ArticlePDF AvailableLiterature Review

DCVax®-L—Developed by Northwest Biotherapeutics

Authors:
  • AHEPA University Hospital, Aristotle University of Thessaloniki, Greece

Abstract

Dendritic cell (DC) immunotherapy is emerging as a potential addition to the standard of care in the treatment of glioblastoma multiforme (GBM). In the last decade or so various research groups have conducted phase I and II trials of DC-immunotherapy on patients with newly diagnosed (ND) and recurrent GBM and other high-grade gliomas in an attempt to improve the poor prognosis. Results show an increase in overall survival (OS), while vaccination-related side effects are invariably mild. Northwest Biotherapeutics, Inc., Bethesda, Maryland, U.S.A. (NWBT) developed the DCVax®-L vaccine as an adjunct to the treatment of GBM. It is currently under evaluation in a phase III trial in patients with ND-GBM, which is the only ongoing trial of its kind. In this review current data and perspectives of this product are examined.
DCVax!-LDeveloped by Northwest
Biotherapeutics
Stavros Polyzoidis* and Keyoumars Ashkan
Department of Neurosurgery; Kings College Hospital; Kings College; London, UK
Keywords: DCVax!-L, glioblastoma multiforme, immunotherapy, vaccine, dendritic cells, overall survival, side effects
Abbreviations: BBB, blood brain barrier; CNS, central nervous system; CTL, cytotoxic T-lymphocyte; DC, dendritic cell; DTH,
delayed tissue hypersensitivity; EORTC, European Organization for Research and Treatment of Cancer; FDA, Food and Drug
Administration; GBM, glioblastoma multiforme; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGG, high-grade
glioma; IL-4, interleukin-4; IMP, investigational medicinal product; MHRA, Medicines and Healthcare products Regulatory Agency;
MRI, magnetic resonance imaging; ND, newly diagnosed; NIHR, National Institute for Health Research; NWBT, Northwest
Biotherapeutics Inc.; OS, overall survival; PEI, Paul-Ehrlich-Institute; PFS, progression-free survival; TAAs, tumor-associated
antigens; UCLA, University of California, Los Angeles, U.S.A., United States of America.
Dendritic cell (DC) immunotherapy is emerging as a
potential addition to the standard of care in the treatment of
glioblastoma multiforme (GBM). In the last decade or so
various research groups have conducted phase I and II trials
of DC-immunotherapy on patients with newly diagnosed
(ND) and recurrent GBM and other high-grade gliomas in an
attempt to improve the poor prognosis. Results show an
increase in overall survival (OS), while vaccination-related side
effects are invariably mild. Northwest Biotherapeutics, Inc.,
Bethesda, Maryland, U.S.A. (NWBT) developed the DCVax!-L
vaccine as an adjunct to the treatment of GBM. It is currently
under evaluation in a phase III trial in patients with ND-GBM,
which is the only ongoing trial of its kind. In this review
current data and perspectives of this product are examined.
Nature of the Disease Being Prevented and the
Basis in Human Biology / Pathology for the Vaccine
or Immunotherapeutic.
Glioblastoma multiforme (GBM) is the most common pri-
mary malignant brain tumour and accounts for more than 50%
of all intracranial gliomas.
1
Despite advances in standard of care
and adjuvant therapy, GBM prognosis remains poor with a mean
OS of 14.6 months for ND-GBM and a mean OS of 7.4 months
for recurrent GBM.
2-4
The poor prognosis and the relatively
young mean age of GBM patients at presentation (53 years),
makes the disease not only devastating for the individual and the
family, but also significant from a socioeconomic stand.
Current standard of care for ND-GBM is set by the landmark
“Stupp” protocol.
2
This was introduced in 2005 and consists of a
six-week regimen of concomitant radiotherapy and temozolo-
mide chemotherapy followed by a six-month course of adjuvant
temozolomide administered over six 28-day cycles, during which
the patient is given temozolomide for five consecutive days per
cycle. Even with the application of this optimized protocol com-
bined with radical surgery mean OS is 14.6 months, two-year
survival (2-YR S) is 26.5% and only »3% of patients survive lon-
ger than five years.
5,6
Despite advances in early diagnosis, especially the use of
advanced MRI techniques, and multi-modal therapy, the contin-
ued poor prognosis of patients with GBM is likely to be due to a
number of factors. The first factor to consider is GBM’s unique
interaction with the immune system both with respect to the
immunosuppression that it causes in its environment and the fact
that it resides in the immunologically “difficult to access” central
nervous system (CNS). The former has been attributed to the
ability of the tumor to secrete glioma-cell derived transforming
mediators such as factor-b, interleukins and prostaglandin E2,
which result in functional compromise of T-cell responsive-
ness.
7,8
The latter is mainly the result of the efficient isolation of
nervous tissue from the peripheral immune system by the blood
brain barrier (BBB). This results in a highly selective accessibility
of the CNS to the immune system, predominantly to activated T
lymphocytes, which are the only cells that can cross the BBB.
The second important factor is that GBM is characterized by a
genetic profile that is highly diverse both in the paediatric and
adult population. Tumors can express a wide variety of tumor-
associated antigens (TAAs), which vary not only between differ-
ent patients, but within the same individual as well. This results
in tumors with different biological behaviors that respond differ-
ently to treatment. In contrast, current treatment options are uni-
form and thus unable to address this diversity. In the current
genome era there is a clear need for novel GBM therapies
designed to adapt to this genetic heterogeneity.
9,10
In the last decade or so active DC-immunotherapy has
emerged as one such novel treatment, addressing challenges
posed by GBM through enhancing the immune-responses to
overcome the tumor-derived immunosuppression, activating T-
lymphocytes to cross the BBB and enter the tumor
*Correspondence to: Stavros Polyzoidis; Email: stavrospolyzoidis@gmail.com
Submitted: 03/30/2014; Revised: 05/08/2014; Accepted: 05/19/2014
http://dx.doi.org/10.4161/hv.29276
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Human Vaccines & Immunotherapeutics 10:11, 3139--3145; November 2014; © 2014 Taylor & Francis Group, LLC
REVIEW
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microenvironment, and utilising a tailored vaccine / immune-
product that has been manufactured based on the specific genet-
ics of each individual tumor.
Previous experience on DC-immunotherapy has shown favor-
able results in other types of malignancies such as metastatic mel-
anoma, hepatocellular, ovarian, breast, lung and haematologic
cancer.
11-16
The first ever DC-vaccine officially introduced in
cancer therapy was sipuleucel-T (Provenge; Dendreon, Seattle,
WA), which was approved by the FDA in 2010 for the use in
advanced prostate cancer after clinical trials had shown increased
survival.
17
Along similar lines many research groups have conducted pre-
clinical studies as well as phase I and II clinical trials to investigate
the efficacy and safety of DC-vaccines in GBM and other high
grade gliomas. The main type of immunotherapy evaluated in
these studies is active autologous DC-based immunotherapy.
DCs are immune cells with the most potent antigen presenting
properties, which reside in tissues that come in contact with the
external environment, such as the skin and the mucosa of the
nose, stomach, intestines and lungs.
The fundamental step in production of DC-vaccine for GBM
is the combination of autologous tumour antigens with patients’
own dendritic cells. Tumor cells are obtained and procured dur-
ing the surgical resection, while DCs are derived from ex vivo dif-
ferentiation of the patient’s peripheral blood monocytes,
obtained via leukapheresis. DCs are then ex vivo pulsed with the
tumor lysate or peptides, and subsequently “trained” to recognize
the patient’s tumor cells. The autologous fusion is then injected
back to the patient enabling the DCs to present their surface
tumor antigens to the CD4 and CD8 T-cells of the immune sys-
tem, leading to the activation of both memory and naive T-cells.
The activated T-cells then cross the BBB resulting in cytotoxic
and cytolytic, antitumor immune responses of high specificity.
DCVax!-L is the commercial vaccine produced by Northwest
Biotherapeutics, Inc., Bethesda, MD, U.S.A. (NWBT) currently
under evaluation in a phase III trial against ND-GBM. This
forms the focus of this article.
Origin and Research Basis for Efcacy of the
Product
Preclinical studies
The assumption that deficient or absent immune-responses to
intracranial tumors play a decisive role in tumor genesis led to
the conduction of experimental immunotherapeutic studies in
rodent glioma models two to three decades ago.
18-20
In these
studies active immunotherapy with the use of DC–based vaccines
was tested for GBM treatment. It was found that this strategy
provoked infiltration of the CNS by activated T-cells,
21,22
which
was subsequently related to improved outcomes. Moreover, T-
cell responses were found to be closely correlated to vaccine effi-
cacy,
23-25
indicating that they can contribute in the prevention of
tumor regrowth. Interestingly in one study there was evidence of
vaccine related autoimmune encephalitis as a result of T-cells tar-
geting normal brain tissue that partly shared antigens found in
tumor cells. This has not however been reproduced in studies
conducted in humans.
26
Other research has focused on the interaction between other
treatment modalities, such as radiotherapy, and DC-vaccinations
in murine brain tumor models.
27
It was found that the combina-
tion of radiotherapy and DC-vaccinations can enhance the effect
of the latter and improve outcomes. This was attributed to irradi-
ation-induced upregulation of MHC molecules in tumor cells,
which rendered them better immunological targets.
The potential of DC-vaccinations as revealed by the encourag-
ing findings of preclinical studies directed clinical trials towards
applying similar protocols on humans.
DCVax!-L phase I and II clinical trials
Data on these trials derive mainly from NWBT public
reports. Prior to the ongoing phase III trial two phase I/II trials
were carried out at the University of California, Los Angeles
(UCLA) by Dr. Linda Liau and Dr. Robert Prins on this prod-
uct. In these trials thirty-nine (n D39) patients were enrolled in
a dose-escalation scheme of 1, 5 or 10 £10
6
DCs/injection.
Enrollees received initially 3 biweekly courses of vaccinations, fol-
lowed by up to 10 booster vaccinations at 3-moth intervals. Fol-
low-up with brain MRI was every 2 months or when clinically
indicated.
28
Twenty (n D20) patients had ND-GBM and nine-
teen (n D19) patients had recurrent GBM and other gliomas.
For patients with ND-GBM, who received DCVax!-L in addi-
tion to standard of care treatment, progression-free survival
(PFS, as evaluated with use of the McDonald’s criteria) was
around 24.0 months and OS was 36.0 months.
29
The long-term data analysis (last updated in July 2011)
showed that 33.0% of patients had reached or exceeded a median
survival of 48.0 months and 27.0% had reached or exceeded a
median survival of 72.0 months. By year 2013, two (n D2) of
the Phase I/II clinical trial patients were still alive reaching a sur-
vival of more than 10.0 years.
At the same institution (UCLA) historic controls sharing the
same characteristics as the recruited patients in the trials [recur-
sive partitioning analysis (R.P.A.) classes III and IV of the Euro-
pean Organization for Research and Treatment of Cancer
(EORTC)] had a mean PFS of 8.9 months (§7.3 months), and
a mean OS of 15.0 months (§13.9 months).
29
The safety profile was favorable with only mild side effects
(grade I and II). These included headache, nausea, loss of appe-
tite, diarrhea, fatigue and low-grade fever. Other less common
adverse events (AEs) included itching and redness at injection
site, back or neck pain, lymph node swelling, arthromyalgia,
depression, dehydration, dizziness, cough, somnolence and aller-
gic rhinitis. Nil vaccination-related serious adverse events (SAEs)
had been reported with the majority of AEs and all SAEs having
been attributed to disease progression.
29
Phase I and II clinical trials on other DC-based vaccines
Apart from the previously mentioned two phase I/II clinical
trials on DCVax!-L, twenty-two (n D22) phase I and II clinical
trials and prospective studies have been conducted to evaluate the
safety and efficacy of other DC-based vaccines on GBM and
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other high-grade gliomas (HGG). Twenty (n D20) of these were
phase I and II trials, one was a pilot study towards a phase I/II
trial and one was a prospective study. GBM patients were exclu-
sively recruited in 12/22 studies, ND-GBM patients only were
recruited in 7/22 studies, while 10/22 studies enrolled patients
with any diagnosis of a HGG. In the vast majority of studies the
vaccine was injected intradermally or subcutaneously and con-
sisted of mature DCs pulsed with tumor lysate or peptides.
Patients received an average of 17.62 (2-24) courses of vaccina-
tions. Mean overall survival (OS) ranged between 16.0 and 38.4
months for ND-GBM and between 9.6 and 35.9 months for
recurrent GBM.
28,30-50
Of interest, Ardon et al.
47
analyzed their
results based on RPA classification and reported a mean OS of
39.7 months on patients with ND-GBM for RPA class III. Thus,
it seems that specific subgroups of GBM patients may benefit
from DC-vaccinations greater than others.
The vast majority of vaccine-related side effects were mild
(grade I and II), with serious adverse events (grade II, IV and V)
only reported rarely.
Timing of vaccination
In almost all trials autologous DCs were obtained via differen-
tiation of autologous monocytes, which were collected by leuka-
pheresis. DCs were then ex vivo matured and pulsed with tumor
lysate or peptides and administered post-standard treatment.
Timing of vaccination and its integration in the timeline of stan-
dard of care is a point of debate. Some research groups have com-
menced vaccinations immediately after surgery.
33,34,43
In most of
the trials, and especially those conducted after the adoption of
the “Stupp” protocol, vaccines were administered after comple-
tion of concomitant radiotherapy and chemotherapy with some
doses coinciding with adjuvant temozolomide. This has been
speculated to improve survival rates through possible interaction
between vaccine and chemotherapy resulting in enhanced chemo-
therapy effect and higher tumor chemo-sensitivities, although the
underlying mechanism has not yet been identified.
36,39,51,52
Others have shown that DC-vaccination combines favorably
with radiotherapy by increasing radio-sensitivity of tumor cells
and up-regulating the expression of MHC antigens in animal
models.
27
In contrast, Chang et al.
43
argue that the development
of radiotherapy-induced mutant tumor cells, immunologically
diverse from the ones obtained during surgery, may render vac-
cines inactive against residual or relapsed tumors.
DCVax!-L phase III clinical trial
The currently ongoing phase III clinical trial is a 312-patient
randomized, placebo-controlled, double blinded, multi-center,
international trial evaluating DCVax!-L on ND-GBM (clinical
trial registration # NCT00045968). It is officially entitled “A
Phase III Clinical Trial Evaluating DCVax!-L, Autologous Den-
dritic Cells Pulsed With Tumor Lysate Antigen For The Treat-
ment Of Glioblastoma Multiforme (GBM)”.
53
The trial is
recruiting across two continents with currently fifty-one sites
across the U.S.A. and one in Europe (present authors’ institu-
tion) enrolling eligible patients. Additional sites are due for
activation and are in varying stages of preparation in the U.K.
and Germany.
The primary endpoint of the trial is PFS, i.e. time elapsed
until disease progression, which could be either recurrence of the
tumor or increase in size of residual tumor. Secondary endpoints
of the trial are OS and parameters such as side effects, perfor-
mance status and immune response. Of note in the trial PFS and
OS times are estimated from time-point of randomization, which
happens approximately three months after initial surgery,
whereas in common clinical practice these are usually calculated
from the time of surgery.
Patients recruited will be aged between eighteen and seventy
years old and have newly diagnosed, unilateral GBM. Randomi-
zation occurs after total macroscopic or gross total surgical resec-
tion and completion of the six-week course of concomitant
radiotherapy and chemotherapy. Patients without evidence of
possible disease progression at baseline are randomized into two
cohorts. Two thirds will be in the treatment cohort and one third
in the placebo cohort. In the first cohort patients will receive the
investigational medicinal product (IMP), while in the placebo
cohort patients will be given only the autologous peripheral
blood mononuclear cells obtained via leukapaheresis. During
each session patients are administered two intradermal injections
of either the vaccine or placebo in their upper arm. Entry into
the trial is contingent on having sufficient tumor removed such
that at least 5 vaccination sessions are possible. Vaccinations take
place at 10 time-points, i.e. at days 0, 10 and 20 and at weeks 8,
16, 32, 48, 72, 96 and 120, depending on the patient’s clinical
condition and the number of vaccine doses that have been manu-
factured. In the case of <10 vaccination doses available, patients
are injected for the remaining vaccinations with placebo while
maintaining the blind.
53
Subjects with possible disease progression or possible pseudo-
progression (radio-necrosis) at baseline return after a set time
period for a second baseline visit. Only if at this time it is con-
firmed that there is no disease progression, they will be enrolled.
Additionally if patients in either cohort develop tumor recur-
rence at any point during the trial, they will then have the
option of receiving DCVax!-L following a specific process that
crosses them over to the IMP arm. From this point onwards
subjects will be in the open label follow up arm, but without
unblinding the previous trial data. Patients are monitored regu-
larly by physical and neurological examination, blood tests and
MRI imaging to evaluate effects and side effects. Immune
responses are also tested for by blood withdrawals at baseline
and follow up visits.
The trial is empowered such that achieving the set target for
PFS (the primary endpoint) could result in a p value of 0.01 one-
sided (0.02 two-sided), with a power of 82%. Statistical signifi-
cance is deemed for a p !0.05; therefore a p value of 0.02 pro-
vides a safety margin in case PFS is less than was initially
anticipated during the protocol design. In case the primary and
secondary endpoints are not achieved, it is planned for the data
to be analyzed further based on sub-classification of the trial pop-
ulation. Finally, three interim analyses have been scheduled to
take place for data evaluation while the trial is ongoing.
29
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Production
DCVax!-L is a tailored, immune-treatment based on DCs.
The vaccine is essentially manufactured by fusing the patient’s
own GBM cells with the patient’s own DCs. At surgery part of
the excised tumor is sent for pathological studies and the remain-
ing part is procured and added to a digestion buffer containing
enzymes. Approximately two weeks after an uneventful operation
the patient undergoes a session of leukapheresis, during which
peripheral blood mononuclear cells are obtained. Then the cells
get ex vivo differentiated to DCs with the addition of interleu-
kin-4 (IL-4) and granulocyte-macrophage colony-stimulating
factor (GM-CSF).
Next follows the process of combining the two ingredients,
tumor tissue and DCs, to manufacture the vaccine. Whole tumor
lysate is used in order to potentially pulse DCs with the entire
spectrum of available tumor antigens. The incubation lasts
16 hours and after that the final product is harvested and stored
under cryopreservation. If sufficient tumor lysate has been
extracted, a significant amount of vaccines can be produced,
which will be available for the patient as a course of treatment.
Usually at least five (n D5) doses of the vaccine are required.
Immune Monitoring of the Product
Accurate immuno monitoring assays/techniques to evaluate
response to vaccinations are yet to be developed and uniformly
used. In the past trials, increased peripheral immune markers,
such as cytotoxic T-lymphocyte (CTL) activity and positive
delayed tissue hypersensitivity (DTH) tests, have been reported,
but their correlation with clinical outcomes was weak and there-
fore they lacked prognostic value.
28,36,38,44,47
Nevertheless Yama-
naka et al.
37
and Wheeler et al.
39
reported some value in
measuring such markers, while Fadul et al.
44
found that 50% of
patients developed a measurable immune response which was
associated with improved OS. Currently the most valid indicator
of vaccination-induced immune responses to GBM is considered
to be tumor infiltration by activated T-cells.
Regulatory Issues
The Food and Drug Administration (FDA) in the U.S.A., the
Paul-Ehrlich-Institute (PEI) in Germany and the Medicines and
Healthcare products Regulatory Agency (MHRA) in the U.K.
have approved conduction of the phase III trial. The DCVax!-L
technology and the Phase III trial have been evaluated by the
National Institute for Health Research (NIHR) in the U.K. and
“adopted” as a priority.
Presently in the U.K. the product may be offered to a limited
quota of patients on a compassionate basis outside the trial.
Though this is distinct from a formal approval, it does signify the
potential that DCVax!-L technology carries and its favorable
safety profile. Very recently DCVax!-L received a similar
approval from the PEI in Germany. Moreover the German
reimbursement authority (Institut Fur Das Entgeltsystem Im
Krankenhaus, or InEK) has ruled that DCVax!-L for gliomas is
eligible for reimbursement from the Sickness Funds (health
insurers) of the German healthcare system. Furthermore both in
the U.S.A. and in Europe DCVax!-L has been granted orphan
drug status for GBM and other gliomas. As a result DCVax!-L
will have market exclusivity for 7 years in the U.S.A. and
10 years in Europe.
29
Final approval of DCVax!-L will await the outcome of the
phase III trial although if interim analysis results are favorable,
then an early approval of the product may well be achieved.
Public-health Implications
Though GBM incidence is 2-3 per 100,000 people per year, it
is the most commonly diagnosed primary brain tumor in adults
and its effect is devastating for the patient, the family and the soci-
ety.
54
Given the poor prognosis and in the absence of preventative
measure, presently the majority of efforts are focused on broaden-
ing treatment options, as well as improving their efficacy and ren-
dering them more tolerable. With this respect and if the phase III
trial confirms the findings of phase I/II studies, an individualized
novel treatment modality, such as active DC-immunotherapy with
a favorable safety profile, could make a significant difference and
have an important impact on the management of these patients.
Commercial Issues
DCVax!-L produced by NWBT is at present the only prod-
uct of its kind in a phase III trial. If the results of the trial trans-
late into approval of the product, then demand is likely to be a
significant consideration. Therefore an international network of
manufacturing sites will be required to enhance NWBT’s infra-
structure and ensure its capacity to address this demand. Another
issue to consider is the manufacturing costs. With the increasing
demand, it is likely that the costs will be reduced, but since
DCVax!-L could potentially monopolize the market for a signif-
icant amount of time, a discussion with the international health
systems and funders is required to ensure accessibility of the
product to the patients.
Advantages and Disadvantages Relative to other
Products for the Same Disease
DCVax!-L is an autologous vaccine that crystallizes the con-
cept of personalized, targeted therapy. It generates an immune
response that is underpinned by two distinct elements: a. it is trig-
gered by autologous antigens and b. whole tumor lysate is used to
obtain these antigens. The first spares the potential disadvantages
caused by the use of artificial peptides, namely lower specificity
and immunogenicity. The second allows exploitation of the whole
spectrum of available tumor antigens accounting for genetic het-
erogeneity that is seen even within the same individual’s tumor.
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A potential disadvantage of the DCVax!-L technology could
be that the use of whole tumor lysate, potentially containing
healthy brain tissue, may result in immune responses against nor-
mal brain leading to autoimmune encephalitis. Presently however
preliminary data from DCVax!-L and other active DC-immu-
notherapy trials have not revealed any SAEs related to autoimmu-
nity. Additionally DC cancer vaccines in general may prove to be
not as robust and durable as required to vanquish the intrinsic
ability of cancers to suppress the immune system.
55
Long term
data is required to shed light on this view point.
Presently according to the clinicaltrials.gov website there are 7
other ongoing clinical trials, evaluating DC-vaccines for either
ND or recurrent GBM. These are exclusively phase I/ II single
center trials primarily recruiting in the U.S.A. (Table 1).
56
Conclusion
The lack of significant improvement in the prognosis of
patients with GBM in the recent years warrants exploration of
new therapeutic avenues. DCVax!-L as an autologous active DC-
immunotherapy agent has achieved promising outcomes with little
side effects in phase I/II trials. The ongoing phase III trial is aimed
at verifying these preliminary results, which if achieved, will have a
major impact in the management of patients with GBM.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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Table 1. Actively recruiting clinical trials evaluating DC-vaccines for ND-GBM, recurrent GBM or high-grade gliomas. Of these trials commercial company
sponsors only #8, while the rest are conducted under Investigator Investigational New Drug (IND) or Institutional IND without a company sponsor.
Sponsor
ClinicalTrials.
gov Identier
Trial
Phase Diagnosis Study Design Antigen Type Comments
1University of Miami
Sylvester
Comprehensive
Cancer Center
NCT01808820 I High Grade Glioma Single-Center
Open Label
Autologous lysate DCs and antigens are
separately injected.
2Cedars-Sinai Medical
Center
NCT02010606 I ND- or recurrent GBM Single-Center
Non-Randomized
Open Label
Allogeneic lysate
3Jeremy Rudnick, M.D,
Cedars-Sinai
Medical Center
NCT02049489 NA Recurrent GBM Single-Center
Open Label
Puried peptides from
CD133 antigen
4University of Miami
Sylvester
Comprehensive
Cancer Center
NCT01902771 I High Grade Glioma Single-Center
Open Label
Autologous lysate DCs and antigens are
separately injected.
5Jonsson
Comprehensive
Cancer Center
NCT01204684 II High Grade Glioma Single-Center
Open Label
Autologous lysate C/- Administration of Toll-
like Receptor Agonists
6Huashan Hospital NCT01567202 II ND-GBM Single-Center
Randomized
Double blind
Autogeneic glioma stem-like
cells
7John Sampson, Duke
University Medical
Center
NCT00890032 I Recurrent GBM Single-Center
Open Label
Brain tumor stem cell
messenger ribonucleic
acid (mRNA)
8NWBT NCT00045968 III ND-GBM Multicenter
Randomized
Double blind
Autologous lysate
DCs, Dendritic cells; GBM, glioblastoma multiforme; NA, Not applicable; ND, Newly diagnosed; NWBT, Northwest Biotherapeutics
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... Some approaches based on vaccines are also investigated as a potential adaptive immunotherapy for GBM. An autologous tumor lysate-pulsed dendritic cell vaccine called DCVax ® -L, produced by Northwest Biotherapeutics, Inc., Bethesda, MD, USA [176], has been used against glioblastoma and appears to be safe. DCVax-L has been approved for GBM treatment in Switzerland, but is still under clinical trials in the United States [177]. ...
Article
Glioblastoma multiforme (GBM) is a grade IV glioma considered the most fatal cancer of the central nervous system (CNS), with less than a 5% survival rate after five years. The tumor heterogeneity, the high infiltrative behavior of its cells, and the blood–brain barrier (BBB) that limits the access of therapeutic drugs to the brain are the main reasons hampering the current standard treatment efficiency. Following the tumor resection, the infiltrative remaining GBM cells, which are resistant to chemotherapy and radiotherapy, can further invade the surrounding brain parenchyma. Consequently, the development of new strategies to treat parenchyma-infiltrating GBM cells, such as vaccines, nanotherapies, and tumor cells traps including drug delivery systems, is required. For example, the chemoattractant CXCL12, by binding to its CXCR4 receptor, activates signaling pathways that play a critical role in tumor progression and invasion, making it an interesting therapeutic target to properly control the direction of GBM cell migration for treatment proposes. Moreover, the interstitial fluid flow (IFF) is also implicated in increasing the GBM cell migration through the activation of the CXCL12-CXCR4 signaling pathway. However, due to its complex and variable nature, the influence of the IFF on the efficiency of drug delivery systems is not well understood yet. Therefore, this review discusses novel drug delivery strategies to overcome the GBM treatment limitations, focusing on chemokines such as CXCL12 as an innovative approach to reverse the migration of infiltrated GBM. Furthermore, recent developments regarding in vitro 3D culture systems aiming to mimic the dynamic peritumoral environment for the optimization of new drug delivery technologies are highlighted.
... No AEs of grade 3 or higher were identified. AEs of grade 1 and 2 included headache, nausea, loss of appetite, diarrhea, fatigue and low-grade fever (35). DCVax ® -L is currently being tested in a phase III clinical trial in patients after glioblastoma resection in combination with radiation and chemotherapy. ...
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The development of immunotherapeutic methods for the treatment of oncological diseases have made it possible to improve the effectiveness of standard therapies. There was no breakthrough after first using of personalized therapeutic vaccines based on dendritic cells in clinical practice. A deeper study of the biology of dendritic cells, as well as the use of new approaches and agents for antigenic work, have made it possible to expand the field of application of dendritic cell (DC) vaccines and improve the indicators of cancer patients. In addition, the low toxicity of DC vaccines in clinical trials makes it possible to use promising predictions of their applicability in wider clinical practice. This review examines new approaches and recent advances of the DC vaccine in clinical trials.
... Furthermore, phagocytosis of tumor cells by APCs was enhanced by blocking the anti-phagocytosis molecule CD47 in combination with TMZ, inducing an effective anti-tumor immune response (von Roemeling et al., 2020). However, the use of whole tumor lysate to pulse DCs could cause autoimmune encephalitis since tumor lysate contains healthy brain tissue and induces an immune response toward the normal brain (Polyzoidis and Ashkan, 2014). ...
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According to the invasive nature of glioblastoma, which is the most common form of malignant brain tumor, the standard care by surgery, chemo- and radiotherapy is particularly challenging. The presence of glioblastoma stem cells (GSCs) and the surrounding tumor microenvironment protects glioblastoma from recognition by the immune system. Conventional therapy concepts have failed to completely remove glioblastoma cells, which is one major drawback in clinical management of the disease. The use of small molecule inhibitors, immunomodulators, immunotherapy, including peptide and mRNA vaccines, and virotherapy came into focus for the treatment of glioblastoma. Although novel strategies underline the benefit for anti-tumor effectiveness, serious challenges need to be overcome to successfully manage tumorigenesis, indicating the significance of developing new strategies. Therefore, we provide insights into the application of different medications in combination to boost the host immune system to interfere with immune evasion of glioblastoma cells which are promising prerequisites for therapeutic approaches to treat glioblastoma patients.
... The double-blinded randomized phase II trial of ICT-107, involving DCs pulsed with six synthetic peptides, increased overall survival of newly diagnosed glioblastoma patients by 2 months compared to placebo control, although it was not statistically significant (114). Another DC vaccine, DCVax ® -L, demonstrated safety and tolerability in early studies and recently underwent phase 3 evaluation, but was unfortunately prematurely suspended due to lack of funds (115). Interestingly, there appears to be subtypespecific benefits of DC-based vaccines, whereby the mesenchymal subtype is associated with heightened responsiveness, including increased infiltration of CD3 + and CD8 + T cells compared to other glioblastoma subtypes, and increased survival compared to historical controls of the same molecular subtype (116). ...
Article
Full-text available
Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.
... 74,76 Last, but not least, DCVax-L, the longest-acting vaccine in history for GBM, 77 acts by utilizing whole tumor lysate from patient GBM tissue to generate autologous DCs. 80 However, this vaccine is considered challenging because it requires the collection of the patient's tumor tissue and then processing the tissue to activate the autologous DCs. 77,78 Furthermore, given the impermeable nature of the BBB, the delivery of the targeted agents to the brain is considered challenging. ...
Article
Full-text available
Glioblastoma is the most aggressive malignant primary brain tumor, with a dismal prognosis and a devastating overall survival. Despite aggressive surgical resection and adjuvant treatment, average survival remains approximately 14.6 months. The brain tumor microenvironment is heterogeneous, comprising multiple populations of tumor, stromal, and immune cells. Tumor cells evade the immune system by suppressing several immune functions to enable survival. Gliomas release immunosuppressive and tumor-supportive soluble factors into the microenvironment, leading to accelerated cancer proliferation, invasion, and immune escape. Mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue, or umbilical cord are a promising tool for cell-based therapies. One crucial mechanism mediating the therapeutic outcomes often seen in MSC application is their tropism to sites of injury. Furthermore, MSCs interact with host immune cells to regulate the inflammatory response, and data points to the possibility of using MSCs to achieve immunomodulation in solid tumors. Interleukin 1β, interleukin 6, tumor necrosis factor α, transforming growth factor β, and stromal cell–derived factor 1 are notably up-regulated in glioblastoma and dually promote immune and MSC trafficking. Mesenchymal stem cells have widely been regarded as hypoimmunogenic, enabling this cell-based administration across major histocompatibility barriers. In this review, we will highlight (1) the bidirectional communication of glioma cells and tumor-associated immune cells, (2) the inflammatory mediators enabling leukocytes and transplantable MSC migration, and (3) review preclinical and human clinical trials using MSCs as delivery vehicles. Mesenchymal stem cells possess innate abilities to migrate great distances, cross the blood-brain barrier, and communicate with surrounding cells, all of which make them desirable “Trojan horses” for brain cancer therapy.
... A dendritic cell vaccine (DCVax-Brain) was approved in Switzerland for the treatment of GBM. It is composed of dendritic cells with purified tumorspecific antigens or tumor cell extracts [64,65]. Experimental studies on the administration of this vaccine for newly diagnosed and recurrent GBM remain ongoing, and some of these trials have demonstrated an increase in vaccine effectiveness if boosted with the tetanus/diphtheria toxoid vaccine [51]. ...
Article
Background: Immune tolerance, immune escape, neoangiogenesis, phenotypic changes, and glioma stem cells are all responsible for the resistance of malignant brain tumors to current therapies and persistent recurrence. The present study provides a panoramic view of innovative therapies for malignant brain tumors, especially glioblastoma, aimed at achieving a tailored approach. Methods: PubMed/Medline and ClinicalTrials.gov were the main sources of an extensive literature review in which "Regenerative Medicine," "Cell-Based Therapy," "Chemotherapy," "Vaccine," "Cell Engineering," "Immunotherapy, Active," "Immunotherapy, Adoptive," "Stem Cells," "Gene Therapy," "Target Therapy," "Brain Cancer," "Glioblastoma," and "Malignant Brain Tumor" were the search terms. Only articles in English published in the last 5 years were included. A further selection was made according to the quality of the studies and level of evidence. Results: Cell-based and targeted therapies represent the newest frontiers of brain cancer treatment. Active and adoptive immunotherapies, stem cell therapies, and gene therapies represent a tremendous evolution in recent years due to many preclinical and clinical studies. Clinical trials have validated the effectiveness of antibody-based immunotherapies, including an in-depth study of bevacizumab, in combination with standard of care. Preclinical data highlights the role of vaccines, stem cells, and gene therapies to prevent recurrence. Conclusion: Monoclonal antibodies strengthen the first-line therapy for high grade gliomas. Vaccines, engineered cells, stem cells, and gene and targeted therapies are good candidates for second-line treatment of both newly diagnosed and recurrent gliomas. Further data are necessary to validate this tailored approach at the bedside.
... It was observed that the treatment was feasible and apparently nontoxic and was able to regress tumor in a child with metastatic fibro-sarcoma [39]. A vaccine, DCVaxV R -L, which targets Glioblastoma Multiforme (GBM) contains mature dendritic cells along with tumor lysate or peptides is in stage III trials [40]. ...
Article
Cancer is one of the proficient evaders of the immune system which claims millions of lives every year. Developing therapeutics against cancer is extremely challenging as cancer involves aberrations in self, most of which are not detected by the immune system. Conventional therapeutics like chemotherapy, radiotherapy are not only toxic but they significantly lower the quality of life. Immunotherapy, which gained momentum in the 20th century, is emerging as one of the alternatives to the conventional therapies and is relatively less harmful but more costly. This review explores the modern advances in an array of such therapies and try to compare them along with a limited analysis of concerns associated with them.
... CVacTM developed from Prima Biomed consists of dendritic monocyte derived cells loaded with the protein mucin 1, the abnormally expressed protein of various epithelial tumors, including ovarian cancer.MUC1, the recombinant protein VNTR is combined with mannan oxidized. CVac has demonstrated its survival in patients with ovarian cancer by 10.3 months and demonstrated increased progression-free survival of patients with second-hand clinical remission in maintenance therapy [74,75]. Vaccell by Tella is another DC-based vaccine used in the identify antigenic system where MHC-I-restricted Wilms tumourgen 1 peptide antigens are incubated with the PBMDs of patients (WT1). ...
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Malignant gliomas are primary brain tumors characterized by profound local immunosuppression. While the remarkable plasticity of perivascular cells - resembling mesenchymal stem cells (MSC) - in malignant gliomas and their contribution to angiogenesis is increasingly recognized, their role as potential mediators of immunosuppression is unknown. Here we demonstrate that FACS-sorted malignant glioma-derived pericytes (HMGP) were characterized by the expression of CD90, CD248, and platelet-derived growth factor receptor-β (PDGFR-β). HMGP shared this expression profile with human brain vascular pericytes (HBVP) and human MSC (HMSC) but not human cerebral microvascular endothelial cells (HCMEC). CD90+PDGFR-β+perivascular cells distinct from CD31+ endothelial cells accumulated in human gliomas with increasing degree of malignancy and negatively correlated with the presence of blood vessel-associated leukocytes and CD8+ T cells. Cultured CD90+PDGFR-β+HBVP were equally capable of suppressing allogeneic or mitogen-activated T cell responses as human MSC. HMGP, HBVP and HMSC expressed prostaglandin E synthase (PGES), inducible nitric oxide synthase (iNOS), human leukocyte antigen-G (HLA-G), hepatocyte growth factor (HGF) and transforming growth factor-β (TGF-β). These factors but not indoleamine 2,3-dioxygenase-mediated conversion of tryptophan to kynurenine functionally contributed to immunosuppression of immature pericytes. Our data provide evidence that human cerebral CD90+ perivascular cells possess T cell inhibitory capability comparable to human MSC and suggest that these cells, besides their critical role in tumor vascularization, also promote local immunosuppression in malignant gliomas and possibly other brain diseases.
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T cells recognize peptides that are bound to MHC molecules on the surface of different types of antigen-presenting cells (APC). Antigen presentation most often is studied using T cells that have undergone priming in situ, or cell lines that have been chronically stimulated in vitro. The use of primed cells provides sufficient numbers of antigen-reactive lymphocytes for experimental study. A more complete understanding of immunogenicity, however, requires that one develop systems for studying the onset of a T cell response from unprimed lymphocytes, especially in situ. Here it is shown that mouse T cells can be reliably primed in situ using dendritic cells as APC. The dendritic cells were isolated from spleen, pulsed with protein antigens, and then administered to naive mice. Antigen-responsive T cells developed in the draining lymphoid tissue, and these T cells only recognized protein when presented on cells bearing the same MHC products as the original priming dendritic cells. In contrast, little or no priming was seen if antigen-pulsed spleen cells or peritoneal cells were injected. Since very small amounts of the foreign protein were visualized within endocytic vacuoles of antigen-pulsed dendritic cells, it is suggested that dendritic cells have a small but relevant vacuolar system for presenting antigens over a several day period in situ.