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Cancer immunotherapy uses the immune system and its components to mount an anti-tumor response. During the last decade, it has evolved from a promising therapy option to a robust clinical reality. Many immunotherapeutic modalities are already approved by the Food and Drug Administration (FDA) for treating cancer patients and many others are in the pipeline for approval as standalone or combinatorial therapeutic interventions, several also combined with standard treatments in clinical studies. The two main axes of cancer immunotherapeutics refer to passive and active treatments. Prominent examples of passive immunotherapy include administration of monoclonal antibodies and cytokines and adoptive cell transfer of ex vivo “educated” immune cells. Active immunotherapy refers, among others, to anti-cancer vaccines [peptide, dendritic cell (DC)-based and allogeneic whole cell vaccines], immune checkpoint inhibitors and oncolytic viruses, whereas new approaches that can further enhance anti-cancer immune responses are also widely explored. Herein, we present the most popular cancer immunotherapy approaches and discuss their clinical relevance referring to data acquired from clinical trials. To date, clinical experience and efficacy suggest that combining more than one immunotherapy interventions, in conjunction with other treatment options like chemotherapy, radiotherapy and targeted or epigenetic therapy, should guide the way to cancer cure.
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© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
Review Article
Harnessing the immune system to improve cancer therapy
Nikos E. Papaioannou, Ourania V. Beniata, Panagiotis Vitsos, Ourania Tsitsilonis, Pinelopi Samara
Department of Animal and Human Physiology, Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Ilissia, 15784,
Athens, Greece
Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)
Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of
manuscript: All authors.
Correspondence to: Pinelopi Samara. Department of Animal and Human Physiology, Faculty of Biology, National and Kapodistrian, University
of Athens, Panepistimiopolis, Ilissia, 15784, Athens, Greece. Email: psamara@biol.uoa.gr; Ourania Tsitsilonis. Department of Animal and
Human Physiology, Faculty of Biology, National and Kapodistrian, University of Athens, Panepistimiopolis, Ilissia, 15784, Athens, Greece.
Email: rtsitsil@biol.uoa.gr.
Abstract: Cancer immunotherapy uses the immune system and its components to mount an anti-tumor
response. During the last decade, it has evolved from a promising therapy option to a robust clinical reality. Many
immunotherapeutic modalities are already approved by the Food and Drug Administration (FDA) for treating
cancer patients and many others are in the pipeline for approval as standalone or combinatorial therapeutic
interventions, several also combined with standard treatments in clinical studies. The two main axes of cancer
immunotherapeutics refer to passive and active treatments. Prominent examples of passive immunotherapy include
administration of monoclonal antibodies and cytokines and adoptive cell transfer of ex vivo “educated” immune
cells. Active immunotherapy refers, among others, to anti-cancer vaccines [peptide, dendritic cell (DC)-based and
allogeneic whole cell vaccines], immune checkpoint inhibitors and oncolytic viruses, whereas new approaches that
can further enhance anti-cancer immune responses are also widely explored. Herein, we present the most popular
cancer immunotherapy approaches and discuss their clinical relevance referring to data acquired from clinical trials.
To date, clinical experience and efficacy suggest that combining more than one immunotherapy interventions, in
conjunction with other treatment options like chemotherapy, radiotherapy and targeted or epigenetic therapy,
should guide the way to cancer cure.
Keywords: Cancer immunotherapy; checkpoint inhibitors; dendritic cells (DCs); monoclonal antibodies (mAbs);
peptide vaccines
Submitted Feb 19, 2016. Accepted for publication Mar 15, 2016.
doi: 10.21037/atm.2016.04.01
View this article at: http://dx.doi.org/10.21037/atm.2016.04.01
Introduction
Cancer immunotherapy involves the exploitation of the
immune system’s machinery to recognize, target and destroy
cancer cells. The idea of using the immune system against
cancer is based, among others, on the following properties
of its components; immune cells (I) provide constant
surveillance, as they continuously travel throughout the
body; (II) are specically stimulated against tumors, which
are by denition antigenic and often immunogenic; and (III)
protect against tumor relapse, due to induction of specic
and long-lasting memory. Nevertheless, tumors escape from
immunosurveillance through a well described procedure
termed “cancer immunoediting”. Koebel and coworkers
elegantly showed that immunoediting comprises three main
sequential events: elimination, equilibrium, escape, and
eventually leads to cancer growth (1).
Cancer immunotherapy came of age particularly after
2000. New knowledge on the mechanisms of anti-tumor
immune responses, novel technological platforms on the
production of active anti-cancer compounds and innovative
advances to quantify clinical responses have resulted in
Papaioannou et al. The immune system in cancer therapy
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
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improved cancer immunotherapeutic protocols for patient
treatment in the clinical setting. Since Coley’s rst anti-cancer
intervention in 1893, major landmarks comprise the 1973
discovery of dendritic cells (DCs) (2); the 1989 development
of the first chimeric antigen receptors (CARs) (3);
the 1991 cloning of the first tumor antigen; and the 1995
identification of the first checkpoint molecule, namely the
cytotoxic T lymphocyte-associated protein 4 (CTLA-4) (4).
Licensing of clinical trials in 2000 and the first results
reported at that time did not boost the enthusiasm of most
cancer immunologists and oncologists. However, recently
accumulated data strongly indicate measurable improvement
in patient outcome and, in several cases, induction of efcient
and durable responses. In the next sections, we will briefly
review the most popular anti-cancer immunotherapeutic
protocols and suggest possible means to exploit their
synergistic potential for the benet of cancer patients.
Classification of cancer immunotherapy
strategies
Cancer immunotherapy is briefly divided into two main
types of interventions: passive and active (Figure 1).
The classification is based on the mechanism of action
of the therapeutic agent used, as well as on the status
of the patient’s immune system. In general, passive
immunotherapeutics are used in cancer patients with
weak, unresponsive, or of low responsiveness immune
systems. Passive protocols consist of ex vivo-activated cells
or molecules that once found inside the body, compensate
for missing or decient immune functions. Among others,
this category includes the infusion of tumor-specific
antibodies, the systemic administration of recombinant
cytokines and the adoptive transfer of immune cells pre-
activated to lyse tumors in vivo. On the other hand, active
immunotherapy strategies aim to stimulate effector
functions in vivo. To apply active immunotherapeutics, the
patient’s immune system should be able to respond upon
challenge, get competently stimulated and mediate effector
functions. The most important active protocols comprise
vaccination strategies with tumor peptides or allogeneic
whole cells, the use of autologous DCs as vehicles for tumor
antigen delivery, and the infusion of antibodies targeting
crucial checkpoints of T cell activation. Finally, although
initially considered as passive intervention, the systemic
immune responses induced by oncolytic viruses shifted this
novel therapeutic modality to the group of active cancer
immunotherapeutics.
Figure 1 Cancer immunotherapy approaches are classified into passive and active. Passive immunotherapy includes the use of tumor-
specic mAbs, cytokines and adoptive cell transfer, whereas active immunotherapy refers to peptide, DC or allogeneic whole cell vaccines,
checkpoint inhibitors and oncolytic viruses. DC, dendritic cell.
Tumor-specific
mAbs Cytokines
Adoptive Cell
Transfer
Peptide
vaccines
DC
vaccines
Checkpoint
inhibitors
Allogeneic
whole cell
vaccines
Oncolytic
viruses
Passive Immunotherapy
Active Immunotherapy
Annals of Translational Medicine, 2016 Page 3 of 15
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
Passive cancer immunotherapy
Tumor-specic monoclonal antibodies (mAbs) target
cancer-specic or cancer-associated antigens and lyse
cancer cells via various mechanisms
Historically, mAbs were described as “magical bullets”. The
rst anti-cancer mAbs of murine origin were recognized as
foreign by the patient’s immune system and the generation
of human anti-mouse antibody (HAMA) responses
abrogated their biological efficacy. Advances in antibody
engineering resulted in greatly reducing HAMA responses
and the currently used mAbs are chimeric, humanized or
fully human.
The most commonly used mAbs in cancer immunotherapy
are of the IgG class due to their long half-life and stability
in serum. Naked anti-cancer mAbs mediate their function
through directly inducing programmed cell death upon
binding to tumor targets and by antibody-dependent cellular
cytotoxicity (ADCC), complement-dependent cytotoxicity
(CDC) and/or antibody-dependent cellular phagocytosis
(ADCP). Briey, mAbs promote ADCC or ADCP-mediated
tumor burden clearance, via interactions of their constant
fragment (Fc) with Fc γ-receptors (FcγRIIIa and FcγRIIa on
NK cells and macrophages, respectively) (5). For example,
the chimeric mAb rituximab targets CD20 on malignant B
lymphocytes facilitating recognition by immune effectors,
induction of apoptosis by NK cells via perforin/granzyme
release and Fas/FasL interactions, and/or phagocytosis by
macrophages (6). In CDC, the activation of complement (C)
factors (e.g., C1q, C3b) leads to the formation of membrane
attack complexes, as well as to the recruitment of immune
cells (C3a and C5a) (7). For example, it has been reported
that the humanized anti-CD52 mAb alemtuzumab exerts
its anti-tumor activity by solely mediating CDC in patients
with chronic lymphocytic leukemia (8). The significance
of both ADCC and CDC in cancer immunotherapy is
evidently supported by the correlation of clinical responses
to mAb therapy with polymorphisms in the FcγR and C1qA
genes (6). Moreover, ADCP facilitates cross-presentation
of tumor peptides derived from engulfed apoptotic cells on
major histocompatibility complex (MHC) molecules and
the expansion of tumor-reactive CD8+ and CD4+ T cells
that, among others, prime B cells to produce host anti-
tumor antibodies (Abs) (9).
Antibodies or antibody fragments can be conjugated
via their Fc to radioisotopes (e.g., the anti-CD20 mAb
131I-tositumomab), cytokines [e.g., the anti-GD2/interleukin
(IL)-2 fusion protein EMD 273063] and toxins (e.g.,
gemtuzumab ozogamicin, a fusion of a cytotoxic antibiotic
to a mAb targeting CD33 on leukemic myeloblasts) (10).
In Ab-directed enzyme prodrug therapy (referred to as
ADEPT), an enzyme linked to the mAb Fc converts a non-
toxic prodrug, given systemically, into a potent cytotoxic
agent (e.g., fusion of Fc to α-lactamase that converts C-Mel
into melphalan) (11). All aforementioned approaches
deposit the cytotoxic agent to the vicinity of the tumor, thus
minimizing adverse events.
Currently, many mAbs used in cancer treatment target
and bind to a certain antigen on cancer cell surface,
blocking specific downstream signaling pathways and
arresting cell proliferation (Table 1). Indicative examples
include cetuximab and panitumumab targeting the
epidermal growth factor receptor (EGFR). Both mAbs
prevent binding of the activation ligand EGF and receptor
dimerization, further blocking PI3K/AKT and Ras/MAPK
signaling (12,13). They are used, so far, as second- and
third-line treatment for metastatic colorectal cancer (CRC).
Trastuzumab and pertuzumab target the truncated form
of EGFR, HER2. They inhibit receptor dimerization,
increase its endocytic destruction, mediate ADCC
and induce apoptosis (14). Other mAbs that target the
immunosuppressive tumor microenvironment also showed
beneficial results in the clinical setting. Bevacizumab
prevents binding of vascular endothelial growth factor
(VEGF) to its receptors and inhibits angiogenesis. Its use is
approved for some solid tumors (e.g., CRC), in combination
with chemotherapy (15). Daclizumab, a CD25 specific
mAb, efficiently depletes CD4+CD25+FoxP3+ regulatory
T cells (Tregs) and is approved for treating patients with
metastatic breast cancer (16). Finally, bispecic mAbs have
also shown promise, acting by bridging immune effectors
to cancer cells and promoting tumor cell eradication. A new
class of such mAbs, the artificially produced bispecific T
cell engagers (BiTEs), can induce T cell-mediated tumor
elimination in the absence of T cell receptor (TCR)-MHC
interactions. Blinatumomab is currently the only Food and
Drug Administration (FDA) approved BiTE for treating
refractory or relapsed Philadelphia chromosome-negative
B-acute lymphocytic leukemia (17).
Cytokine administration demonstrates some efcacy,
mainly in combinatorial anti-cancer treatments
Although being one of the rst therapeutic interventions in
cancer, cytokine use as monotherapy is no longer popular.
The most prominent cytokines are interferon-alpha
(IFN-α), IL-2 and IL-12. High dose IL-2, as well as IFN-α,
Papaioannou et al. The immune system in cancer therapy
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
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received FDA approval for use in metastatic melanoma (in
1992 and 2011, respectively) and renal cell carcinoma (RCC;
in 1998 and 2009, respectively), as both act pleiotropically
and reportedly exert immunomodulatory effects on immune
cells (18,19). IFN-α further demonstrated a marked
suppressive effect on Tregs in the tumor microenvironment.
Specifically, post-operative IFN-α administration in RCC
patients for 4 weeks resulted in decreased frequency of
tumor and peripheral blood Tregs (20). Recent in vitro data
suggest that integration of IFN-α in a DC-based protocol
notably improved its therapeutic efcacy (21).
IL-2 is preferably administered in combination with
standard treatments, such as chemotherapy, other cytokines,
peptide vaccines and mAbs. For example, the combined
administration of IL-2 and IFN-α in RCC patients with
lung metastases exhibited a signicant survival benet (22).
In patients with advanced melanoma, administration of a
gp100 peptide vaccine with IL-2 led to higher rates of clinical
response, prolonged progression-free and overall survival
(OS), compared to high dose IL-2 monotherapy (23).
Another widely used cytokine is IL-12, which is normally
secreted from antigen presenting cells (APCs) in response
to antigen stimulation. Among its other biological activities,
IL-12 promotes CD4+ T cell polarization to Th1 cells,
orchestrates anti-cancer responses and inhibits tumor-
derived Tregs (24,25). Although the rst phase II trial failed
due to severe toxicity (26), IL-12 treatment of cutaneous T
cell lymphoma (27), non-Hodgkin’s B cell lymphoma (28)
and AIDS-associated Kaposi sarcoma (29) showed
encouraging results. In addition, IL-12-based gene therapy
with electroporation-mediated plasmid transfers (30) and
immunocytokine approaches (e.g., NHS-IL-12) (31) have
also been tested.
Adoptive cell transfer (ACT) strategies signicantly
improve patient outcome in solid and hematological
malignancies
In ACT protocols, patients are treated with ex vivo
expanded autologous cells, including tumor infiltrating
lymphocytes (TILs), cytokine-induced killer (CIK) or
cascade-primed (CAPRI) cells (Table 2). TILs are isolated by
dissociation of tumor specimens into single cell suspensions
and in vitro lymphocyte expansion in the presence of high
dose IL-2. Promising results were shown in metastatic
melanoma patients, where treatment with TILs proved
highly efcient, inducing durable responses irrespective to
prior therapies applied (32). Remarkably, tumor-reactive
CD4+ TIL infusion in a female patient with widely spread
metastatic cholangiocarcinoma resulted in regression of her
liver and lung metastases (33).
CIK cells comprise a heterogeneous population, mainly
consisting of CD3+CD56+ cells. They are generated upon
in vitro stimulation of peripheral blood mononuclear cells
with anti-CD3, IL-1β and IFN-γ, while addition of IL-2
Table 1 Monoclonal antibodies and conjugates approved for the treatment of cancer in humans (February 2016)
Antibody Trade name (company) Target Antibody type Cancer type
Alemtuzumab Campath (Genzyme) CD52 Humanized Chronic lymphocytic leukemia
Bevacizumab Avastin (Roche) VEGFA Humanized CRC, NSCLC, RCC, glioblastoma
Cetuximab Erbitux (Bristol-Myers Squibb/Lilly) EGFR Chimeric CRC, breast, lung
Denosumab Xgeva/Prolia (Amgen) RANK Ligand Human Solid tumor bony metastases
Gemtuzumab ozogamicin Mylotarg (Wyeth) CD33 Humanized Acute myeloid leukemia
Nimotuzumab Theraloc/TheraCIM (YM Biosciences) EGFR Humanized Head and neck
Ofatumumab Arzerra (GlaxoSmithKline) CD20 Human Chronic lymphocytic leukemia
Panitumumab Vectibix (Amgen) EGFR Human CRC
Pertuzumab Perjeta (Roche) HER2 Humanized Breast
Rituximab Rituxan/MabThera (Biogen, Roche) CD20 Chimeric Non-Hodgkin’s lymphoma
Tositumomab and
131I-tositumomab
Bexxar (GlaxoSmithKline) CD20 Mouse Lymphoma
Trastuzumab Herceptin (Roche) HER2 Humanized Breast
Annals of Translational Medicine, 2016 Page 5 of 15
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
and IL-15 further augments their effector functions (34).
CIK cells are non-MHC restricted, migrate into tumors and
exert their cytotoxicity via NKG2D receptor engagement,
allowing their clinical application in a wide range of solid
and hematological malignancies (35,36).
CAPRI cell therapy uses the patient’s own peripheral
blood monocytes, which present cancer peptides, to prime
in vitro naïve T cells into cytotoxic effectors. The CAPRI
quartet contains monocytes, DCs, CD4+ and CD8+ T
cells. The procedure followed for their generation starts
with autologous T cell stimulation with OKT3 and IL-
2, which next activate monocytes to display more cancer
immunogenic peptides. Subsequent co-culture of these
monocytes with unstimulated T cells primes the expansion
of CAPRI cells, which upon infusion, exhibit boosted
cytotoxicity against tumors. The first results of CAPRI
cell therapy in patients with metastatic breast cancer led
to prolongation of their survival, compared to non-treated
patients (37), whereas favorable results were also shown in
non-small cell lung cancer (NSCLC) patients. It should be
noted that preparative lymphodepletion by chemotherapy
or whole body irradiation usually renders the recipient
prone to all of the aforementioned ACT approaches,
enhancing adoptively transferred cell persistence and their
in vivo anti-tumor effectiveness (38,39).
T cells constitute a further option for cancer immunotherapy,
as they can be genetically engineered to express TCRs with
high avidity for specic tumor antigens (Table 2). TCR genes
of variable origin (e.g., human or from humanized mice) are
cloned into viral vectors and used to transduce autologous
T cells from patients. The rst clinical trials in melanoma
patients were promising (40).
CARs, initially constructed in 1989, are surface proteins
that combine the single chain variable fragments (scFv) of an
antibody recognizing a tumor antigen with intracellular T
cell signaling domains (3). First generation CARs comprised
a scFv joined to the CD3ζ chain (41) (Table 3). Second and
third generation CARs contained additional co-stimulatory
domains such as CD28 and/or CD137, which improved
cytokine production by and in vivo persistence of infused
CAR-modified T cells, respectively. Recently developed
T cells redirected for universal cytokine-mediated killing
Table 2 Advantages and disadvantages of some adoptive cell therapy approaches
Adoptive cell
therapy Advantages Disadvantages
Tumor infiltrating
lymphocytes
(TILs)
Strictly directed against tumor-specific antigens; successful
application in melanoma patients
Inactive against tumor changes due to immunoediting;
tedious quantitative isolation from tumors; delay of
therapy due to prolonged ex vivo expansion; bathed in the
immunosuppressive tumor microenvironment; tumor cells
down-regulate MHC class I molecules
Cytokine-induced
killer (CIK) cells
MHC-independent cytotoxic effect; infusion possible to
allogeneic patients; easily isolated from peripheral blood;
large scale expansion in vitro; lack of antigen specificity;
efficacy against cancer immunogenic profile changes
Need concurrent high dose IL-2 administration; low in
vivo persistence as they comprise terminally differentiated
cells; variable percentages of effector cells due to
population heterogeneity
Cascade-primed
(CAPRI) cells
Tumor site-independent lymphocyte isolation; no antigen
specificity, not affected by immunoediting; short-term
expansion protocol, no cytokine administration; effective in
several types of cancer
Efficacy shown only in case studies and in vitro assays
T cell receptor
(TCR) transduced
T cells
Selection of engineered population (type, differentiation
and effector stage); insertion of genes improving efficacy,
functionality and polarization
Mostly monoclonal specificity; not effective against tumor
escape variants; unexpected toxicity due to endogenous
and transfected TCR α and β chains mispairing
Chimeric antigen
receptor (CAR)-
modified T cells
MHC-independent; overcome tumor MHC molecule down-
regulation; potent in recognizing any cell surface antigen
(protein, carbohydrate or glycolipid); applicable to a broad
range of patients and T cell populations; production of large
numbers of tumor-specific cells in a moderately short period
of time
Capable of targeting only cell surface antigens; lethal
toxicity due to cytokine storm reported
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(TRUCKs/fourth generation CARs) are modified with an
inducible IL-12 vector and, upon engagement of the cognate
antigen, release IL-12 (42,43). IL-12 sensitizes APCs
within the tumor microenvironment and produces a local
inammatory response, improving tumor eradication (44).
To bypass T cell modication for a distinct tumor antigen,
universal CARs with unlimited antigen adaptability have
also been designed. These avidin (45) and anti-uorescein
isothiocyanate (FITC) (46) -bearing CARs bind with high
affinity any biotinylated or FITC-labeled tumor antigen-
specic mAb and exhibit potent anti-tumor activity.
First generation CARs used in early clinical trials
showed no objective clinical responses. However, clinical
trials on hematological malignancies using second or third
generation CARs demonstrated notable responses (47).
CAR T-meso in patients with mesothelin-expressing tumors
and CAR T cells secreting IL-12 for recurrent ovarian
cancer are among the most promising constructs (48).
Lymphodepletion prior CAR infusion (38,39), cytokine
supplementation, integration of multiple co-stimulatory
intracellular domains (49) and expression of chemokines and
their receptors (50) enhanced persistence and homing of
CAR T cells to the tumor site, and were strongly correlated
with treatment outcome (51).
Nevertheless, CAR therapy is accompanied by adverse
events (e.g., toxicity due to cytokine storm), imposing the
need to regulate uncontrolled or hyper-activation. For this
reason, negative regulation approaches, like incorporation
of suicide switches (e.g., an inducible caspase-9 gene) in
CAR T cells were developed. Unfortunately, such strategies
led to complete eradication of the engineered cells from the
patients’ circulation (52). In contrast, positive regulation
strategies, recently applied, integrate in the CAR construct
a domain, which requires both an exogenous user-provided
signal (e.g., rapamycin analogs) and the scFv target-antigen
for its activation (53,54). The clinical efficacy of such
transient CAR-modied T cells needs to be evaluated.
Active cancer immunotherapy
Peptide vaccines can generate effective anti-tumor T
cell responses
Anti-cancer vaccines are designed to induce tumor-
specific or tumor-reactive immune responses in vivo; the
most popular category comprises peptide-based vaccines,
usually consisting of immunogenic epitopes from tumor-
specific or tumor-associated antigens (TSAs or TAAs,
respectively). Most tumor antigens derive from products
of mutated oncogenes (e.g., K-RAS, BCR/ABL) or tumor
suppressor genes (e.g., p53), oncogenic viruses (e.g., HPV,
HBV, EBV), oncofetal proteins (e.g., CEA, a-FP), cell-
type specific differentiation proteins (e.g., PSA, Melan-A/
Mart-1), overexpressed or aberrantly expressed self-proteins
(e.g., HER-2/neu), or altered glycolipids and glycoproteins
(e.g., MUC-1, CA-125, GM2). TAAs also include cancer-
testis (CT) antigens, whose normal expression is restricted
to male germ cells in the testis (55). In fact, the rst tumor
antigens cloned were the melanoma-associated antigen 1
(MAGE-1) and the New York esophageal squamous cell
cancer-1 (NY-ESO-1), both classied as CT antigens (56).
Initial clinical trials with TSA- or TAA-derived peptide
vaccines used as monotherapy, showed limited effectiveness
due to the narrow spectrum of immune responses induced
in vivo and the limitation of MHC-restriction (57). Single
and multiple peptide vaccines restricted to selected patients
expressing the appropriate MHC alleles were followed by
Table 3 Characteristics of rst to fourth generation CAR-engineered T cells
Properties First generation Second generation Third generation Fourth generation
Intracellular domains CD3ζCD3ζ and CD28/CD137/
CD134/ICOS
CD3ζ and CD28 and CD137 CD3ζ and CD28/CD137/
CD134/ICOS
Additional transgenes IL-12 or co-stimulatory
ligands
Signaling and function T cell activation; modest
IL-2 secretion; adequate
target cell lysis
Increased proliferation, IL-2
secretion and target cell
lysis; increased resistance to
apoptosis; increased in vivo
persistence
High proliferation, cytokine
secretion and cytotoxicity;
high resistance to apoptosis;
high in vivo persistence
Same as third generation
CARs; additional pro-
inflammatory cytokine
secretion that reforms the
tumor microenvironment
Application in clinical trials Yes Yes Yes Pending
Annals of Translational Medicine, 2016 Page 7 of 15
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
vaccines comprising of cytotoxic T lymphocyte (CTL) and
helper T (Th) cell epitopes, albeit efficacy was not much
improved. The new generation of anti-cancer peptide
vaccines consists of multi-peptide cocktails, synthetic long
or hybrid peptides, which include both CTL and Th cell
epitopes. These are administered in combination with
other therapies and are used for the treatment of various
types of cancer (e.g., colorectal, lung, pancreatic, gastric,
prostate and breast). Specically in breast cancer, vaccines
containing epitopes of HER2/neu, MUC1 and CEA have
been tested in phase I-III clinical trials, showing promising
results (58). Personalized peptide vaccination (PPV) is also
gaining ground, based on the concept of boosting pre-
existing host immunity. In the most recent randomized
phase II clinical trial, PPV combined with metronomic low-
dose cyclophosphamide in patients with metastatic castrate-
resistant prostate cancer prolonged OS of those patients
who responded immunologically after vaccination, i.e.,
mounted peptide-specic humoral and CTL responses (59).
Dendritic cells (DCs) are ideal vehicles for anti-cancer
vaccine delivery
DCs have been characterized as nature’s adjuvant because
of their high potency to initiate and support immune
responses (60). Given their potential to stimulate both
adaptive and innate anti-tumor immunity, DCs have
been used in recent years as “vehicles” of cancer vaccines.
Traditionally, two DC-based vaccination approaches have
been widely applied, direct targeting of antigens to DC
receptors in vivo and ex vivo generation of antigen-loaded
DCs. To improve DC-based vaccine efcacy and given the
growing understanding of DC biology, research focuses
on exploiting the competence of different DC subsets,
optimizing ex vivo DC maturation and manipulating co-
stimulatory molecule expression (61).
The most widely used DC subset in the clinic is
differentiated from peripheral blood monocytes ex vivo
cultured with recombinant granulocyte macrophage colony-
stimulating factor (GM-CSF) and IL-4 (mDCs). Although
proven clinically benecial, there are both advantages and
disadvantages associated with their use. For example, mDCs
are easily manipulated before administration, can be loaded
with any tumor antigen and optimally activated with a
plethora of adjuvants. Nevertheless, ex vivo production of
mDCs is labor intensive and costly, and limited numbers
thereof are often available. Thus, an attractive alternative
is to specically target DCs in vivo, i.e., load them with the
appropriate tumor antigens and activate them to produce
pro-inflammatory cytokines. Although in this case, less
control over quality and magnitude of induced responses
is offered, a number of new molecules are pre-clinically
tested, e.g., immune stimulating complexes (referred to as
ISCOMs) (62).
The safety, as well as the ability of DC-based vaccines to
activate tumor antigen-specic CD4+ and CD8+ T cells in vivo
has been thoroughly tested in phase I-III trials for more than
10 years. The rst and only, for now, DC-based anti-cancer
vaccine that earned FDA approval is Sipuleucel-T (Provenge,
Dendreon Corporation) for the treatment of metastatic
asymptomatic hormone-refractory prostate cancer. For this,
autologous monocytes are harvested from the patient, pulsed
ex vivo with a fusion protein of prostatic acid phosphatase
and GM-CSF, and then infused back into the patient (63).
Moreover, phase II/III clinical trials using similar approaches
in patients with melanoma, glioma and glioblastoma, ovarian
cancer, RCC and multiple myeloma induced robust responses
and improved clinical outcome (64).
A relatively new and promising approach involves the
fusion of patient’s DCs with autologous tumor cells, based
on the concept that DC/tumor hybridomas can deliver,
process, and subsequently present the entire array of
patient-specific TAAs, including those yet unidentified.
In preclinical models, DC/tumor vaccines resulted in
eradication of established tumors. In clinical trials, DC/
tumor hybrids were well tolerated, but limited responses
were observed in patients with advanced tumors. Current
exploitation of means to render each hybrid component
more immunogenic before fusion, e.g., by pre-activating
DCs with TLR agonists and by pre-treating cancer cells
with ethanol so as to express abundant danger signals, is
expected to improve their therapeutic potential (65).
From autologous to allogeneic whole cell vaccines
Autologous tumor cells are an apparent source of TAAs
for PPV, since, by definition, they encompass all relevant
candidate TAAs. Allogeneic tumor cells also represent a
good source of TAAs, as in vitro cultured immortalized cell
lines: (I) are a limitless source of TAAs; (II) allow for large-
scale production of allogeneic vaccines; and (III) provide
well-defined batches for use in a wide range of patients,
eliminating variability in the composition of the vaccine,
facilitating comparison of the clinical outcome and being
cost-effective. Allogeneic whole cell vaccines comprise
irradiated whole tumor cells that, prior to irradiation, are
transfected to produce cytokines or express co-stimulatory
molecules, thereby presenting enhanced immunogenicity.
Papaioannou et al. The immune system in cancer therapy
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
Page 8 of 15
Upon administration to patients, the inactivated tumor
cells do not proliferate, but express and optimally present a
wide range of TAAs to T cells, ideally orchestrating an anti-
tumor reactive immune response (66).
A prominent category of whole cell anti-cancer vaccines
are GM-CSF gene-transduced tumor cells, which are
generally referred to as GVAX. GVAX vaccines have already
proven active against a wide range of cancers, including
prostate, NSCLC, RCC, pancreatic and melanoma (67).
The secreted cytokine GM-CSF acts locally in a paracrine
manner, recruits and activates APCs and promotes uptake
of shed tumor antigens from irradiated cells for cross-
presentation. The most studied GVAX is prostate GVAX,
which comprises two GM-CSF gene-transfected irradiated
prostate cancer cell lines, PC3 and LNCaP. Although a
phase III clinical trial with prostate GVAX was terminated
due to increased mortality, pancreatic GVAX is widely
tested in phase III trials, especially in combination with
checkpoint inhibitors (68).
Checkpoint inhibitors release the “brakes” of the
immune system
It is known that cancer cells can be destroyed through
processes of cellular immunity, during which T cells
recognize and respond to tumor antigens exposed on
the surface of APCs. However, optimal T cell activation
against the target antigen initiated by the interaction of the
MHC molecule-tumor peptide with the TCR, else termed
signal 1, should be complemented by the interaction of co-
stimulatory molecules on T cells (CD28) and APCs (B7-
1/CD80 and B7-2/CD86), i.e., signal 2 (69). Activated
T cells also express CTLA-4, a negative regulator of
T cell activation that competes for binding to B7, thus
counteracting the positive CD28-mediated signals (70).
Another described T cell co-inhibitory pathway involves
programmed cell death protein 1 (PD-1) and its ligands
PD-L1/L2, the engagement of which leads to decreased
T cell proliferation and cytotoxicity, and increased T
cell susceptibility to apoptosis (71). Under physiological
conditions, the PD-1/PD-L1/2 pathway prevents excessive
effector activities by T cells, controls tissue damage
during inflammation and prevents the development of
autoimmunity by promoting tolerance to self-antigens
(72,73). In cancer, engagement of either of the two
molecules, leads to T cell exhaustion and down-regulation
of the anti-tumor response (74). In other words, tumor
cells exploit the PD-1/PD-L interaction as a protective
mechanism to “shut down” the generated anti-tumor
immune response.
Tumor-induced down-regulation of T cell function
can be reversed by using immune checkpoint molecules/
inhibitors that block CTLA-4- and/or PD-1-mediated
signaling cascades, consequently preserving and maintaining
T cell activation within the tumor microenvironment (75).
Additionally, it has been recently reported that inhibiting the
CTLA-4 pathway leads to depletion of suppressive Tregs
and blocking of the PD-1 pathway revives the functionality
of exhausted T cells (76). Most importantly, simultaneous
blockage of both pathways significantly amplifies the anti-
tumor reactivity of T cells (77). Although following CTLA-
4 and PD-1, a plethora of immune checkpoints have
been identified and numerous clinical trials explored the
clinical utility of their blockade, to date only three immune
checkpoint inhibitor mAbs have received FDA approval for
the treatment of cancer, the CTLA-4 inhibitor ipilimumab (in
2011), and the PD-1 blockers nivolumab and pembrolizumab
(both in 2014; Figure 2).
Ipilimumab
Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human
IgG1 mAb that blocks the interaction of CTLA-4 and B7-
1/2. As of February 2016, ipilimumab is approved for treating
unresectable or metastatic melanoma, where it demonstrated
significant survival advantage (78,79). Currently, 120 open
clinical studies are or will be recruiting patients with various
types of cancer, who will receive ipilimumab as monotherapy
(e.g., for recurrent platinum-sensitive ovarian cancer;
NCT01611558) or as a combinatorial treatment (e.g.,
with chemoradiation for locally advanced cervical cancer;
NCT01711515).
Pembrolizumab
Pembrolizumab (Keytruda, Merck) is a humanized IgG4 mAb
that targets PD-1, thus disrupting its inhibitory interaction
with PD-L1/2. As of February 2016, pembrolizumab is
approved for the treatment of advanced melanoma progressed
on ipilimumab, and BRAF mutant melanoma progressed
on a BRAF inhibitor (e.g., dabrafenib, vemurafenib). It is
also approved for treating metastatic PD-L1+ NSCLC, after
progression on platinum-containing chemotherapy and/or on
EGFR/ALK-targeted medication (e.g., erlotinib, gefitinib,
ceritinib) for tumors bearing EGFR or ALK mutations (80-82).
Nivolumab
Nivolumab (Opdivo, Bristol-Myers Squibb) is a fully
human IgG4 anti-PD-1 mAb with the same mode of action
as pembrolizumab, but with 10-fold reduced affinity for
PD-1 compared to pembrolizumab. As of February 2016,
it is approved for the treatment of metastatic melanoma
Annals of Translational Medicine, 2016 Page 9 of 15
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
progressed on ipilimumab and BRAF-mutated melanoma
progressed on a BRAF inhibitor (e.g., vemurafenib) (79,83).
Recently, it was also approved for the treatment of patients
with metastatic squamous NSCLC with progressive disease
on or after platinum-based chemotherapy (84). Nivolumab
has demonstrated promising anti-tumor activity in kidney
cancer, showing a survival advantage and durable responses
regardless of tumor PD-L1 expression levels (85,86). Most
importantly, nivolumab displayed less adverse events and
lower toxicity, compared to ipilimumab (87).
Due to the high clinical efcacy of immune checkpoint
inhibitors, the evaluation of their combinatorial synergistic
oncotherapeutic effects is actively being investigated
in clinical trials. The first phase I study evaluated the
combination ipilimumab plus nivolumab in patients with
advanced stage III/IV melanoma. Patients who progressed
on ipilimumab achieved positive anti-tumor responses after
subsequent treatment with nivolumab, suggesting that
sequential administration of immune checkpoint inhibitors
can be used to restore anti-tumor immunity in patients
progressing upon treatment with one inhibitor (88). Among
others, a phase III trial (NCT01844505) evaluating the
same combination is currently ongoing for patients with
previously untreated unresectable or metastatic melanoma.
Taken altogether, licensing of immune checkpoint
inhibitors has yielded impressive therapeutic results,
thereby opening new frontiers for their use in other cancer
types, including brain tumors, head and neck squamous
carcinoma, pancreatic adenocarcinoma, bladder urothelial
tumors, gastric and breast cancer.
Oncolytic viruses directly lyse tumors and systemically
stimulate anti-tumor immune responses
Lytic viruses, by definition, replicate inside a host cell,
which is subsequently destroyed. Oncolytic viruses are
innocuous viral strains that selectively target and kill tumor
cells, but, as reportedly shown, also induce tumor-specic
cell-mediated immunity. Specifically, viral replication in
Figure 2 Schematic representation of important signals mediating T cell, APC and tumor cell interactions. During the activation phase
(left), T cells interact with APCs and receive signal 1 (MHC/tumor epitope-TCR) and signal 2 (B7-CD28). Activated T cells express the
inhibitory molecule CTLA- 4, which is blocked by ipilimumab, thus allowing their constant activation. During the effector phase (right),
activated T cells migrate to the tumor, where their TCR recognizes tumor epitopes in the context of MHC molecules. Pembrolizumab and
nivolumab block the checkpoint molecule PD-1 and, consequently, its interaction with the inhibitory regulator PD- L expressed by tumor
cells. As a result, T cells overcome tumor-induced suppression. APC, antigen presenting cell; MHC, major histocompatibility complex;
TCR, T cell receptor; CTLA -4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L, PD-1 ligand.
APC T cellT cell Tumor cell
MHC
B7
TCR
CD28
CTLA-4
B7
TCR MHC
PD-1 PD-L
Ipilimumab Pembrolizumab/Nivolumab
APC T cell T cell Tumor
Activation Phase Effector Phase
Papaioannou et al. The immune system in cancer therapy
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
Page 10 of 15
cancer cells, followed by cancer cell lysis, results in the
release of more viruses, as well as of tumor antigens (89).
Consequently, antigen uptake by APCs indirectly promotes
a systemic T cell immune response (90,91). Genetic
engineering of oncolytic viruses may further enhance their
oncolytic properties and redirect them exclusively in the
tumor vicinity (92).
The most prominent oncolytic virus-based therapy,
Talimogene laherparepvec (T-VEC), consists of a GM-CSF-
transfected modied form of the herpes simplex virus-1 that
infects and lyses only tumor cells, with concurrent GM-CSF
production. Following an international randomized phase
III trial in melanoma patients (OPTiM), where T-VEC
exhibited endurable treatment responses, this oncolytic virus
was the rst to receive FDA approval for use in melanoma
patients with unresectable tumor lesions (93). Oncolytic
viruses have also shown therapeutic potential in preclinical
models, when combined with other immunotherapeutic
modalities, such as ACT (e.g., increased tumor trafcking
and cytotoxicity of adoptively transferred T cells loaded
with vesicular stomatitis virus) (94,95) or checkpoint
inhibitors (e.g., tumor regression after administration of
vaccinia strains and anti-CTLA-4) (96). Some issues need
further investigation, particularly if oncolytic viruses are
administered systemically. These relate to increased toxicity,
mainly due to sequestration in various organs; ineffective
viral dissemination, due to clearance by macrophages or
neutralization by pre-existing Abs and complement; and
reduced inltration in the tumor microenvironment, due to
low extravasation and the presence of connective tissue and
extracellular matrix barriers (97).
Some novel approaches that can further boost
anti-cancer immune responses
New delivery methods facilitate in vivo transfer of
therapeutic molecules
Over the last years, a variety of nanocarrier systems have
been evaluated, as they comprise an appealing vehicle
for highly targeted therapy. Nanomaterials can achieve
selective, localized and even simultaneous delivery of
multiple immunomodulators, TAAs and drugs to targeted
tumor sites or lymphoid tissues (98). Among the most
frequently used nanoparticles are polymeric nanocarriers
like the FDA approved synthetic biodegradable polylactide,
lipid nanocarriers like liposomes and phospholipid micelles,
acid-degradable hydrogels, gelatin-based nanocarriers
and the most modern metal nanocarriers, like quantum
dots, which are additionally used for imaging analysis.
For example, gold nanoparticles have been shown to
increase the immunostimulatory effect of the CpG
oligonucleotide adjuvant when coupled together (99). Other
preclinical studies reported that poly-lactic-co-glycolic
acid nanoparticles delivering melanoma antigens induced
an effective anti-tumor CTL response (100). In general,
nanocarriers bypass the problem of inconsistent antigen
delivery and uptake and constitute a promising anti-cancer
modality for the future.
Exploiting immunogenic cell death in anti-tumor
immunity
A novel concept first described in 2013, is that certain
cancer treatment modalities, like radiotherapy and
chemotherapy with specific drugs (e.g., anthracyclines,
oxaliplatin) induce in tumor cells the so-called immunogenic
cell death (ICD). ICD is a cell death mode characterized
by: (I) excessive and extended lysis and release of tumor cell
components, including intracellular danger/alarm signals;
(II) increased activation of DCs; (III) high uptake and
presentation of tumor antigens by DCs; (IV) cross-priming
and expansion of tumor-specic CTLs; and (V) production
of tumor-specic mAbs. Chemoradiotherapy can also alter
the frequency and function of regulatory immune cells
including Tregs, myeloid-derived suppressor cells and
tumor-associated macrophages. Important mediators which
act as danger signals and, in practice, as in situ vaccines, and
are released during ICD include high-mobility group box 1,
calreticulin, ATP and fragments of polynucleotides (101).
At present, we still need to understand the molecular and
cellular mechanisms underlying ICD. This can eventually
lead to the development of (I) algorithms for optimal
management of cancer patients, based on ICD induction
by the given anti-cancer treatment; and (II) combinatorial
treatments of immune modulation therapy with ICD-
inducing chemo/radiotherapies. As for the latter, promising
results have already been reported from clinical trials in
various cancer types (e.g., cervical, head and neck, advanced
and metastatic melanoma), evaluating the combination of
local irradiation with ipilimumab (102).
Future perspectives
During the last decade, we experienced remarkable
progress in cancer therapy. Deeper understanding
Annals of Translational Medicine, 2016 Page 11 of 15
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
of cellular and molecular pathways leading to tumor
development, escape and spread were clinically translated
to novel treatment options. New classes of molecularly
targeted drugs emerged and promptly gained approval for
use in humans. We managed to reprogram the host’s own
immune system components to target and attack cancer.
We prolonged survival of patients that previously had no
effective treatment options. We improved the quality-of-
life of cancer patients and survivors. Most importantly,
we noted that immunotherapeutic interventions
control tumor growth/relapse for years after treatment
completion. Thus, it is of no surprise that in 2015, 16 new
drug approvals and 7 expanded indications by the FDA
concerned targeted or combinatorial immunotherapy.
What we also learned is that the combination of various
immunotherapeutics should be elegantly orchestrated on
the one hand, to boost anti-cancer responses (PUSH) and
on the other, to neutralize or eliminate negative immune
regulators (PULL) (Figure 3).
We are on the road to cancer cure. In the years to
come, we need to focus on more specific issues, like the
development of personalized treatments (e.g., using PPV),
the improvement of guided delivery of drugs (e.g., with
nanoparticles), the exploitation of the synergy between
different cancer treatment modalities (e.g., chemotherapy
and checkpoint inhibitors) and the broadening of targeted
drug repertoire through the discovery of new targets, new
drugs and new molecules targeting multiple molecular
pathways (e.g., pan-tyrosine kinase inhibitors). But we also
need to invest in the discovery of predictive/prognostic
cancer biomarkers that can early enough and reliably
guide treatment decisions. Some biomarkers are already
available (e.g., PSA, CEA, BRAF V600E mutation), while
more are extensively studied (e.g., CTCs, miRNAs). In
this way, cancer patients who are likely to benefit from
immunotherapeutic interventions will be early on selected,
appropriately treated and, hopefully, cured.
Acknowledgements
Funding: The study was supported by European Union FP7
Capacities grant REGPOT-CT-2011-284460, INsPiRE (to
Figure 3 The PUSH and PULL approach could optimize anti-cancer immunity. Suitable tumor antigen-selection stimulates anti-tumor-
reactive immune responses, which can be further boosted by several approaches (e.g., by co-stimulatory molecules; PUSH). Robust anti-
cancer responses generated can be subsequently enhanced and sustained by blocking negative regulators (e.g., CTLA-4; PULL), leading to
highly effective cancer immunotherapy interventions.
Tumor
antigen
Robust anti-cancer
response
Effective Cancer
Immunotherapy
Boost
immune responses
Optimization of
target -antigen
epitope selection
co-stimulatory molecules, PRR agonists,
immunomodulators
/adjuvants, glycolipids,
cytokines, chemokines
block negative regulation
(e.g. anti-CTLA-4, anti-PD-1,
anti-TGF
β
,anti-IL-10 …)
PULL
PUSH
Papaioannou et al. The immune system in cancer therapy
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2016atm.amegroups.com
Page 12 of 15
OT) and IKY Fellowships of Excellence for Postgraduate
Studies in Greece-Siemens (to PS).
Footnote
Conicts of Interest: The authors have no conicts of interest
to declare.
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... Active cellular immunotherapy (ACI) (also termed "cancer vaccines") is a modern and quickly developing anti-tumor immunotherapeutic approach [1]. The ACI is based on ex vivo-produced antigen-presenting cells (APCs) that elicit a targeted immune response in vivo [1]. ...
... Active cellular immunotherapy (ACI) (also termed "cancer vaccines") is a modern and quickly developing anti-tumor immunotherapeutic approach [1]. The ACI is based on ex vivo-produced antigen-presenting cells (APCs) that elicit a targeted immune response in vivo [1]. Researchers have developed multiple ways to produce APCs ex vivo, namely, dendritic cells (DCs), which constitute the core of current ACI [2,3]. ...
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... It controls ptive and innate immune response to provide a long-lived elimination of diseased cells. It is categorized broadly into passive (adoptive & antibody-based) and active (vaccine therapy & allergen-specific) approaches (Papaioannou et al, 2016). Active immunotherapy esulting in development of specific immune effectors (antibodies and T cells) which control the disease (Naran et al, 2018). ...
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... Also, it regulates the host's adaptive and innate immune responses to disease regression or progression. In other words, immunotherapy is a therapeutic attitude that manipulates and controls the immune system to overcome diseases or disorders [1]. Some studies have classified immunotherapy as active (allergen-specific and vaccine therapy) and passive immunotherapies (adoptive and antibody-based immune). ...
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... Non-specific immunotherapies with biologic response modifiers such as TLR agonists have been used for years to induce tumor immunity [42][43][44]. The most effective biologic response modifiers are typically those capable of generating strong interferon responses, along with activation of innate immune effector cells, especially macrophages and NK cells. ...
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This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.
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Background: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Methods: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. Results: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). Conclusions: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
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Bone marrow-derived dendritic cells are potent stimulators of several subsets of lymphocytes, including CD4+, CD8+ and NK T cells. One approach to demonstrating the adjuvant role of dendritic cells is to expand them ex vivo, charge the cells with antigens, and then reinfuse the dendritic cells into autologous recipients to initiate immunity. Several groups are currently testing if this approach can elicit immunity to tumor antigens in humans. Recent studies have emphasized the control of dendritic cell function per se, i.e., the requirements for developing potent antigen-presenting cells from less active precursors. A key step is termed maturation. Using model peptides and proteins, we find that dendritic cells must receive a maturation stimulus to optimally present antigens as MHCpeptide complexes. Maturation in addition permits irreversible differentiation to motile cells that express high levels of IL-12 and several costimulatory molecules such as CD40 and CD86. Dendritic cells also efficiently process and present peptides derived from other apoptotic cells, including tumor cells. Dendritic cell maturation is likely to be a pivotal control point in the initiation of immunity, since it allows for efficient antigen presentation and the acquisition of several other functions pertinent to stimulating T cells in situ.
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