole-cell suspen-
sions, necrotic cell lysates or cellular DNA or
mRNA, and employing both viral and nonviral
techniques [102,103].
In the present authors’ study, and in others
in mesothelioma, whole-cell material is used.
The need for patients’ tumor material for anti-
gen loading of the DCs unfortunately results
mDC
NK T
T
T
T
T
T
T
T
T
T
T
T
T
TT
T
T
T
TT
T
T
T
NK NK
NK
NK
NK
NK
B
B
mDC
mDC
Ex vivo generated and
matured DCs
Figure 2. Administration of ex vivo maturated autologous dendritic cells into a patient,
resulting in antigen presentation in the lymph node and a specific cytotoxic antitumor
response.
B: B cell; DC: Dendritic cell; mDC: Mature dendritic cell; NK: NK cell; T: T cell.
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Dendritic cell-based immunotherapy in mesothelioma ReviewReview Cornelissen, Lievense, Heuvers et al.
in patients being excluded from these trials if
there is an inability to collect sufficient tissue
samples. The University Hospital of Antwerp
(Belgium) has started a trial of DC immuno-
therapy in mesothelioma and several other solid
tumors, using WT-1 as antigen loading for the
DCs [20 4] , circumventing the need for patient’s
tumor material. In the present authors’ view, this
approach limits the antitumor response to a sin-
gle peptide, making it obligatory for the tumor to
significantly express this peptide in order for the
immunotherapy to be effective. In addition, it is
becoming clear that most tumors consist of dif-
ferent clones of tumor cells expressing different
TAAs. Elimination of one clone does not prevent
outgrowth of another.
But even when the preferable method of
DC preparation and antigen loading has been
established, immunotherapy has to overcome an
immunosuppressive environment caused by the
tumors’ recruitment of suppressive cell types that
inhibit an effective antitumor response, among
which are myeloid-derived suppressor cells,
tumor-associated macrophages (TAMs) and
Tregs. Dampening of this immuno suppression
through various methods of cell modulation
might be an important key to increasing the
efficacy of DC-based immunotherapy.
Myeloid-derived suppressor cells are increased
in cancer patients and play a suppressive role
in the innate and adaptive immune responses
to cancer. The present authors have recently
shown the role of myeloid-derived suppressor
cells in DC immuno therapy recently and sev-
eral strategies are being studied to counteract this
immuno suppression, for example gemcitabine,
5-fluorouracil, celecoxib or sunitinib [104–106 ].
TAMs are a major component of the leukocyte
infiltrate in the tumor microenvironment and are
described as key orchestrators of cancer-related
inflammation [10 7] . Evidence is accumulating on
their role in tumor initiation, progression and
metastasis [1 08 ] . TAMs are considered as ‘alter-
natively activated’ macrophages and have a dif-
ferent phenotype compared with the ‘classically
activated’ macrophages. Classically activated
macrophages are characterized by the expres-
sion of high levels of proinflammatory cytokines
and reactive oxygen species and have antitumor
activity. By contrast, alternatively activated mac-
rophages are considered to be involved in tissue
remodeling and wound healing and are able to
suppress the adoptive immune response through
various mechanisms and contribute to angio-
genesis and tumor invasiveness [1 0 9] . Suppressing
these TAMs might prove crucial to improving
the efficacy of immunotherapy; zoledronic acid,
the anti-IL-6 antibody siltuximab, antibod-
ies against CD40 and antagonists of CSF-1
receptor are candidates for suppression of these
TAMs [110–114] .
Tregs are a population of CD4+ T cells with a
central role in the prevention of autoimmunity
and the promotion of tolerance via their suppres-
sive function on a broad repertoire of cellular
targets; they have several pathways that limit the
antitumor response [115] . An engineered recom-
binant fusion protein of IL-2 and diphtheria
toxin and other CD25-directed immunotoxins,
low-dose cyclophosphamide, a p300-inhibiting
molecule, sorafinib and anti-CCL2/CCL12
mono clonal antibodies have been investigated
for Treg depletion [116 –12 3 ] .
Another method that is being extensively
studied is to enhance the antitumor immune
response by blockading immune checkpoints.
Immune checkpoints refer to a plethora of inhibi-
tory pathways hardwired into the immune system
that are crucial for maintaining self-tolerance and
modulating the duration and amplitude of physi-
ological immune responses in peripheral tissues
in order to minimize collateral tissue damage. It
is now clear that tumors co-opt certain immune
checkpoint pathways as a major mechanism of
immune resistance, particularly against T cells
that are specific for tumor antigens. Because
many of the immune checkpoints are initiated by
ligand–receptor interactions, they can be readily
blocked by antibodies or modulated by recombi-
nant forms of ligands or receptors. CTLA4 anti-
bodies were the first of this class of immunothera-
peutics to achieve a survival benefit in a Phase III
trial in melanoma [124], but several blockers of
additional immune checkpoint proteins, such as
PD1, are now being studied [1 25 ] .
Conclusion
The role of the immune system in mesotheli-
oma is vast. In malignant diseases, progress in
modulating the immune system has been slow
at first but, more recently, immunotherapy has
taken flight. In mesothelioma, multiple strate-
gies are currently being tested and many com-
binations of therapeutic options await research,
with DC-based therapy being one of the most
exciting options in our view.
Future perspective
In the coming years, we expect that a num-
ber of mechanisms that reduce the efficacy of
immunotherapy will be clarified and possible
therapeutic strategies will find their way into
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Dendritic cell-based immunotherapy in mesothelioma
ReviewReview Cornelissen, Lievense, Heuvers et al.
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Executive summary
Mesothelioma is an immunogenic cancer and can induce immune recognition, immune cell infiltration and immune-mediated killing,
the extent of which defines disease prognosis.
Immunotherapy in mesothelioma has been studied for over 30 years, with significant progress mainly being made in the last decade.
Dendritic cells (DCs) are the most potent APCs, specialized in inducing activation and proliferation of cytotoxic CD8+ and helper CD4+
T lymphocytes.
DC-based immunotherapy of mesothelioma in a murine model was capable of preventing mesothelioma development when applied
before tumor inoculation and slows down mesothelioma growth if given after tumor implantation.
In mesothelioma patients, immunotherapy with autologous DC vaccines after chemotherapy is feasible and well tolerated, and capable
of inducing specific immune responses.
Improvements to DC-based immunotherapy include further optimization of DC harvesting and tumor-associated antigen loading,
modulation of immunosuppressive cells and immune checkpoints, and combining immunotherapy with chemotherapy and/or surgery.
clinical trials. Furthermore, the combination
of immunotherapy with traditional treatments
(e.g., chemotherapy, targeted therapy, radiother-
apy and [debulking] surgery) is currently being
studied to elucidate which therapeutic combi-
nation is most effective in individual patients.
DC-based therapy and other immunothera-
peutical approaches will see their critical test in
Phase II and III clinical trials to prove their place
in cancer treatment.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan‑
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
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