Review

Clinical use of dendritic cells for cancer therapy

Sbastien Anguille, Evelien L Smits, Eva Lion, Viggo F van Tendeloo, Zwi N Berneman

Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccination
of patients with cancer. Dendritic cell-based immunotherapy is safe and can induce antitumour immunity, even in
patients with advanced disease. However, clinical responses have been disappointing, with classic objective tumour
response rates rarely exceeding 15%. Paradoxically, ndings from emerging research indicate that dendritic cell-based
vaccination might improve survival, advocating implementation of alternative endpoints to assess the true clinical
potency of dendritic cell-based vaccination. We review the clinical eectiveness of dendritic cell-based vaccine therapy
in melanoma, prostate cancer, malignant glioma, and renal cell carcinoma, and summarise the most important
lessons from almost two decades of clinical studies of dendritic cell-based immunotherapy in these malignant
disorders. We also address how the specialty is evolving, and which new therapeutic concepts are being translated
into clinical trials to leverage the clinical eectiveness of dendritic cell-based cancer immunotherapy. Specically, we
discuss two main trends: the implementation of the next-generation dendritic cell vaccines that have improved
immunogenicity, and the emerging paradigm of combination of dendritic cell vaccination with other cancer therapies.

Introduction

Safety

2013 marked the 40th anniversary of the discovery by

Cohn and Steinman1 of a new type of immune cell:
dendritic cells. Although our knowledge of their biology
and function is incomplete, evidence shows that
dendritic cells play a crucial part in the induction of
antitumour immunity.2 Immunotherapeutic approaches
involving dendritic cells aim to capitalise on the ability
of the cells to direct cytotoxic T lymphocytes and natural
killer cells to become potent antitumour eectors
capable of eradicating malignant cells (gure).3 The
basic immunological principles that provide a
compelling rationale for use of dendritic cells in
immunotherapy and the dierent ways to prepare these
cells for clinical application have been reviewed
elsewhere,2,4 and are beyond the scope of this Review. In
this Review, we rst aim to examine the most important
lessons gained from almost two decades of clinical
studies of dendritic cell-based immunotherapy,
particularly regarding the actual therapeutic usefulness
of dendritic cells. We then describe how the specialty of
dendritic cell-based immunotherapy is evolving, and
provide an update of new models and approaches that
are being adopted in clinical trials.
Since the rst published clinical trials in the mid1990s, many early-phase clinical trials have been done
across a wide range of tumour types. Dendritic cellbased treatments have been tested most often in
patients with malignant melanoma,5 with more than
1250 patients treated (appendix pp 23), followed by
prostate cancer (>750 patients treated; appendix p 4),
malignant glioma (>500 patients treated; appendix p 5),
and renal cell cancer (>250 patients treated; appendix
p 6). These malignant diseases are the only tumour
types in which phase 3 clinical trials of these treatments
have been done or are underway (table 1). Therefore, in
this Review we focus on these four tumour types, and
use them to summarise the conclusions that can be
gathered about the clinical use of dendritic cells in
cancer immunotherapy.

The safety of dendritic cell-based immunotherapy has

been well documented in many phase 1 clinical studies.6
Local reactions at the injection sites (ie, pain, rash, and
pruritus) are common, but these reactions are generally
mild and self-limiting.6 Systemic side-eects, including
pyrexia, malaise, and other inuenza-like symptoms, can
occur; however, systemic grade 34 (US National Cancer
Institute-Common Terminology Criteria) toxicity is
extremely uncommon when dendritic cell vaccination is
given as monotherapy.6 One particular concern with
immunotherapy is the possibility of induction of
autoimmunity.7 However, cancer vaccine strategies are
rarely associated with severe immune-related toxicity,
which contrasts sharply with other immunotherapeutic
methods such as monoclonal antibodies and cytokines.7
For example, immune-related adverse events have been
reported in up to 60% (of which 15% are grade 34 toxicity)
of patients treated with the anti-cytotoxic T lymphocyte
antigen-4 (CTLA-4) monoclonal antibody ipilimumab,8
which has been approved by US and European health
authorities for the treatment of melanoma.
In line with its low toxicity, dendritic cell-based
immunotherapy is expected to preserve the quality of life
of patients with cancer.9 Quality of life is an important
outcome in assessment of novel anticancer agents,
especially in the non-curative setting. However, reports on
the quality-of-life outcomes of dendritic cell-based
immunotherapy are scarce. One study9 assessing
55 patients with renal cell carcinoma treated with dendritic
cells showed no negative eect of dendritic cell-based
immunotherapy on quality of life, thereby comparing
favourably with other existing and emerging therapies for
renal cell carcinoma that can cause substantial toxicity and
seriously impair quality of life.

www.thelancet.com/oncology Vol 15 June 2014

Lancet Oncol 2014; 15: e25767

Center for Cell Therapy and
Regenerative Medicine,
Antwerp University Hospital,
Edegem, Belgium
(S Anguille MD,
Prof E L Smits PhD,
Prof Z N Berneman FRCP); and
Laboratory of Experimental
Hematology, Tumor
Immunology Group (TIGR),
Vaccine and Infectious Disease
Institute (VAXINFECTIO)
(S Anguille, E Lion,
Prof V F van Tendeloo PhD,
Prof Z N Berneman), and Center
for Oncological Research
(Prof E L Smits), University of
Antwerp, Faculty of Medicine
and Health Sciences, Antwerp,
Belgium
Correspondence to:
Dr Sbastien Anguille, Antwerp
University Hospital (UZA), Center
for Cell Therapy and
Regenerative Medicine (U111),
Wilrijkstraat 10, 2650 Edegem,
Belgium
sebastien.anguille@uantwerp.
be

See Online for appendix

Antitumour immune responses

The main goal of cancer vaccine strategies involving
dendritic cells is to stimulate tumour antigen-specic
cytotoxic T lymphocytes that can recognise and eliminate
e257

Review

Increase in immune
eector response

Reversal of
immunosuppression

Decrease in tumour burden

Increase in tumour immunogenicity

Chemotherapy

Adoptive
T-cell therapy

Increase of
lymphopeniaassociated
cytokines

COX-2
inhibitor

Radiation
therapy

Decrease of
tumour mass;
immunogenic
cell death

Decrease of
Tregs, MDSCs

Hormone
therapy

ATRA
TC

NK
MDSC

TC
VEGF

DC

TLR-L/cytokines

Interleukin 2 IMID/TKI
IDO

TC

MHC/Ag
TCR

CTL

CTLA-4
mAb

Treg

PD-1 CD25
mAb mAb

1-MT

Denileukin
diftitox

Patient selection
MRD or low tumour burden
(increase in likelihood of
developing immunity)
Early disease stage
(increase in time for
immunity to develop)

Figure: Combination strategies to maximise the therapeutic eectiveness of dendritic cell-based

immunotherapy and their underlying mechanisms of action
Dendritic cell-based cancer therapies seek to exploit the intrinsic capacity of dendritic cells to stimulate antitumour
immune eector cells, such as tumour antigen-specic cytotoxic T lymphocytes and natural killer cells. Therapeutic
interventions that aim to enhance the strength of the immune eector response (A), reverse tumour-associated
immunosuppression (B), or reduce the tumour burden and increase the immune susceptibility of the tumour cells
(C), are being actively pursued in combination with dendritic cell therapy. DC=dendritic cell. MHC/Ag=antigen bound
to major histocompatibility complex. TCR=T-cell receptor. CTL=cytotoxic T lymphocyte. NK=natural killer cell.
TLR-L=toll-like receptor ligand. mAb=monoclonal antibody. CTLA-4=cytotoxic T lymphocyte antigen-4.
PD-1=programmed death-1. MDSC=myeloid-derived suppressor cell. Treg=regulatory T cell.
IMID=immunomodulatory drug (eg, lenalidomide). TKI=tyrosine kinase inhibitor (eg, sunitinib).
COX-2 inhibitor=cyclooxygenase-2 inhibitor. ATRA=all-trans retinoic acid. VEGF=vascular endothelial growth factor.
IDO=indoleamine-2,3-dioxygenase. 1-MT=1-D-methyl-tryptophan. TC=tumour cell. MRD=minimal residual disease.

cancer cells in an antigen-specic way.2 According to

results of a meta-analysis of dendritic cell-based
immunotherapy, such cellular immune responses can be
elicited in 77% of patients with prostate cancer and 61%
with renal cell carcinoma.6 In view of the fact that most of
these patients have metastatic disease, this result
conrms that active immunisation with dendritic cells
can elicit adaptive antitumour immunity in many
patients, even in those with advanced disease who are
thought to be less immune responsive.10
Emerging evidence from clinical trials indicates that
dendritic cells, in addition to inducing tumour-specic
cytotoxic T lymphocytes, can also enhance natural-killercell immunity.11 Positive natural-killer-cell responses (eg,
increases in frequency, or induction of phenotypic or
functional activation, or both) have been noted in about
50% of patients after dendritic cell vaccination.11 This
e258

nding is particularly relevant in view of the growing

evidence indicating that natural killer cells play a key
part in the generation of protective anti-tumour
immunity.11 Natural killer cells can contribute to tumour
rejection both directly and indirectly by supporting the
generation of cytotoxic T-lymphocyte immunity.11 In a
murine melanoma model, Boudreau and colleagues12
showed that dendritic cells mediate tumour eradication
via both cytotoxic T lymphocytes and natural killer cells.
Notably, this eect was completely abrogated after
natural-killer-cell depletion,12 which underscores the
possibly pivotal role of natural killer cells in the
development of eective antitumour immunity by
dendritic cell vaccination.11,12
Taken together, these data indicate that dendritic cellbased immunotherapy can elicit adaptive and innate
antitumour immunity in at least half of all patients. This
action, coupled with the low occurrence of immunerelated adverse events, challenges the notion that
induction of cancer immunity by immunotherapy must
come at the cost of autoimmunity, as has been suggested
for other immunotherapies such as ipilimumab.7

Overall objective response

Despite their favourable safety proles and proven
immunogenicity, cancer vaccine strategies have received
a great deal of criticism, and even scepticism, because of
their poor therapeutic ecacy in terms of inducing
objective clinical responses.13 The same criticism has also
been levied at dendritic cell-based cancer vaccine
approaches.14 We did a systematic review of all published
clinical trials to document the proportion of patients who
had an objective response (achieving either a complete
response or partial response as dened by WHO criteria,
or by the Response Evaluation Criteria In Solid Tumors
[RECIST]13) after dendritic cell vaccination in melanoma,
prostate cancer, malignant glioma, and renal cell
carcinoma (appendix pp 112). From this review, we
conclude that the clinical benet of dendritic cell-based
immunotherapy in terms of objective response is real,
but small. With 85% of melanoma patients achieving an
objective response (appendix pp 23), dendritic cell
therapy has similar ecacy to dacarbazine (the standard
chemotherapeutic drug for treatment of melanoma) or to
ipilimumab, for which 515% of patients have an
objective response.15,16 For prostate cancer, 71% of
patients treated with dendritic cell therapy had an
objective response when assessed by either imaging
studies or by assessment of the prostate-specic antigen
(PSA) tumour marker level (appendix p 4), which is
similar to the 10% of patients with metastatic, androgenresistant prostate cancer who are treated with conventional
chemotherapeutic drugs.17 In patients with malignant
glioma, 156% of patients treated with dendritic cell
therapy had an objective response (appendix p 5). In
advanced renal cell carcinoma, dendritic cell therapy
produces an objective response in 115% of patients
www.thelancet.com/oncology Vol 15 June 2014

Review

Dendritic cell product

Control group

Status

ClinicalTrials.gov
identier

Melanoma

Autologous monocyte-derived DCs pulsed with melanoma peptides

Autologous DCs mixed with irradiated autologous tumour cells
suspended in GM-CSF (melapuldencel-T)

Dacarbazine
Autologous PBMCs
suspended in GM-CSF

Completed
Not yet recruiting

NA5
NCT01875653

Prostate

Autologous APCs (including DCs) loaded with PAP/GM-CSF

(sipuleucel-T)

Autologous APCs

Completed

NCT00005947
NCT00065442
NCT00779402
NCT01133704

Brain (GBM)

Autologous DCs pulsed with autologous tumour lysate (DC-VAX-L)

Autologous PBMCs

Recruiting

NCT00045968

Renal

Autologous DCs electroporated with autologous tumour mRNA and Sunitinib

CD40L mRNA, in combination with sunitinib (AGS-003)

Recruiting

NCT01582672

Excludes one study in prostate cancer that was withdrawn before enrolment (NCT00043212) and three studies with phase 2/3 design (NCT01759810, NCT01782274, and
NCT01782287). DCs=dendritic cells. GM-CSF=granulocyte macrophage colony-stimulating factor. PBMCs=peripheral blood mononuclear cells. APCs=antigen-presenting cells.
PAP/GM-CSF=chimeric antigen consisting of the prostate tumour antigen prostatic acid phosphatase (PAP) linked to GM-CSF. GBM=glioblastoma multiforme. NA=not available.

Table 1: Overview of completed and ongoing randomised phase 3 clinical trials of dendritic cell-based cancer immunotherapy, by cancer type

(appendix p 6), which is also similar to that obtained with

other immunotherapies such as interleukin 2.18

Survival benet
Whereas objective response is a rapid and direct
parameter with which to assess the antitumour activity
of an experimental treatment, survivalparticularly
overall survivalis generally thought of as the most
important outcome measure of therapeutic benet.19,20
Table 2 provides an overview of all published trials5,2162 of
dendritic cell vaccines in melanoma, prostate cancer,
malignant glioma, and renal cell carcinoma in which
overall survival comparisons have been done. Although
results of two melanoma trials did not show survival
benet,5,22 an increase in median overall survival of at
least 20% has been documented in most studies
(table 2).21,2335 Although many of these trials were early
phase and not designed primarily to measure survival,
the results obtained are nevertheless noteworthy,
especially in view of the fact that the bar for establishment
of a clinically meaningful improvement in median
overall survival is generally set at 20%.63 Perhaps the
most compelling evidence that dendritic cell therapy can
confer survival benet comes from the IMPACT study
in prostate cancer (table 2).42 In this phase 3 randomised
controlled trial, the dendritic cell-based therapeutic
sipuleucel-T (Dendreon, Seattle, WA) showed
signicantly larger median overall survival of patients
with metastatic hormone-resistant prostate cancer than
did placebo (table 1): median overall survival was
258 months in the experimental group versus
217 months in the control group.42 On the basis of this
survival advantage and despite few patients achieving an
objective response (<5%), sipuleucel-T was approved by
the US Food and Drug Administration in 2010.3 Phase 3
trials using overall survival as the primary endpoint are
underway in patients with advanced melanoma, glioma,
and renal cell carcinoma (table 1).
Importantly, a positive association between immunity
induced by dendritic cells and patient survival is
www.thelancet.com/oncology Vol 15 June 2014

increasingly being reported (appendix pp 1415). For

example, an integrated analysis of the immune
monitoring data collected during the IMPACT trial and
two other phase 3 studies of sipuleucel-T in prostate
cancer39,40,42 has shown a correlation between the
induction of antigen-specic immune responses by
sipuleucel-T and prolonged overall survival.64 These data
provide a mechanism for the clinical benet noted in
patients with prostate cancer treated with sipuleucel-T,
and link the increased overall survival in these patients to
the induction of tumour-specic immunity.6

Therapeutic eectiveness
The observed dissociation between objective response
and survival indicates that alternative surrogate endpoints
should be used to assess the therapeutic eectiveness of
dendritic cell-based immunotherapy. As outlined,
dendritic cell-based immunotherapeutic approaches can
positively aect clinical outcome in terms of increasing
patient survival rather than by inducing objective tumour
responses. Although this notion might seem
counterintuitive, for several tumour types and disease
settings tumour response criteria cannot be used to
accurately assess the eect of a certain treatment on
survival.65 This absence of association between objective
response and overall survival has been reported
particularly with the use of immunotherapeutic drugs
and targeted therapies.66 For example, ipilimumab
therapy signicantly improved overall survival of patients
with metastatic melanoma by 45 months (compared
with a control group given a tumour peptide vaccine),8
despite only 515% of patients having an objective
response.16 A phase 3 clinical trial of the tyrosine kinase
inhibitor sorafenib in patients with advanced renal cell
carcinoma yielded similar results, in which only 10% of
patients had an objective response,67 but survival was
nevertheless signicantly prolonged by 35 months
(compared with a placebo control group).68 These two
examples, along with the evidence presented in this
Review, suggest that the dissociation between objective
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Review

Evidence level

Overall survival
DC group
(months)

Dendritic cell product

Control group
(months)

% change

Dendritic cell type

Activation

Melanoma
N=1121

III-3

93

40

+133%

IL-4 moDCs

MCM

N=1322

III-1

62

148

58%

IL-4 moDCs

Immature

N=542325

III-1

640

310

+107%

IL-4 moDCs

GM-CSF

N=1726

III-3

224

80

+180%

IL-4 moDCs

TNF-

N=1127

III-3

73

40

+83%

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

N=16/22*28

III-2

123

58

+112%

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

N=2029,30

III-3

86

40

+115%

IL-4 moDCs

TNF-+Poly(I:C)

N=535

II

93

116

20%

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

N=3431

III-3

185

116

+60%

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

N=2832

III-3

94

51

+84%

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

N=2433

III-3

136

73

+86%

IL-4 moDCs

Immature

N=2934

III-3

150

83

+81%

IL-4 moDCs

TNF-/PGE2

N=1535

III-3

220

76

+189%

Natural pDCs

FSME-IMMUN

N=333638

III-3

>200

60

+233%

IL-4 moDCs

Immature

N=147/22539,40

II

232

189

+23%

Sipuleucel-T

GM-CSF

N=1241

III-3

210

1219

+1075%

IL-4 moDCs

TNF-/PGE2

N=341/51242

II

258

217

+19%

Sipuleucel-T

GM-CSF
Immature

Prostate

Brain
N=8/1443

III-2

333

75

+344%

IL-4 moDCs

N=1944

III-1

380

240

+58%

IL-4 moDCs

Immature

N=1245

III-2

234

183

+28%

IL-4 moDCs

Immature

N=1846

III-3

157

131

N=5647

III-3

96

N=1248

III-3

228

N=849

III-3

240

N=16/1750

III-3

170

N=1051

III-3

N=1552

+20%

IL-4 moDCs

OK-432

+3962%

IL-4 moDCs

TNF-/IL-1/PGE2

156

+46%; NS

IL-4 moDCs

TNF-/IL-1/IL-6

120

+100%

IL-4 moDCs

TNF-/IL-1/PGE2

125

+36%

IL-4 moDCs

Immature

280

146

+92%

IL-4 moDCs

TNF-/PGE2

III-3

359

140

+156%

IL-4 moDCs

+Imiquimod or poly(I:C)LC

N=7753

III-3

183

146

+25%

IL-4 moDCs

TNF-/IL-1/PGE2

N=1854

III-1

319

150

+113%

IL-4 moDCs

Immature

N=1355

III-2

170

105

+62%

IL-4 moDCs:

TNF-/IL-1/PGE2

N=556

III-3

270

123

+120%

IL-4 moDCs

TNF-/IFN-/Poly(I:C)

N=757

III-3

249

192

+30%; NS

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

6070

Renal
N=1058

III-3

198

+65120%

IL-4 moDCs

Immature

N=959

III-3

290

120

90120

+142%

IL-4 moDCs

MCM/CD40L/IFN

N=2760

III-3

166

127

+31%

IL-4 moDCs

TNF-/IL-1/IL-6/PGE2

N=1861

III-3

>180

138

+29%

IL-4 moDCs

TNF- +/ PGE2

N=10 (PR)62

III-3

91

53

+72%

moDCs

CD40L mRNA

N=11 (IR)62

III-3

395

207

+91%

moDCs

CD40L mRNA

Last update: Nov 14, 2013. DC=dendritic cell. N=total number of vaccinated patients. PR=poor-risk group. IR=intermediate-risk group. Evidence level is according to NHMRC
gradation system (http://www.nhmrc.gov.au), derived from dierent trial types: II=randomised controlled trial. III-1=pseudorandomised controlled trial (eg, other
treatment). III-2= trial including a non-randomised concurrent control group. III-3=trial without concurrent control group (eg, historical controls or comparison of two or
more single-group trials). % change=percentage change from overall survival in control group to DC group. NS=not signicant. IL-4 moDCs=interleukin-4-dierentiated
monocyte-derived DCs. pDCs=plasmacytoid DCs. MCM=monocyte-conditioned medium. GM-CSF=granulocyte macrophage colony-stimulating factor. TNF=tumour necrosis
factor. PGE2=prostaglandin E2. Poly(I:C)=polyinosinic:polycytidylic acid, a toll-like receptor (TLR)3 agonist. Poly(I:C)LC=poly(I:C) stabilised with lysine and
carboxymethylcellulose. FSME-IMMUN=tick-borne encephalitis vaccine. OK-432=picibanil, a TLR4 agonist. IFN=interferon. *M1c patient subgroup. newly diagnosed
glioblastoma multiforme patient subgroup. combined with sunitinib.

Table 2: Overview of dendritic cell vaccine trials in melanoma, prostate cancer, primary brain tumours (glioma), and renal cell cancer reporting overall
survival outcome

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Review

response and overall survival is a class-specic occurrence

of immunotherapies and targeted therapies,66 and
corroborate the notion that the objective response might
not show the true clinical activity of these therapies.66,69,70
If eective, classic cytotoxic drugs usually cause fairly
rapid reductions in tumour size and, in such cases, the
objective response is a suitable parameter to assess
treatment response.69,70 By contrast, immunotherapies
often produce dierent clinical response patterns, none
of which are accurately captured by establishment of
objective response.69,70 Among these atypical response
proles, which are also frequently observed in the context
of dendritic cell-based immunotherapy, are delayed initial
increases in tumour burden associated with inammation
or immune cell inltration of the tumour lesions later
followed by regression, and changes in disease
progression kinetics.21,71 The response prole changes in
disease progression kinetics have been well documented
in patients with prostate cancer, in whom results of many
studies show that therapeutic cancer vaccines, including
dendritic cell-based vaccines, can attenuate the PSA
progression rate without signicantly reducing PSA
levels.71,72 Such response patterns cannot be classied as
objective with classic response assessment criteria;
however, they might be highly clinically relevant in view
of the association between changes in PSA kinetics and
the survival of patients with prostate cancer.73 Taken
together, these data underscore the idea that dendritic
cell-based immunotherapeutic strategies, and, by
extension, all cancer immunotherapies, necessitate
ecacy endpoints other than the traditional outcome
parameters used in oncology clinical trials.19,70 As outlined,
overall survival is the most appropriate endpoint in latestage clinical trials.20 For early-phase clinical trials, the
immune-related response criteria might be a valid
alternative to the classic WHO or RECIST criteria to
assess antitumour responses, because they accommodate
the atypical tumour response patterns recorded with
immunotherapies.69,70

How is the specialty evolving?

Trends
Among the studies of dendritic cell cancer vaccines
registered at http://www.clinicaltrials.gov, two main
emerging trends in dendritic cell-based anticancer
immunotherapy can be identied. The rst revolves
around the use of next-generation dendritic cell products
with improved immunostimulatory activity. The second
is to potentiate the eectiveness of dendritic cell
immunotherapy through combination therapy.

Next-generation dendritic cell vaccines

Most published clinical trials have been done with earlygeneration dendritic cell vaccines, including dendritic
cell-enriched cell preparations (eg, sipuleucel-Ta crude
preparation of prostate antigen-loaded, GM-CSFactivated blood mononuclear cells of which dendritic
www.thelancet.com/oncology Vol 15 June 2014

cells constitute only a small proportion) and interleukin-4

monocyte dendritic cells (dendritic cells generated ex
vivo from peripheral blood monocytes in the presence of
GM-CSF and interleukin 4; table 2).3 The interleukin-4
monocyte dendritic celleither used in its immature
form or after activation or maturation with a proinammatory cytokine cocktail composed of tumour
necrosis factor (TNF) , interleukin 1, interleukin 6, and
prostaglandin E2is by far the most commonly used
dendritic cell type in clinical trials (table 2).4
Which dendritic cell vaccine parameters are important
for clinical eectiveness is not fully understood. Although
clinical benet has been shown in trials using immature
interleukin-4 monocyte dendritic cells (table 2) and many
individual studies have not established a correlation
between dendritic cell activation parameters and survival
outcome,28,31,33,43 results of a meta-analysis of dendritic cell
immunotherapy in prostate cancer have shown a clear
superiority of mature monocyte dendritic cells over their
immature counterparts in terms of clinical outcome.6
Similar observations have been made in the context of
melanoma74 and malignant glioma.46 In addition to
maturation state, the ability of dendritic cells to produce
interleukin 12p70which favours the induction of a
protective T-helper type 1 (Th1) immune responseis
being increasingly recognised as an important determinant
of clinical activity.3 In two clinical trials, one in glioma75 and
one in melanoma,76 high concentrations of dendritic cellderived interleukin 12p70 were predictive of favourable
clinical outcome.
This evidence explains the impetus behind the recent
and ongoing eorts to develop the next generation of
dendritic cell vaccines biased to induce a Th1 immune
response (referred to as type 1-polarised dendritic cells)
and endowed with a superior capacity to elicit tumour
antigen-specic cytotoxic T lymphocytes and naturalkiller-cell immunity.3 The aim of this work is not to
provide an exhaustive compilation of all available nextgeneration dendritic cell vaccine protocols, but to touch
on some salient examples to show the main trends in
this eld of research. Several groups, including ours,
have shown interest in use of Langerhans cell-type
dendritic cells as vehicles for dendritic cell vaccination in
view of their remarkable eciency to stimulate cytotoxic
T lymphocyte immunity.77 Langerhans cell-like dendritic
cells can be derived from CD34-positive haemopoietic
progenitors,78 or from CD14-positive monocytes cultured
with interleukin 15 (instead of interleukin 4).79 Clinical
studies using these Langerhans cell-type dendritic cells
are
underway
in
melanoma
(NCT00700167,78
NCT01456104, and NCT01189383). In view of the key role
of interleukin 12p70 and the observed absence of
interleukin 12p70 production with use of the classic
maturation cocktail of TNF-, interleukin 1,
interleukin 6, and prostaglandin E2, much work has
been devoted to development of alternative maturationinducing regimens.4 Examples of maturation stimuli that
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Review

allow for the generation of dendritic cells with the desired

capacity to produce interleukin 12p70 are CD40L with
interferon ;76 toll-like receptor ligands (eg, TLR3 agonist
poly[I:C]);80 or a combination of TNF-, interleukin 1,
interferon , interferon , and polyI:C.75 In patients with
malignant glioma, dendritic cells matured with the latter
combination (designated as -type-1-polarised dendritic
cells) have shown potent ability to produce interleukin
12p70 and to augment the expression of the cytotoxic
T-lymphocyte-attracting chemokine CXCL10 in the
tumour microenvironment,75 which has been identied
as another key factor in the therapeutic activity of
dendritic cell vaccines in a murine study of malignant
glioma.81 The clinical eectiveness of -type-1-polarised
dendritic cells is being further assessed in several clinical
trials in melanoma (NCT00390338), prostate cancer
(NCT00970203), and glioma (NCT00766753).

Combination therapy
Categorisation
The appendix (pp 1618) provides an overview of the
dierent therapeutic interventions being assessed in
terms of their potential synergistic interaction with
dendritic cell vaccination. In this Review, for clarity, we
have divided these interventions into three categories on
the basis of their principal mechanism of action (gure).

Interventions that enhance the strength of the immune

eector response
Immune inhibitory pathways often dominate in
patients with cancer and can aect the eectiveness of
dendritic cell-based immunotherapy by preventing
cytotoxic T lymphocytes and natural killer cells from
exerting their eector function (gure). The immune
checkpoint receptors CTLA-4 and programmed death-1
(PD-1) are among the best understood molecules
involved in the negative regulation of cytotoxic
T-lymphocyte function.3 In recent years, several
monoclonal antibodies that can interfere with these
inhibitory molecules have become available for clinical
application, opening up the prospect of their use in
combination with dendritic cell-based immunotherapy.3
Preliminary clinical evidence obtained in patients with
advanced melanoma suggests that dendritic cell therapy
in combination with CTLA-4-targeting monoclonal
antibodies is more eective than is use of these agents
as monotherapies.82,83 However, we believe that these
monoclonal antibodies should be used with caution in
view of their potential (immune-related) toxicity. AntiPD-1 monoclonal antibodies seem to have a more
favourable toxicity prole, and can even be combined
with ipilimumab without a signicant increase in the
rate of immune-related adverse events.84,85 In view of
this prole, therapeutic blockade of the PD-1/PD
ligand 1 pathway might be a more viable strategy from
the perspective of clinical applicability. Several antiPD-1 monoclonal antibodies have entered the clinical
e262

trial stage,84,85 one of which (pidilizumab; CT-011) is

being tested in combination with dendritic cell therapy
in four clinical trials (appendix p 18).
Toll-like receptor agonists and cytokines (eg,
interferon ) have also come under intense scrutiny as
dendritic cell vaccine adjuvants to harness the antitumour
eector response (gure).86,87 These stimuli can either be
incorporated into the vaccine itselfeg, as ex-vivo
maturation agentsor applied concomitantly with the
dendritic cell vaccine (appendix pp 1718).75 Perhaps the
most extensively studied cytokine used in combination
with dendritic cell vaccination is interleukin 2. Despite
strong preclinical evidence supporting this combination,88
results of clinical trials have not shown that the addition
of interleukin 2 to dendritic cell vaccine regimens results
in a superior induction of antitumour immunity.89,90
Moreover, interleukin 2 could negatively aect dendritic
cell immunotherapy by causing an undesired stimulation
of regulatory T cells (Tregs) or of myeloid-derived
suppressor cells (MDSCs), or both (gure).32,91
The antitumour immune responses elicited by
dendritic cell therapy can also be potentiated by
stimulation of the endogenous production of immunostimulatory cytokines. This process can be achieved with
lymphodepleting chemotherapy regimens, such as
temozolomide or cyclophosphamide with or without
udarabine.92 These therapies seek to reboot the immune
system by elimination of negative immune-cell
populations (eg, Tregs) and creation of an optimum
cytokine milieu (eg, interleukin 7 and interleukin 15) for
expansion of antitumour eector cells, including natural
killer cells and tumour antigen-specic cytotoxic
T lymphocytes (gure).93,94 This recovery phase after
lymphodepletion provides an ideal opportunity for
dendritic cell vaccination in combination with adoptive
transfer of immune eector cells (gure).94 This strategy
has generated promising results in preclinical studies
and in a pilot clinical trial,95,96 and is being pursued in
several ongoing clinical studies (appendix p 18).

Interventions that reverse tumour-associated

immunosuppression
The translation of dendritic cell-induced antitumour
immunity into clinical activity needs to overcome the
immune suppressive barrier that is imposed by Tregs,
MDSCs, and other negative immune regulators
(gure).3,10,97 Tregs are by far the best characterised cells
that prevent the generation of eective antitumour
responses.98 Two main strategies are being used to
modulate Tregs in dendritic cell-based immunotherapy
protocols. First, dendritic cells themselves can be
harnessed to target Tregs, which can be achieved, for
example, by loading dendritic cells with antigenic
components of the Treg transcription factor forkhead
box P3 (FoxP3) to mount a FoxP3-directed cytotoxic
T-lymphocyte response.98 Second, dendritic cells can be
combined with Treg-targeting drugs, such as the
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Review

monoclonal antibodies basiliximab and daclizumab

(appendix p 17; gure).98 These monoclonal antibodies are
directed towards the interleukin-2 receptor chain
(CD25), which is abundantly expressed on the surface of
Tregs (gure). The combination of dendritic cell therapy
and daclizumab has been examined in patients with
metastatic melanoma.99 Daclizumab eectively depleted
Tregs but also targeted tumour-specic T cells
(presumably because of the expression of CD25 on
activated T cells) and impaired their functionality.99
Denileukin diftitox, a fusion protein composed of
interleukin 2 and diphtheria toxin, is another CD25directed approach to deplete Tregs (gure). In patients
with advanced renal cell carcinoma, the addition of
denileukin diftitox to dendritic cell vaccination resulted in
a 16-fold increase in the frequency of tumour-specic
cytotoxic T lymphocytes.100 In another study,101 dendritic
cell therapy induced a more persistent cytotoxic
T-lymphocyte response after Tregs were depleted by
denileukin diftitox. By contrast, Baur and colleagues102
showed that denileukin diftitox can negatively aect the
capacity of dendritic cells to induce tumour-specic
cytotoxic T lymphocytes by inducing a tolerogenic
phenotype in dendritic cells, and by promoting the
survival of non-activated Tregs.102 Moreover, CD25 can
also be expressed on activated natural killer cells (gure)
and, consequently, denileukin diftitox can also lead to
depletion of natural killer cells.103 Collectively, these data
indicate that CD25-based Treg-targeting strategies, such
as denileukin diftitox, can produce paradoxical
immunological eects that can impair the activity of
dendritic cell vaccination. Non-CD25-based methods,
such as low-dose cyclophosphamide or 1-methyl-Dtryptophan,98 might therefore be more appropriate.
Clinical trials of metronomically dosed cyclophosphamide
in combination with dendritic cell therapy have yielded
mixed results and have not consistently shown a reduction
in the frequency of Tregs.93 However, these results do not
necessarily preclude a possible benecial eect of
cyclophosphamide on dendritic cell vaccine ecacy,
because cyclophosphamide might enhance antitumour
immunity via mechanisms other than Treg elimination
(eg, by directly aecting the dendritic cell compartment).104
Indoleamine-2,3-dioxygenase, an immunoregulatory
enzyme that supports Treg function and numbers, can be
inhibited by 1-methyl-D-tryptophan (gure);87 clinical
trials of its combined use with dendritic cell therapy are
underway (appendix p 17). The antitumour activities of
several newer anticancer drugs, such as the VEGFtargeting monoclonal antibody bevacizumab, the
immunomodulatory drug lenalidomide, and the tyrosine
kinase inhibitors dasatinib and sunitinib also seem to
rely, at least in part, on their inhibitory activities on Tregs
(gure).105,106 Sunitinib is being tested in combination with
dendritic cell-based immunotherapy in a phase 3 clinical
trial in patients with advanced renal cell carcinoma
(table 1, appendix pp 1718).
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In addition to Tregs, MDSCs are being increasingly

recognised as important mediators of tumour-induced
immunosuppression.107 MDSCs exert negative eects on
both T cells and natural killer cells,107 and can directly
impair the activity of dendritic cell vaccines.108 This eect
provides a compelling rationale to combine dendritic cell
vaccination with MDSC-targeted interventions, such as
VEGF inhibitors, lenalidomide, all-trans retinoic acid,
chemotherapeutic drugs (eg, gemcitabine), and
cyclooxygenase-2 (COX-2) inhibitors (gure, appendix
pp 1718).105,107 COX-2 inhibitors diminish expression of the
MDSC-attracting chemokine CCL2 in the tumour bed, and
promote tumour inltration by cytotoxic T lymphocytes
through increasing the concentration of CXCL10, thereby
creating a favourable immune context for the induction of
antitumour immunity by dendritic cells.75,109 Tyrosine
kinase inhibitors such as sunitinib and vemurafenib can
also reverse MDSC-mediated immunosuppression.107,110
Vemurafenib, a BRAF inhibitor, has become available for
treatment of advanced BRAFV600E-positive melanoma.111
Apart from its direct antimelanoma activity, vemurafenib
exerts a wide range of benecial immunomodulatory
eects. Like COX-2 inhibitors, vemurafenib reduces
tumour CCL2 expression and mobilises antitumour
eector cells into the tumour microenvironment.111 These
eects, coupled with its inhibitory action on Tregs111 and
MDSCs,110 make vemurafenib an attractive candidate for
combination therapy with dendritic cell vaccination.112

Interventions to reduce tumour burden and increase immune

susceptibility of tumour cells
The level of tumour-induced immunosuppression is a
function of the total burden of the tumour.10 This
observation led to the suggestion that immunotherapies
might function less well in the context of high tumour
burden.10 Ample evidence supports the hypothesis that
patients with advanced or bulky disease are less likely to
benet from cancer immunotherapy, including dendritic
cell therapy, than are patients with less-advanced
disease.97,113 A good example of this inverse association
between tumour burden and the eectiveness of
immunotherapy comes from haematology, in which
dendritic cell therapy has shown little eectiveness in
patients with relapsed or progressive acute myeloid
leukaemia, but strong antileukaemic activity in patients
with minimal residual disease.114,115
These considerations provide a rationale for combination
of dendritic cell therapy with cytoreductive cancer
treatments (eg, chemotherapy) to bring the patient to a
state of low tumour burden or minimal residual disease
state (gure).10,113 In view of the fact that chemotherapy by
itself has immunosuppressive eects, and that patients
heavily pretreated with chemotherapy are less responsive
to subsequent immunotherapy,94 the idea of combination
of immunotherapy and chemotherapy seems counterintuitive. Nevertheless, this theory has been challenged by
several clinical trials, the results of which showed that this
e263

Review

Search strategy and selection criteria

We selected references through a PubMed search with the terms dendritic cells, cancer,
and immunotherapy. We retrieved data presented in table 1 and appendix pp 1718 from
the online clinical trial database http://www.clinicaltrials.gov with the search term
dendritic cells. We excluded studies with the status withdrawn. We identied relevant
records for the data presented in table 2, appendix pp 212, and appendix pp 1415 by a
systematic search of PubMed for all studies published between Jan 1, 1995, and Nov 14,
2013, containing the following search terms: dendritic cells AND clinical trial AND
melanoma OR prostate cancer OR glioblastoma OR renal cell carcinoma. We
identied additional records by screening bibliographies of key articles on the subject and
by screening conference proceedings of the American Society of Clinical Oncology (ASCO).
We excluded articles not published in English, case reports, and duplicate publications.

combinatorial approach might be highly synergistic.92,97,116,117

Many mechanisms seem to be involved in the synergistic
interaction between chemotherapy and dendritic cell
therapy. Apart from the aforementioned immunepotentiating eects (ie, reversal of tumour-induced
immunosuppression associated with high tumour burden,
creation of a lymphopenic state favouring expansion of
antitumour eector cells, and inhibition or depletion, or
both, of Tregs and MDSCs), many chemotherapeutic
drugs seem able to induce immunogenic tumour cell
death, making these cells more susceptible to antitumour
immunity elicited by dendritic cell therapy (gure).94,118
Dendritic cell therapies are being increasingly integrated
into existing chemotherapy schedules, which indicates
that the concept of chemoimmunotherapy is becoming an
important treatment model in the area of dendritic cellbased immunotherapy (appendix p 17). Other conventional
anticancer treatmentsie, radiation therapy and hormonal
therapyalso have pleiotropic immunomodulatory eects
that extend beyond their primary mode of action, and that
can be exploited to increase the activity of dendritic cellbased immunotherapy.97,119,120

Conclusion
We conclude that dendritic cell therapy is a safe and well
tolerated immunotherapeutic method that can elicit
immunity even in patients with advanced-stage cancer.
This work also conrms that dendritic cell-based
interventions have only some capacity to produce
objective tumour responses, as established by classic
response assessment criteria such as RECIST. Although
not all studies were designed primarily to measure
survival, an increasing number indicate that dendritic cell
therapy could confer a survival benet. These preliminary
but encouraging survival data provide a strong incentive
to begin a new series of clinical trials using overall
survival as the primary endpoint or using surrogate
endpoints for clinical eectiveness (eg, the proposed
immune-related response criteria).69,70 We foresee that the
specialty will benet from two developments, which are
already beginning to be incorporated in clinical trials: the
implementation of the next generation of dendritic cell
e264

vaccines with optimised activity; and the rational use of

these vaccines in combination with other anticancer
therapies that could improve their eectiveness. These
developments might hold the key to the full therapeutic
potential of dendritic cells for cancer immunotherapy.
Contributors
SA researched the data, wrote the Review, and designed the gure. ELS,
EL, VFvT, and ZNB reviewed and revised the manuscript for intellectual
content.
Declaration of interests
We declare no competing interests.
Acknowledgments
We thank Jan-Baptist Vermorken for critical reading of the manuscript,
and acknowledge the Research Foundation Flanders (FWO Vlaanderen),
the Flemish League against Cancer (Vlaamse Liga tegen Kanker), the
Belgian Foundation against Cancer (Stichting tegen Kanker), and the
Belgian public utility foundation VOCATIO for their invaluable support.
SA holds an Emmanuel van der Schueren fellowship of the Flemish
League against Cancer.
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