Advances in T-cell checkpoint immunotherapy for head and neck squamous cell carcinoma
OncoTargets and Therapy
Advances in T-cell checkpoint immunotherapy for head and neck squamous cell carcinoma
Xinmeng Qi 1 2
Bo Jia 0
Xue Zhao 2
Dan Yu 2
0 Department of Thoracic Medical Oncology, Peking University Cancer Hospital and institute , Beijing People's Republic of China
1 Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University
2 Department of Otolaryngology Head and Neck Surgery, The Second Hospital, Jilin University , Changchun, Jilin
8 1 0 2 - l u J - 2 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re .
immune checkpoint; PD-1/PD-L1; CTLA-4; HNSCC; immunotherapy
open access to scientific and medical research
*These authors contributed equally
to this work
It has been projected that 450,000 new cases of head and neck squamous cell carcinoma
(HNSCC) are diagnosed worldwide each year, which is the sixth most common cancer
among human malignancies.1 Of these diagnoses, ~90%–95% fall into the histological
subtype of HNSCC,2 including nasopharyngeal carcinoma (NPC), oropharyngeal
carcinoma, laryngeal carcinoma, and hypopharyngeal carcinoma. Unlike many other
epithelial malignancies, the majority of HNSCC present at a locally advanced stage with
5%–10% cervical lymph node metastases. If diagnosed at an early stage, HNSCC could
be treated with traditional surgery, also radiation plus chemotherapy. For recurrent or
metastatic (R/M) HNSCC conditions, cytotoxic chemotherapy remains the standard
therapeutic option. Recommended first-line chemotherapy regimens include cisplatin or
carboplatin plus 5-Fu, cisplatin or carboplatin plus docetaxel or paclitaxel, etc. Adding
cetuximab, an epidermal growth factor receptor (EGFR) monoclonal antibody (mAb),
could improve survival compared with palliative chemotherapy alone, but resulting in
a median survival of only 10.1 months. A number of recent studies have focused on
immunotherapy which is considered to be an alternative treatment approach for cancers
in general, while several studies are underway testing the effectiveness of
immunotherapeutic strategies in HNSCC which is commonly understood as an immunosuppressive
disease. Despite approaches targeting growth factors and receptors such as epidermal
growth factor receptor (EGFR), cell surface associated or polymorphic epithelial
mucin (MUC-1), the receptor for advanced glycation end
products (RAGE), G antigen (GAGE) families,
melanomaassociated antigens A (MAGE-A) and various cytokines and
tumor antigens3–5 interfering with known molecular pathways
activated in HNSCC have been extensively studied; only
few and limited benefit has been seen to be sufficient to
prevent tumor progression. Since around 2010, inhibitory
checkpoint molecules have been considered as new targets
for cancer immunotherapies due to the effectiveness of two
checkpoint inhibitor drugs that were initially indicated for
advanced melanoma – Keytruda (pembrolizumab), targeting
programmed cell death 1 (PD-1) receptor,6 and Yervoy
(ipilimumab), targeting cytotoxic T-lymphocyte-associated
antigen 4 (CTLA-4),7 which called attention to the
possibility of T-cell checkpoint immunotherapy for HNSCC. In this
review, we will summarize the latest developments of T-cell
checkpoint immunotherapy in HNSCC, with a particular
focus on PD-1 and CTLA-4.
.vdoep lsyeon T-cell recognition and immune
/ww lan checkpoints
/:tsp rsoe T-cell activation
trohm ropF It is now established that various components in the immune
fd system play pivotal roles in protecting humans from cancer.
dea It has been broadly recognized that T-cell-dependent immune
lonw response specific to tumor antigens plays a crucial role in
yod tumor immune surveillance and that the critical effector
repa cells of adaptive antitumor immunity are the activated CD8+
hT cytotoxic T-lymphocytes (CTLs).8 T-cells have been the
pridan mary focus of cancer immunotherapy primarily due to their
trsge ability to initiate diverse immunoreactions via CD4+ helper
oaT T-cells that provoke innate and adaptive immunity.9 To evoke
cnO their proper activation, two sets of signals are required from
antigen presenting cells (APCs) regulating T-cell survival,
proliferation, and immune response in the lymph node. In a
normally functioning immune system, the first signal initiates
through binding of T-cell receptor (TCR) and a matching
antigen packaged onto major histocompatibility complex
(MHC) proteins on APCs. However, this interaction is not
sufficient for complete T-cell activation and tumor cytolysis.
A second co-stimulatory signal is needed to promote T-cell
clonal expansion and cytokine secretion. The best understood
co-stimulatory signal pathways are engagements of CD28 on
T-cells with CD80 or CD86 (B7 superfamily genes) on APCs.
In order to ensure that T-cell activation can only be stimulated
by appropriate antigens and maintain their immunologic
homeostasis, T-cell-mediated immunity is simultaneously
controlled by co-inhibitory signals which are transduced by
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immune inhibitory checkpoints expressed upon T-cells such as
CTLA-4 and PD-1.10 Under physiologic conditions, a balance
between co-stimulatory and co-inhibitory signals is crucial to
determine whether T-cells are activated or become anergic to
the specific antigens displayed on the MHC molecules. These
immune checkpoints are responsible for immune homeostasis
and the maintenance of organ-specific tolerance in normal
tissue, protecting organs from unnecessary damage while
immune system could still eliminate pathogens efficiently.11
Therefore, immune checkpoint molecules highly expressed
in the tumor microenvironment are one of the main reasons
for tumor immune escape and therapy failure. In this case, the
balance between co-signals is greatly biased toward the side
of inhibitory factors, resulting in T-cell functions dampened
and antitumor responses significantly restricted.
Tumors develop numerous strategies to avoid detection
and eradication by the host immune system. An enhanced
understanding of the precise activators and inhibitors of the
immune system has brought about therapeutic advances in
cancer treatment. Currently, there are several “targetable”
immune checkpoint blockade molecules. Lymphocyte
activation gene 3 works to suppress the immune response
via regulatory T-cells (Tregs) and direct effects on CD8+
T-cells. T-cell immunoglobulin domain and mucin domain-3
triggers cell death to negatively regulate Th1/Tc1 functions
upon binding its ligand galectin-9. Among all the
inhibitory checkpoint molecules, two that have been shown to be
clinically effective are PD-1 and CTLA-4.
PD-1 and PD-L1/2
PD-1 (CD279) is a 288 amino acid type I transmembrane
protein encoded by the PDCD1 gene on chromosome 2 in
humans. It presents not only on effector T-cells, but also on
activated myeloid lineage cells such as monocytes, dendritic
cells (DCs), and natural killer (NK) cells, suggesting its
contribution to other important immune cell functions.12,13 PD-1
comprises an extracellular IgV region, a transmembrane
domain, and an intracellular tail containing an immune
tyrosine-based inhibitory motif followed by an immune
receptor inhibitory tyrosine-based switch motif.12 PD-1
receptor has two ligands, PD-L1 and PD-L2.14 PD-L1 (B7-H1/
CD274) is a type I transmembrane protein of the CD28 family
encoded by the CD274 gene on homo chromosome 9. It is
found constitutively on APCs, non-hematopoietic cells, and
nonlymphoid organs.12 PD-L2 (B7-DC/CD273) is expressed
only upon professional APCs, which is in line with its
function of regulating T-cell priming. Compared to PD-L2,
PD-L1, with a broader expression profile, is involved in
delivering negative signals of T-cell activation and regulating
cytokine expression and secretion. Through binding with the
two ligands of PD-1 receptor, PD-1 delivers an inhibitory
signal to shut down T-cell function. Many studies recently
showed that the expression of PD-L1 is closely related to
tumor grade in several types of malignancies and has become
a new diagnostic and prognostic biomarker for tumors.10
PD-L1, highly expressed on tumor cells,15–21 binds with
TCR PD-1, negatively regulates T-cell response, resulting in
tumor antigen-specific T-cells-induced apoptosis and anergy,
and makes the cancer cells evade immune surveillance
PD-1/PD-L1 signaling pathway is involved in the process
of immune regulation through several distinct mechanisms.
The ligation of PD-L1/PD-L2 to PD-1 inhibits the PI3K/AKT
pathway and downregulates expression of the antiapoptotic
gene Bcl-xl to promote T-cell apoptosis.22 The binding of
PD-1 and PD-L1 restricts naive T-cell migration and
accumulation in APCs and downregulates TCR, which prevents
effective antigen presentation.23 PD-1–PD-L1/2 ligation
upregulates expression of gene PTEN causing blockade of
Akt/mTOR/S6 pathway, and converts Th1+CD4+ T-cells to
become Foxp3+ Tregs that restrain cell-mediated immunity,
which is in line with exhaustion of tumor infiltrated
lymphocytes (TILs) in the tumor microenvironment.24
CTLA-4 or CD152 was first discovered to belong to the
immunoglobulin super family when researchers were
screening the cDNA library.25 A later study showed that CTLA-4
knockout mice suffered from massive lymphoproliferation
and severe autoimmune disease resulting in tissue destruction
and death within 3–4 weeks of age, which demonstrated that
the CTLA-4 receptor is an important negative co-stimulatory
signal for T-cell activation and proliferation.26,27 Currently,
it is well established that CTLA-4 is a CD28 homologue
with .30% of similar sequence expressed exclusively on the
surface of T-cells upon activation, but with a much higher
binding affinity for CD80 (B7.1) and CD86 (B7.2) than
CD 28 (about 10–40 fold).28
The engagement of CTLA-4 and CD80/86 competes with
that of CD28 causing direct inhibition of antigen presenting
followed by T-cell anergy.29–31 Besides “stealing” B7 from
CD28, other mechanisms of CTLA-4 as an inhibitory signal
for immune response have also been proposed. Some studies
suggest that engagement of CTLA-4 with B7 itself may
transduce inhibitory signals that antagonize the stimulatory
signals from CD28 and TCR.32–34 CTLA-4 may increase
T-cell mobility resulting in decreased effective antigen
presentation.35 In vitro and in vivo studies have shown that
deficiency of CTLA-4 in Tregs leads to systemic
lymphoproliferation, fatal T-cell-mediated autoimmune disease,
increased IgE production, and furthermore, potent tumor
immunity. Constitutive expression of CTLA-4 by CD4+ Tregs
is critical for their immune-suppressive function.36,37
Correlation of immune inhibitors expression in HNSCC with tumor prognosis
Of late, many studies have shown that the expression of
immune checkpoint is demonstrably correlated with tumor
grade or prognosis in several types of malignancies and
has become a new biological index for tumor detection and
prognosis.38 The expression of CTLA-4 and PD-1 in Tregs
of HNSCC tumor tissue is higher than that in peripheral
blood, which confirms that Tregs in tumor tissues have more
immune suppression features.39 Montler et al investigated the
expression of CTLA-4 and PD-1 on effector T-cells from
peripheral blood and tumor tissue in 29 HNSCC patients
after surgery, and the data suggested that the two proteins
were increased significantly in all T-cell subsets isolated
from tumor compared with peripheral blood lymphocytes
(PBLs) from the same patient.40 And, the level of PD-1 is even
higher on effector CD4+ and CD8+ T-lymphocytes of human
papilloma virus (HPV)-positive HNSCC patients. Malm et al
showed that the PD-1 expression in healthy peripheral blood
donors is generally under 15%, while the rate surged to over
50% of both the CD4+ and CD8+ T-cells among the PBLs,
draining lymph nodes and TILs in the tumor
microenvironment in HNSCC patients.41 The ligand of PD-1, PD-L1, has
been shown in different solid tumors including HNSCC and
studies have found that PD-L1 was present in 66%–87% of
HNSCC primary tumors.42 Chikamatsu et al demonstrated
that the expression of PD-L1 on myeloid-derived suppressor
cells in the peripheral blood of HNSCC patients was higher
than that in the healthy control group.43
Oropharynx squamous cell carcinoma (OPSCC) and PD-1/PD-L1
Besides the usual risk factors of tobacco and alcohol
addiction, an increasing proportion of OPSCC is related to the most
common high-risk HPV genotype, HPV-16, accounting for
5%–20% of the total HNSCC cases worldwide.44 Given the
recognized significance of HPV as an emerging etiological
risk factor for OPSCC, several investigators recently
managed to correlate the expression of PD-L1 with HPV status.
In the study of Lyford-Pike et al, 59% of the 20 analyzed
HPV-HNSCC samples displayed PD-L1. PD-L1
expression was present in 70% HPV mRNA-positive cases versus
29% in those that were HPV-negative.45 In a study of 181
OPSCC patients, Ukpo et al found that 46.4% of the samples
were positive of PD-L1 expression with rates of 49.2% and
34.1% in the HPV (+) and HPV (−) groups, respectively.
The majority of CD8+ TILs in HPV (+) OPSCC samples
produce the cytokine interferon-γ, which upregulates PD-L1
expression on the surface of tumor cells. Twenty eight
cases of recurrence and distant metastases showed PD-L1
expression of 43% and 70%.46 Furthermore, with the novel
tissue microarray technique, an even higher rate of PD-L1
expression could be identified.
rsse . Oral cavity squamous cell carcinoma
.vdoep lsyeon (OSCC) and PD-1/PD-L1
w u Both patients with OSCC and actinic cheilitis (AC), an oral
/ww lan premalignant lesion, presented much higher percentage of
tsp rse PD-1 expression in peripheral blood and lesions than normal
trohm ropF individuals. And there is an increased proportion of PD-1
fd in tumor cells from OSCC patients than lesion cells from
dae patients with AC. In all, 21.1%±14.6% of the lymphocytes
lonw were CD8+PD-1+ T-cells in OSCC, but AC samples showed
yod only 0.84%±0.6% CD8+PD-1+ T-cells among their
lymphorpae cytes. The number of CD4+PD-1+ cells was also higher in
hT OSCC than in the AC group.47 A study conducted by Zhang
dna et al investigated PBLs of 82 OSCC patients and 25 healthy
trsge individuals using flow cytometry analysis. Their data showed
oaT a significant difference in the percentage of PD-1 and PD-L1
cnO expression on CD4+ and CD8+ T-cells in PBLs of OSCC
patients (CD4+PD-1+ 11.4%±1.3%, CD8+PD-1+ 10.6%±1.8%;
CD4+PD-L1+ 9.5%±1.6%, CD8+PD-L1+ 20.8%±2.8%) and
the control subjects (CD4+PD-1+ 5.5%±0.9%, CD8+PD-1+
6.7%±1.2%; CD4+PD-L1+ 5.0%±1.1%, CD8+PD-L1+
9.2%±1.6%). Moreover, the soluble PD-1 level in plasma
was also higher in OSCC group than in normal controls.48
NPC and PD-1/PD-L1
Analysis of 59 nasopharyngeal tumor specimens presented
high levels of PD-1 (67.8%, 40/59) and PD-L1 mRNA
(66.6%, 20/30), whereas there was no PD-L1 detected in
healthy nasopharyngeal tissues. These results suggested that
expression of PD-L1 was not significantly correlated with
age and gender, but had strong correlations with clinical
tumor stage, lymphatic metastasis, and local recurrence.49
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The expression rate of PD-1 and PD-L1 has been
investigated in CD8+ and CD4+ T-cells in 28 NPC patient samples.
Twenty-eight point four percent and 3.9% of CD8+ T-cells
were found to be PD-1-positive in nasopharyngeal tumor
tissues and controls, respectively. As for PD-L1, all the 28
NPC tissues were positive for PD-L1, while 79% (23/29)
of the nasopharyngeal control subjects were found to be
PD-L1+. Eighteen out of 28 cases of NPC expressed B7-H1
on EpCAM+ epithelial cells.50
Laryngeal carcinoma and PD-1/PD-L1
To study the expression of PD-L1 in human laryngeal
carcinoma tissues and peritumoral tissues, Cao et al assessed
the expression of PD-L1 in 31 cases of laryngeal carcinoma
and 24 cases of paraneoplastic tissues, and demonstrated
that PD-L1 was significantly higher in poorly and
moderately differentiated larynx squamous carcinoma than that
in well-differentiated tumor tissues. Immunohistochemical
analysis showed that PD-L1 was mainly expressed in blood
vessels and rarely in cancer cells in poorly and moderately
differentiated groups, but displayed weakly positive in blood
vessels and partially positive in cancer cells of the
welldifferentiated group. PD-L1 expression was intensely
correlated with lymphatic metastasis. The expression of PD-L1
in the surrounding tissues was significantly lower than that
in cancer tissues, but the rates were in keeping with that of
tumor tissues.51 Automated quantitative protein analysis was
utilized to examine PD-L1 protein expression on TILs in 260
laryngeal squamous cell cancer patients. Scientists
speculated that superior disease-free survival and overall survival
(OS) were both correlated with PD-L1 levels. And, mRNA
level of PD-L1 was up-modulated in tumors compared to
esophageal squamous cell carcinoma
(eSCC) and PD-1/PD-L1
The expression of PD-1 was detected by immunohistochemical
Streptavidin-perosiase (SP) analysis in 118 cases of ESCC
(54.2%), 39 cases of adjacent atypical hyperplasia (35.9%),
and 39 cases of normal esophageal tissues (2.6%).53 Results
of another research found that 26 of the 54 (48.15%)
esophageal carcinoma tissues were positive for B7-H1
protein expression, while normal esophageal tissues were
totally negative for both B7-H1 mRNA and protein
expression. Scientists further explored the relationship between
B7-H1 expression and prognostic clinical parameters. They
found no association between B7-H1 expression and age,
gender, tumor size, location, or differentiation. In contrast,
the expression of B7-H1 was significantly correlated to
invasion depth, lymphatic metastasis, distant metastasis, and pT
classification of the tumor.54
HNSCC and CTLA-4 (role of CTLA-4 in HNSCC)
Jie et al isolated TILs and lymphocytes from peripheral
blood from a group of HNSCC patients and discovered that
CTLA-4 was displayed more frequently on intratumoral
Tregs than circulating Tregs.55 A study conducted among
laryngeal squamous cell carcinoma patients demonstrated
that intracellular CTLA-4 presented with a higher
expression in CD8+ lymphocytes among patients than in control
subjects (8.2%±8.7% vs 2.3%±3.5%). These rates in CD4+
and CD19+ lymphocytes were also significantly higher in
patients. In terms of surface CTLA-4, the difference was
only detected in the case of CD8+ lymphocytes (0.7%±0.6%
vs 0.3%±0.3%).56 NPC patients with lower tumor CTLA-4
expression were found to have higher 3-year OS rates
(91.4%), failure-free survival rates (82.8%), and distant
failure-free survival rates (85.8%) than those who fell into
the high CTLA-4 expression group (81.2%, 68.0%, and
72.3%, respectively).57 Expression of CTLA-4 was present
in 87% (137/158) of the ESCC cases. With respect to tumor
imaging metrics core, 65 patients (42.2%) fell into the
negative category, while 89 (57.8%) patients were found positive
for CTLA-4 expression. Scientists further speculated that the
OS of CTLA-4 ESCC patients (65 months) was longer than
that of the CTLA-4+ group (36 months).58
Several studies have explored the association between
oncogenesis and CTLA-4 single nucleotide
polymorphisms (SNPs), namely +49A/G (rs231775), −1661A/G
(rs4553808), −318C/T (rs5742909), −1722T/C (rs733618),
and CT60G/A (rs3087243) SNPs, etc.59,60 Kämmerer et al
found that the genotype CTLA-4 (−1661A/G) was detected
more frequently in patients with OSCC than in healthy
controls, and that several combinations of SNPs were found
only in patient tissues.61 However, a study conducted by Wong
et al demonstrated that there was no significant difference
in CTLA-4 SNPs between OSCC and control groups. They
found that the genotype CTLA-4 A/A was correlated with a
younger onset age and lower survival rate.62 A hospital-based
case-control study and meta-analysis results suggest that in the
Chinese Han population, the CTLA-4 +49 G.A
polymorphism was not associated with the risk of developing
esophageal cancer.63 Another case-control study among the Chinese
population showed that there was significant association in the
frequency of CTLA-4 +49 A/G and NPC risk.64 Therefore, the
correlation between CTLA-4 SNPs and their roles in
cancerogenesis in HNSCC remains to be further studied.
Checkpoint inhibitors as novel strategies for HNSCC and clinical outcome
Immunotherapies against existing tumors include diverse
approaches, ranging from stimulating effector mechanisms
to eliminating inhibitory mechanisms.38 In conventional
cancer immunotherapy, the aim is focused on “putting the
weights on the stimulatory side”. However, unfortunately,
it is difficult to provide sufficient stimulatory co-signals to
exceed heavily inhibitory factors in the tumor
microenvironment. Even though such methods could be performed on
patients in clinical practice, their adverse effects associated
with over-activation of immune cells in non-tumoral organs
would be extremely severe.65 As mentioned above, immune
checkpoint molecules, which belong to inhibitory co-signals,
exist to counteract stimulatory co-signals. Currently, several
mAbs targeting those molecules have been developed to
“decrease the weights from the inhibitory side” and have
shown impressive promise in Phase I–III clinical trials for
advanced solid tumors like melanoma, renal cell cancer,
and non-small cell lung cancer.66–68 Unlike conventional
antibodies used for the treatment of tumors, antibodies
that block immune checkpoints do not bind directly to the
tumor cells, but target lymphocyte receptors or their ligands
to modulate their antitumor activity. Among these immune
checkpoint blockades, ipilimumab (anti-CTLA-4 antibody),
nivolumab, and pembrolizumab (anti-PD-1 antibody) have
been designed and used in some solid tumors to block
coinhibitory signaling, recovering the CTL from anergy in
the antitumor immune response.69,70 It has been reported
that, compared to traditional modalities, those Abs display
superior clinical efficacies with long-term disease remission
and increased objective response rates in selected patients.
The anti-CTLA-4 mAb ipilimumab was first approved as a
new agent by the US Food and Drug Administration (FDA)
for the treatment of high-risk and metastatic postoperative
melanoma. In addition to anti-CTLA-4, mAbs targeting
PD-1 and its ligand PD-L1 have also been investigated as
important therapeutic tools in several early phase clinical
trials. Based on intriguing preclinical data from many groups,
several ongoing clinical trials (Table 1) are investigating
the role of immune checkpoint blockades in R/M HNSCC
including single agent and combinations with tumor vaccines,
chemotherapy, or radiation.71 Each of these categories will
be discussed briefly below.
Locoregional recurrence rates; distant failure rate PFS, OS
ReCiST criteria OR
Abbreviations: PFS, progression-free survival; ORR, overall response rate; OS, overall survival; RT, radiation therapy; iMRT, intensity-modulated radiotherapy; HNSCC,
head and neck squamous cell carcinoma; PD-1, programmed cell death 1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; R/M, recurrent or metastatic; HPv, human
papilloma virus; AJCC, American Joint Committee on Cancer; OR, odds ratio; ReCiST, response evaluation criteria in solid tumors.
The anti-CTLA-4 antibody ipilimumab has shown the
greatest clinical curative effect in patients with advanced
melanoma in two randomized Phase III trials.72 Some
observations have recently evaluated the role of CTLA-4 as a
potential therapeutic target in HNSCC. In a cohort of patients
with HNSCC (n=22), treatment with cetuximab increased the
expression of CTLA-4 in the majority of intratumoral Tregs,
and it was also demonstrated that ipilimumab can decrease
suppression of NK cells from Tregs.73 Ipilimumab is currently
being assessed in clinical trials in combination with
cetuximab and intensity-modulated radiotherapy in patients with
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advanced HNSCC (NCT01860430 and NCT01935921).74
Tremelimumab (CP-675, 206) is a fully humanized mAb
specific for CTLA-4, which has been successfully used to treat
patients with metastatic melanoma and some other cancers.
Currently, clinical testing of tremelimumab for HNSCC in
combination with other therapies including cetuximab and
intensity-modulated radiation therapy (IMRT) is underway
Regarding anti-PD-1 antibodies, the humanized
pembrolizumab and fully human nivolumab are IgG4 mAbs that
block the binding of PD-1 receptor to PD-L1 and PD-L2.
Pembrolizumab (also named MK-3475), with a high affinity
for PD-1, is the first mAb targeting PD-1 approved by the
FDA, which has been the most extensive immunotherapeutic
strategy in HNSCC. An ongoing multicenter Phase I trial
(KEYNOTE-012, NCT01848834) is the largest to date
completed immune checkpoint therapy trial in HNSCC.
Preliminary results show that 49.5% of patients demonstrated
partial response or stable disease following treatment with
pembrolizumab given a fixed dose of 200 mg every 3 weeks.
Eighty six percent of these patients demonstrated durable
responses.75 In another ongoing clinical trial, of the 104
patients with head and neck cancer who were enrolled, the
overall response rate (ORR) was 18.2%; response rates were
similar regardless of HPV status.71 Pembrolizumab has shown
minimal adverse effects when administered in head and
neck cancer patients.76 Further updates on this trial reported
that pembrolizumab was twice as effective as cetuximab in
HNSCC, with disease control of 50% and tumor shrinkage
in 57% of patients.77 In a combined update of two cohorts of
patients with R/M HNSCC that was heavily pre-managed,
pembrolizumab resulted in a response rate of 24% and an
additional 25% of patients with stable disease, which were
both slightly improved compared with earlier reports.78
Another trial KEYNOTE-048 evaluating pembrolizumab
either as monotherapy or in combination with chemotherapy
versus standard chemotherapy is underway in patients with
R/M HNSCC (NCT02358031). Pembrolizumab is also
currently being assessed in conjunction with re-irradiation
and as part of primary treatment in multiple clinical settings
(NCT02289209, NCT02296684). Some Phase II/III trials are
underway to evaluate the clinical efficacy (ORR, response
duration, and side effects) of pembrolizumab in R/M HNSCC
(NCT02255097, NCT02252042). Nivolumab, a fully human
immunoglobulin G4 PD-1 immune checkpoint inhibitor
antibody, was active and generally well tolerated in patients with
advanced solid tumors. In patients with HNSCC refractory to
platinum therapy, a randomized Phase III trial of nivolumab
(NCT02105636) resulted in improved OS compared with
treatment with the weekly methotrexate, docetaxel, or
cetuximab (NCT02105636). Furthermore, a Phase II nivolumab
monotherapy study for R/M NPC is currently in progress
At present, representative antibodies targeting PD-L1 include
BMS-936559 (also known as MDX1105), MPDL3280A, and
durvalumab (MEDI-4736), which have been applied as
monotherapy or adjuncts to conventional therapies in clinical trials
for a variety of tumors.79 Two ongoing Phase I trials, with
antiPD-L1 mAb (IgG1 isotype) MEDI-4736 (NCT01693562) and
anti-PD-1 mAb (IgG4 isotype) MK-3475 (NCT01848834),
have recruited cohorts of R/M HNSCC patients. The disease
control rate at 6 months was 15% (18% for PD-L1-positive
vs 11% for PD-L1-negative), and the ORR in patients with
HNSCC was 11%. Efficacy of durvalumab, an engineered
IgG1 antibody to PD-L1, has also been tested among
62 patients with R/M HNSCC. Results showed an ORR of
12%, and the duration of response ranges from 4 to 43 weeks.
A second trial (NCT02291055) has combined PD-L1 inhibitor
durvalumab (MEDI-4736) with ADXS11-001, live attenuated
Listeria monocytogenes engineered to express, and
subsequently elicit, an immune response against an HPV-16-E7
fusion protein.80 In another randomized Phase I/II trial to
assess the combination of MEDI-4738 with either AZD9150
or AZD5069 in patients with metastatic squamous cell
carcinoma of head and neck (NCT02499328), the clinical safety/
efficacy and ORR are being evaluated.
Combinatorial immunotherapy clinical trials in HNSCC
Some studies are currently active or under development to
investigate the efficacy of immune checkpoint inhibitors in
combination with one another. Some trials evaluating the
utility of MEDI-4736 monotherapy alone or in conjunction with
tremelimumab (anti-CTLA-4) compared to the standard
treatment for first-line R/M HNSCC are ongoing (NCT02551159,
NCT02369874, NCT02319044). This is a novel perspective
in the application of immune therapy, and the results as well
as analysis of the outcomes are much looked forward to.81,82
HNSCC has been recognized as an immunosuppressive
disease. There have been multiple recent developments using
immunotherapy for the management of HNSCC patients.
Blockades of immune checkpoints have proved to play a
vital role in enhancing immune surveillance and tumor cell
clearance, which provides oncologists with a significant set
of antitumor therapies with promising potentials. Studies
of immune checkpoint inhibitors should not only lead to a
novel strategy for advanced HNSCC, but also for many other
solid tumors. However, more investigations are required
and further studies need to be better designed to explore the
possibility and efficacy of combinations of different agents
and still keep an eye on their side effects, thus to bring about
more desired tumor outcomes.
This work is supported by the National Natural Science
Youth Foundation of China (81502348); the National Natural
Science Foundation of China (81572653); and Science and
Technology Department of Jilin Province Youth Foundation
The authors report no conflicts of interest in this work.
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management of cancer patients. The journal also focuses on the impact
of management programs and new therapeutic agents and protocols on
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