Drug Discovery Today  Volume 00, Number 00  March 2021 REVIEWS

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The emerging role of immune
checkpoint inhibitors in the treatment
of triple-negative breast cancer
Sima Singh1, Arshid Numan2, Balaji Maddiboyina3, Saahil Arora1,
Yassine Riadi4, Shadab Md5,6, Nabil A. Alhakamy5,6 and Prashant Kesharwani7
1
University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab 140413, India
2
State Key Laboratory of ASIC and System, SIST, Fudan University, 200433 Shanghai, China
3
Department of Pharmacy, NRK & KSR Gupta College of Pharmacy, Tenali, Guntur, 522202 AP, India
4
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
5
Deptartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
6
Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
7
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India

Triple-negative breast cancers (TNBCs) form a heterogeneous group of breast carcinomas that lack
expression of estrogen receptor, progesterone receptor and epidermal growth factor receptor 2. In the
past decade, immune checkpoint inhibitors (ICIs) have revolutionized the arena of cancer
immunotherapy. Early results are now accumulating from trials involving the treatment of TNBCs with
radical ICIs therapies, including combinational therapies that include ICI technologies. In this review,
we provide a broad overview of the progress of immunotherapy-based treatments and discuss future
opportunities for their use in TNBC.

Introduction skin cancer with no melanoma as the most common cancers in

Triple-negative breast cancers (TNBCs) are a complex type of
highly aggressive breast cancer, in which the expression of the
estrogen receptor (ER), the progesterone receptor (PR) and the
human growth factor receptor 2 (HER2) is impaired [1–3]. All of
these impairments are established during the molecular evalua-
tion of a patient’s tumor and the subsequent identification of
therapeutic molecular targets [4]. TNBCs are recurrent in nature,
even after the treatment, constitute 12–17% of breast cancers, and
are viewed scientifically as a distinct subgroup of breast cancers [5].
When compared to other subtypes of breast cancer, they have
relatively aggressive clinical behavior, characteristic metastatic
patterns and poor prognosis [4]. The incidence of TNBC, which
comprises 24% of newly diagnosed breast cancers, is steadily
increasing due to both increased exposure to risk factors and
improved diagnostics [6]. According to Globocan, 2,088,849
new instances were recorded in 2018, and TNBC ranked alongside
Corresponding authors: Arora, S. (director.uips@cumail.in), Kesharwani, P.
(prashantdops@gmail.com)
women [7,8].
At diagnosis, assessments using pathological criteria frequently
show that TNBC patients have clinically affirmative axillary lymph
nodes, greater primary tumor scale score, and worse Nottingham
prognosis index [4]. Monitoring of TNBCs remains challenging
because of the heterogeneity of the tumors and the associated
difficulty in determining prognosis. Therefore, deliberate attempts
have been made to grasp the molecular source of this heterogene-
ity and to explore molecular targets for TNBC. Thus, TNBC treat-
ment strategies are thus predominantly centered on the use of
traditional predictors, followed by surgeries, standard chemother-
apy regimens (anthracyclines and taxanes), radiation therapies
and combinational approaches ([9]; Fig. 1). Systemic chemothera-
py is optimal, but fewer than 30 percent of women with metastatic
breast cancer survive for 5 years after diagnosis and the disease is
inevitably terminal in the longer term [10,11]. A relatively high
proportion of patients with TNBC experience resistance to stan-
dard treatments and, unfortunately, no targeted TNBC treatment
has been approved for human use by the US Food and Drug

1359-6446/ã 2021 Elsevier Ltd. All rights reserved.

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Please cite this article in press as: Singh, S. et al. The emerging role of immune checkpoint inhibitors in the treatment of triple-negative breast cancer, Drug Discov Today (2021), https://doi.
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 DRUDIS-2964; No of Pages 7
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Hormonal
therapy
Reviews  POST SCREEN
Surgery
Bone marrow
transplant
Chemotherapy
FIGURE 1
Treatment therapies available for triple-negative breast cancer.
Administration (FDA) [12]. Thus, because of the toxicity of the
drugs in current use and dearth of targeted remedies, profuse
endeavors to produce feasible molecular targets for TNBCs are
ongoing. Novel therapeutic approaches will benefit patients with
aggressive and persistent types of breast cancer such as TNBCs.
In addition to surgery, chemotherapy and radiotherapy, immu-
notherapy—in which the immune system of the patient develops
anti-tumor potential—is the fourth mainstay of cancer manage-
ment. It has been known for several years that the immune system
plays an important role in battling cancer, and in the past few
years, immunotherapy has been recognized as an important clini-
cal option in cancer therapy [13]. We have seen that progress in
treating TNBCs with various immunotherapies could further boost
the anti-tumor response to treatments while decreasing their
toxicity profile. Immunotherapy approaches directly utilize con-
stituents of a patient’s peculiar immune organization to destroy
cancer cells, avoiding many of the side effects that are associated
with conventional management choices [14]. When detecting
cancer cells, the immune system recognizes two different entities:
tumor-specific antigens or mutations (molecules that are exclu-
sively expressed in cancer cells) or tumor-associated antigens
(molecules that are differently represented in cancer cells com-
pared to normal cells) [15]. Immunotherapy provides the strongest
response in tumors identified as ‘inflamed’, in which dendritic
cells remain profuse and T-lymphocytes are the principal CD8+
cytotoxic effectors. Recently, the development of immune check-
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Drug Discovery Today  Volume 00, Number 00  March 2021
Immunotherapy
Radiotherapy
Personalized
therapy
Drug Discovery Today
point inhibitors (ICIs) has provided crucial progress towards a
modern approach for TNBC treatment, because these therapies
are able to relieve immunosuppression and facilitate the anti-
tumor effect of T-cells in cancer patients. These treatments have
the potential to enhances progression-free survival dramatically
with an overall survival benefit [16].
Studies have shown that the immune tumor microenvironment
(TME) plays a key function in cancer growth and progression. The
ability of tumors to evade immunity is a hallmark of cancer
initiation and progression [17]. This is usually due to the instiga-
tion of checkpoints that reduce the immune response. Amongst
these checkpoints, the most significant are programmed death 1
(PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) [18].
Tumors can also develop an immunosuppressive microenviron-
ment by allowing particular immune cells to facilitate tumor
development and progression; for example, exceptionally high
CD4+ regulatory T (Treg) cells levels remain allied with poor
prognosis [19].
In this overview, we focus on previous findings and new infor-
mation emphasizing the importance of the immune response in
controlling TNBC along with critical analysis of biomarkers. We
highlight new and continuing immune-based therapies and ad-
vanced TNBC preclinical treatment models. In addition, we ad-
dress the future of immunotherapy approaches for TNBC patients,
including the advancement of immunotherapy strategies that
have already progressed to clinical trials, with a focus on the
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Drug Discovery Today  Volume 00, Number 00  March 2021
FIGURE 2
Tumor immune response and its growth in the triple-negative breast cancer tumor microenvironment.
immunological and clinical perspectives. We also summarize pos-
sible approaches to address issues relevant to immunotherapies
and to strengthening their checkpoint blockade in TNBC. Finally,
we discuss and explore the impending immunotherapies for TNBC
patients.
Tumor microenvironment
The role of Treg cells in inhibiting immune response and stimu-
lating tumor growth has been established, and the immune mi-
croenvironment greatly affects clinical results in TNBCs. The latest
research has centered on the effects of TME on TNBC endurance,
intrusiveness, and metastasis [20]. T-cells represent a significant
proportion of tumor-infiltrating lymphocytes (TILs), and recent
research has demonstrated that CD8+ T cells remain a vital ele-
ment of the immune response with important clinical conse-
quences [21]. The presence of TILs suggests improved prognosis
in patients treated with and without chemotherapies [22]. TILs
contain a combination of various groups of cells that are normally
categorized as T cells, as well as varying concentrations of B cells,
NK cells, macrophages and dendritic cells ([23]; Fig. 2). Therefore,
Please cite this article in press as: Singh, S. et al. The emerging role of immune checkpoint inhibitors in the treatment of triple-negative breast cancer, Drug Discov Today (2021), https://doi.
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quantification of TIL and their characterization have been used to
evaluate tumor immunogenicity [24]. The existence of CD8+ TILs
is also correlated with the expression programmed cell death-
ligand 1 (PD-L1) and is postulated to be an indicator of response
to ICIs [25]. Therefore, the number of CD8+ TILs remains a
worthwhile indicator of the clinical outcome and therapeutic
response of breast cancer patients.
The function of lymphocytic immune tumor infiltrates in
TNBCs has been proved by different researchers. Compared to
hormone receptor-positive tumors, TNBCs contain more activated
CD8+ TIL [22,23]. The identification of unique antigenic peptides
on the surface of malignant cells by T cell receptors plays an
important role in defending against cancer [28]. Studies involving
the content of various solid breast tumors indicated that the CD8+
TILs that were present included a subpopulation of T cells, T-
resident memory cells (TRM) [29]. TRM form a subset of memory T
cells other than circulating memory T cells, effector memory T
cells and other tumor-infiltration T cells [30]. They provide an
initial response to infections on body surfaces, where pathogen
clearance is accelerated [31]. They are non-recirculating and re-
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T-cell deactivation
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FIGURE 3
Mechanisms of action of immune checkpoint (PD1 and CTLA-4) inhibitors in promoting anti-tumor immune responses.
main in previously infected tissues where they facilitate a site-
specific response if re-infection occurs. TRM cells are primarily
distinguished indeterminately by their potential for tissue resi-
dence and their ability to facilitate a swift immune response
towards a small number of similar antigens [32]. CD8+ TRM cells,
for instance, have been classified as TILs in multiple solid tumors,
particularly in breast cancer patients, and they continue to be
classified as a separate subpopulation of CD8+ TILs [33]. Zhong
et al. [34] identified a total of 194 high-grade differentially
expressed genes in TNBC vs. non-TNBC. Importantly, genes
encoding immune checkpoint proteins such as PD-1 and
CTLA-4 have been found to be highly expressed in TRM cells in
TNBC [33].
Rationale for immune-based therapies
TNBCs are extremely heterogeneous disease conditions, which
are known to arise from multiple cells of origin and with genetic
and epigenetic modifications contributing to the substantial
intra- and inter-tumor heterogeneity. Targeted treatments for
TNBCs have not been possible due to the lack of specific molecu-
lar targets.
Interactions between the immune system and tumors are
regulated by a diverse network of biological pathways. The use
of monoclonal antibodies (mAbs) to block tumor-induced im-
mune checkpoints have been shown to restore cell-mediated
immune functions and facilitate antitumor response. PD1-tar-
geted ICIs therapies have already been studied in a wide variety of
cancers, but unfortunately, the overall response rate (ORR) in
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Drug Discovery Today  Volume 00, Number 00  March 2021
T-cell activation
Drug Discovery Today
most of these cancers varies widely, from 6% to 87%. One strategy
to increase the ORR is the screening of the patients using tumor
tissue immune profiling in an attempt to assess their ability to
respond to ICI therapies. Great efforts are currently being made to
identify biomarkers that are predictive of response. For example,
high intensities of TRM cell expression, as assessed by single-cell
RNA sequencing, are correlated with a favorable prognosis and
with enhanced probability of response to the anti-PD-1 antibody
pembrolizumab in TNBC patients [33,35]. This result indicates
that certain TRM cells remain in the target cell population
intended for antibodies. In melanoma patients treated with
anti-PD1 therapy, larger ratios of CD8+ TRM cells were associated
with improved results [36]. Consequently, it was proposed that
CD8+ TRM cells might serve as a biomarker of suitability for ICI
therapy [37]. The high expression of numerous immune check-
point proteins proceeding the expression of high levels of CD8+
TRM cells underlines the potential of these cells as a target
population for ICIs. However, the therapeutic benefits of adop-
tive T-cell therapies in patients are frequently impaired by im-
munosuppressive TMEs, which include upregulated Tregs,
myeloid-derived suppressor cells and inhibitory immune control
points. The activated T cells are thus located together with both
stimulatory surface receptors and inhibitory ones such as CTLA-4
and PD-1. The inhibitory receptors act as immune checkpoints
that normally safeguard the host following over-initiation of T
cells. When affixed to their ligands, they trigger downstream
signals that inhibit the activation of T cells. However, tumor
cells overexpress inhibitory receptor ligands and thus utilize the
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Drug Discovery Today  Volume 00, Number 00  March 2021 REVIEWS

TABLE 1
Treatment therapies based on PD-L1 or PD-1 inhibitors and targeted drugs for the management of TNBC
Agent Combinatorial agent Clinic trial Phase Recruitment position
CTLA-4
Ipilimumab and nivolumab Cryoablation NCT03546686 II Not yet recruiting
Ipilimumab and nivolumab Pegylated liposomal doxorubicin and cyclophosphamide NCT03409198 II Recruiting
Ipilimumab or pembrolizumab SV-BR-1-GM, cyclophosphamide, and interferon inoculation NCT03328026 I/II Recruiting
Ipilimumab and/or nivolumab INCAGN01949 NCT03241173 I/II Recruiting
PD-L1

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Avelumab TRX518, cyclophosphamide NCT03861403 I/II Active, not recruiting
PF-06647020 NCT02222922 I Completed
Atezolizumab Ipatasertib, paclitaxel NCT04177108 III Recruiting
RO6870810 NCT03292172 I Terminated
Varlilumab NCT02543645 I Terminated
Entinostat NCT02708680 I/II Active, not recruiting
Rucaparib NCT03101280 I Active, not recruiting
IPI-549, Nab-paclitaxel NCT03961698 II Recruiting
Cabozantinib NCT03170960 I/II Recruiting
Durvalumab Olaparib NCT03544125 I Active, not recruiting
NCT03594396 I/II Recruiting
NCT03801369 II Recruiting
PD-1
PDR001 NZV930, NIR178 NCT03549000 I Recruiting
LCL161/Everolimus/Panobinostat/QBM076 NCT02890069 I Recruiting
Canakinumab/CJM112/Trametinib/EGF816 NCT02900664 I Active, not recruiting
MCS110 NCT02807844 I/II Recruiting
Pembrolizumab Bemcentinib NCT03184558 II Completed
CPI-006 NCT03454451 I Recruiting
LY3475070 NCT04148937 I Recruiting
Dinaciclib NCT01676753 I Recruiting
INCB024360, INCAGN01876 NCT03277352 I/II Active, not recruiting
INCB024360 NCT02178722 I/II Active, not recruiting
SGN-LIV1A NCT03310957 I/II Recruiting
Binimetinib NCT03106415 I/II Suspended
Olaparib NCT04191135 II/III Recruiting
Niraparib NCT02657889 I/II Active, not recruiting
Talazoparib NCT04158336 I/II Recruiting
Lenvatinib NCT03797326 II Recruiting
TTAC-0001 NCT03720431 I Recruiting
Nivolumab NKTR-214 NCT02983045 I/II Recruiting
Daratumumab NCT03098550 I/II Active, not recruiting
BT5528 NCT04180371 I/II Recruiting
Romidepsin, Cisplatin NCT02393794 I/II Recruiting
IPI-549 NCT02637531 I Recruiting
TPST-1120 NCT03829436 I Recruiting
COM701 NCT03667716 I Recruiting
TAK-659 NCT02834247 I Terminated
NKTR-262, Bempegaldesleukin NCT03435640 I/II Recruiting
Cabozantinib NCT03316586 II Active, not recruiting

checkpoint system to prevent their exclusion. Therefore, it might
be possible to impede the inhibitor–ligand interactions in T cells
and thus effectively enhance tumor management. ICIs represent
another major breakthrough in cancer therapy [38], which has
provided unique insights into the treatment of TNBCs. The
mechanisms of action of ICIs against tumor cells are shown in
Fig. 3.
Immune checkpoint inhibitors
ICIs are therapeutic antibodies that break immune regulatory
checkpoints and activate anti-tumor immune responses. Interest
in tumor immunotherapy was initiated almost a century ago, but
has now achieved mainstream recognition among oncologists
[18]. This new strategy has the potential to be a game-changer
in cancer treatment due to the popularity of ICIs in tumor therapy.
In general, we can refer to immunotherapy as the management of
ailments by deploying the body’s innate immune system [38].
Immune checkpoints involve an increasing number of known
molecules that negatively adjust the immune response. Several
immune checkpoints are triggered by ligand–receptor interactions
and thus can be easily inhibited by antibodies or modulated by the
introduction of recombinant ligands [39].

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When considering the modes of action of inhibitors of different
immune checkpoints, it remains important to understand the
variety of immune functions that are controlled by these inhibi-
tors. ICIs are antibodies that help to attach molecules that inhibit
the immune response to the tumor-infiltration surfaces of lym-
phocytes, causing the reactivation of antitumor immune
responses. PD-1 and its ligand PD-L1, as well as CTLA-4, are the
most studied checkpoint inhibitors [40], and the discovery of the
Reviews  POST SCREEN
CTLA-4 immune checkpoint protein revolutionized the field of
cancer treatment. Antibodies against CTLA-4 were the first ICIs to
obtain FDA approval for human use. Next, in March 2019, the FDA
approved a combination of anti-PD-L1 antibodies, atezolizumab
and nab-paclitaxel.
Data in the published literature have revealed that ICI such as
the anti-PD-1 and anti-PD-L1 antibodies, in conjunction with
taxanes or anti-CTLA-4 antibodies, are appealing treatments for
TNBC-metastatic patients [42]. The acceptance of and consent for
use for the first chemo-immunotherapy combination designed for
metastatic TNBC therapy remains a significant landmark. This
approved immunotherapy is one of the most fascinating and
promising TNBC treatment on the horizon, especially given that
the checkpoints in breast cancer have not responded to medica-
tions that limit PD-L1. Numerous ICIs are currently in different
stages of clinical trials; for example, anti-CTLA-4 mAbs (ipilimu-
mab), anti-PD-1 mAbs (nivolumab, pembrolizumab) and anti-PD-
L1 mAbs (atezolizumab, durvalumab, avelumab) have shown ex-
cellent initial results [41]. Although the early findings are promis-
ing, in most of the cases, the suppression of the immune control
point alone is not palliative and therefore is unsuccessful in some
patients. Several treatment combinations for TNBCs that modu-
late the tumor cells and/or the TME in order to boost the effec-
tiveness of ICI therapies are being studied concurrently. Many
combination therapies aim to reduce established T cell response
barriers by reducing tumor burden and overcoming immune
suppression. Table 1 outlines the current clinical studies of im-
mune-checkpoint inhibitors against breast cancer.
Challenges for and limitations of immune checkpoint
inhibitors
The blockage of checkpoints by new agents has become the focus
of numerous experimental trials for the effective treatment of
breast cancer. Nevertheless, early results from treated patients
show that substantial challenges remain to improve the effective-
ness of these therapies. An important step forward will be the
ability to recognize specific biomarkers that can help clinicians to
predict which patients will respond best to immunotherapies
involving ICIs. Atezolizumab, a PD-L1 antibody, is the only ICI
approved for the use in metastatic TNBC patients. Furthermore,
PD-L1 ligand itself has been characterized and proven to be a
predictive biomarker that can be efficiently tested for by an FDA-
approved test, VENTANA PD-L1 (SP142) [43]. This was a crucial
development in establishing the therapeutic value of one combi-
nation of ICIs and chemotherapy in breast cancer.
The development of novel predictive biomarkers to identify ICI
targets within tumors will be essential in facilitating the proper
selection of treatments to avoid toxicities and to optimize the
benefit from the ICI treatment. The selection of the best combi-
nation of Immunotherapeutics and standard cancer medicines is
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further complicated by the fact that immunotherapies may have
novel antagonistic impacts. Growing evidence suggests that only a
small portion of cancer patients will benefit from ICI therapies,
and in most cases, immune-related adverse events (irAEs) remain
an issue in the few patients who are given ICI therapy [44]. irAEs
remain because the inhibition of immune checkpoints strength-
ens typical physiological issues such as autoimmunity, prompting
a number of different local and systemic immune system reac-
tions. The most commonly reported unfavorable responses
amongst patients treated by ICIs are weakness (43%), musculo-
skeletal pain (27%), imbalanced bowel movements (23%), abdom-
inal pain (22%), and loss of appetite (21%). Serious adverse
reactions to ICIs are also observed in 39% of patients [45], and
these include anemia (7%), fistulae (4.1%), hemorrhages (4.1%),
and infections (4.1%) [46]. These severe side effects frequently lead
to treatment discontinuation.
Conclusions
TNBCs are high-grade tumors within a generally aggressive sub-
type of breast cancers that have poor prognosis. Despite multiple
pioneering studies, treatment of these tumors remains a challenge,
with adjuvant and neoadjuvant chemotherapies producing only
limited responses. The treatment strategies range from traditional
chemotherapy and radiotherapy to the newer exploration of
immune control point inhibitors as immunotherapies. Although
these explorations are unparalleled, the effectiveness of these
immunotherapies and their response rates remain limited. As
molecular knowledge of TNBCs and the immune system improves,
there is potential that this new information could be used to select
therapies that could contribute to better clinical results in TNBC
patients. In general, improved knowledge of immunotherapies
and the immune response has made a valuable contribution to
overcoming problems in the treatment of various diseases.
The advent of checkpoint inhibitor-based immunotherapy,
particularly the approval of the first such therapies, has provided
a novel and powerful weapon against cancer. Nevertheless, early
findings relating to ICI-monotherapy-based treatments in TNBCs
have shown that this method will not substitute for the existing
clinical standard, and that targeting to TME is a promising way
forward. In addition, immune checkpoints are only a small frac-
tion of the immune receptors and ligands that have been identified
as potential targets in genetic and biological studies. Larger clinical
trials will be necessary to establish the response rate and to regulate
the long-term efficiency of ICIs. Likewise, new phase I and phase II
clinical trials will seek to translate the initial disease responses to
ICIs to improved patient outcomes, and to identify the mecha-
nisms and limitations of these treatments.
Correlative exploration of ongoing clinical trials might identify
suitable response and resistance biomarkers that lead to the gen-
eration of immunotherapies for patients with progressive TNBCs.
Indeed, the future of ICI therapies should revolve around the
rational selection of appropriate disease biomarkers that will indi-
cate the particular requirements of each patient. The use of such
biomarkers will allow clinicians to recognize and evaluate tumor-
reactive T-cell responses in cancer patients, and thus will facilitate
the forecasting and monitoring of patient responses to ICI thera-
pies. Increased awareness of the tumor immune response, as well
as the selection of suitable patients and biomarker discovery, will
DRUDIS-2964; No of Pages 7
Drug Discovery Today  Volume 00, Number 00  March 2021
increase the number of patients benefiting from checkpoint block-
ers.
This article discusses the existing understanding of the function
of ICIs in TNBCs, thereby informing the future progress of next-
generation clinical trials to combat this deadly cancer. Rationally
developed therapeutic interventions will be essential in resolving
the remaining challenges, and consequently, immunotherapies
are the only sensible option for treating TNBCs in the near future.
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Conflict of interest
The authors declare that there is no conflict of interest or necessary
disclosure associated with this manuscript.
Acknowledgement
The deanship of Scientific Research (DSR) at King Abdulaziz
University, Jeddah, Saudi Arabia has funded this project under
grant no (FP-135-42).
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