Intro and Vaccine

diagnostics
Review
Vaccines in Breast Cancer: Challenges and Breakthroughs

Gul Naz Fatima, Hera Fatma and Shailendra K. Saraf *
Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Babu Banarasi Das Northern India Institute
of Technology, Lucknow 226028, Uttar Pradesh, India
* Correspondence: [email protected]; Tel.: +91-983-922-8022
Abstract: Breast cancer is a problem for women’s health globally. Early detection techniques come in
a variety of forms ranging from local to systemic and from non-invasive to invasive. The
treatment of cancer has always been challenging despite the availability of a wide range of
therapeutics. This is either due to the variable behaviour and heterogeneity of the proliferating
cells and/or the individual’s response towards the treatment applied. However, advancements in
cancer biology and scientific technology have changed the course of the cancer treatment
approach. This current review briefly encompasses the diagnostics, the latest and most recent
breakthrough strategies and challenges, and the limitations in fighting breast cancer, emphasising
the development of breast cancer vaccines. It also includes the filed/granted patents referring to
the same aspects.
Keywords: breast cancer; diagnostics; biomarkers; therapeutics; vaccine strategies; antigens;

adjuvants; challenges; patents
1. Introduction
Cancer is a heterogeneous disease [1–6] with a poor median survival rate [3]. Accord-
ing to the WHO, it is the second-leading cause of death worldwide [5,6], with breast cancer
(BC) being the most common form diagnosed in females [7]. About 5–10% of patients
diagnosed with BC exhibit its metastatic form [8]. Moreover, it is highly challenging to
Citation: Fatima, G.N.; Fatma, H.; forecast the prognosis of the illness with high certainty [3]. BC is classified as invasive or
Saraf, S.K. Vaccines in Breast non-invasive [9,10]. The invasive form includes infiltrating ductal carcinoma (IDC) and
Cancer: Challenges and invasive lobular carcinoma (ILC), while the non-invasive form includes ductal carcinoma in
Breakthroughs. situ (DCIS) and lobular carcinoma in situ (LCIS) [10]. BC is further categorised depending
Diagnostics 2023, 13, upon the expressing hormone receptor such as the estrogen receptor (ER+), the human
2175. epidermal growth receptor 2 (HER2+), the progesterone receptor (PR+) and triple-negative
https://doi.org/10.3390/ breast cancer (TNBC), i.e., ER, PR, and HER2-all negative [11]. TNBC makes up 10–30%
diagnostics13132175 instances of BC [12] and is distinguished by a higher rate of relapse, higher potential for
Academic Editor: Mauro Giuseppe metastasis, and a shorter overall survival [13]. Additionally, cases of male BC, which may
Mastropasqua be either congenital, developmental, or acquired [14], have recently increased by about
40%, outpacing female cases by 25% of the affected population and by 18% in terms of
Received: 17 April 2023
mortality [15,16], though accounting for fewer than 1% of total BC diagnoses [14,17–19].
Revised: 9 June 2023
The article discusses at length the principle, approaches, and types of vaccines; and
Accepted: 21 June 2023
the routes of administration, antigens, and adjuvants used in the development of a BC
Published: 26 June 2023
vaccine, including combination therapeutic approaches and the clinical trials taking place
in the field, along with a brief discussion on the diagnostics and the treatment
strategies.
Copyright: © 2023 by the authors.
2. Diagnostics and Treatments in BC
Licensee MDPI, Basel, Switzerland.
This article is an open access article In the recent past, various diagnostics have been developed for the detection of
distributed under the terms and cancer in human subjects. The review briefly presents the diagnosis and its advancements,
conditions of the Creative Commons especially in BC detection. These include computer aided diagnosis (CAD), magnetic
Attribution (CC BY) license (https:// resonance imaging (MRI), tomography, Raman imaging, mammography, biopsy, radiomics,
creativecommons.org/licenses/by/ pathomics, and the use of artificial intelligence (AI), exosomes, and biomarkers.
4.0/).
Diagnostics 2023, 13, 2175. https://doi.org/10.3390/diagnostics13132175 https://www.mdpi.com/journal/diagnostics
Diagnostics 2023, 13, 2 of 27
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CAD is a technique that is helpful in detecting cancer in tissue samples and dis-
tinguishes healthy from unhealthy tissue [20]. It also classifies cancer stages [21] using
artificial intelligence. A digital multiple classifier database, called the Mammographic
Image Analysis Society (MIAS), is a recent advancement for the better classification of
lesions in mammograms [22,23]. MRI is a potential technique that is helpful in determining,
with fineness and accuracy, the size and vascularisation of a tumour tissue [24]. It also
provides the best soft tissue resolution [25] and, thus, has become a widely used tool for
the in vivo characterisation of BC, which reduces the need for unnecessary biopsies
[26]. Related to the tomographic technique, computed tomography (CT) in combination
with positron emission tomography (PET) has become more crucial in the staging and
restaging of BC [27]. The detection of distant metastases, using 18F-fluorodeoxyglucose
positron- emission tomography (FDGePET/CT), was recently reported to have good
sensitivity and specificity [28]. Along with MRI, a CT scan is more frequently utilised
and offers a greater imaging resolution [29], with a high accuracy of up to 98% [27].
Raman spectroscopy is a quick and non-destructive optical technique [30] that does not
require any staining process [31,32] for the diagnosis of human cancer [33]. The major
advantage it offers is a label-free way of evaluating biological samples with great
molecular specificity [34]. Despite the advanced diagnostics, conventional
mammography still plays an important role in detecting BC. It is the art of capturing a
picture of the breast [35] using a low-dose X-ray [20,36–39]. A combination of
mammography with MRI or ultrasonography further improves the chances for the early
detection of BC [40]. The technological advancement of mammography resulted in the
following two forms: contrast-enhanced mammography [41] and contrast-enhanced
spectral mammography. These techniques help to improve the sensitivity towards
providing the detailed functional particulars of the anatomic and morphologic
characters, as compared to a conventional mammogram [42,43]. When a mammogram
or other imaging modality identifies some kind of abnormality, it is most likely that the
technique called biopsy works. This includes surgical, core, and fine-needle aspiration
[20]. Image-guided biopsy, through the utilisation of advanced interventional radiology
techniques, improved the accuracy and safety of the procedure [44]. Another technique
used is radiomics, which involves the extraction of information from the images obtained
from high-dimensional imaging biomarkers. The technique helps to study the
mechanisms occurring at the genetic and molecular levels for predictive and prognostic
modeling [45,46]. It also enables the quantitative measurement of intra- and intertumoural
heterogeneity, thereby enabling analysis of the entire tumour volume [47]. Similar to ra-
diomics but based on a machine learning program, pathomics is useful for the study of
breast oncology. It largely employs in vivo/ex vivo imaging, and analysis of the digital
microscopy images of tissue, cells, and subcellular structures [46]. An added advantage
is that it quantitatively assesses the structural features at multiple magnifications to
com- plement the traditional histopathologic evaluation, with improved prediction of
biological behaviour and clinical outcomes to guide treatment strategies [48].
In addition to the above diagnostic methodologies, the latest advancement in
recent years is the use of machine learning programs. This has gained enormous
popularity in the field of clinical BC research [3]. With its exceptional precision, AI is
increasingly being suggested for use in BC screening [49], diagnosis, and prognosis [3,50].
The use of AI in BC risk assessment and prediction is also possible [16]. This uses digital
mammography and digital breast tomosynthesis for detection [50–52]. Tomosynthesis
involves removing the top layers of breast tissue for the ease of visualisation of the features
and boundaries of the lesions [41]. AI is expected to be widely used in this field in the
near future [52].
Exosomes are membrane-bound extracellular nanovesicles of endocytic origin [53–55].
They are present in diverse body parts [56,57] and may be extracted from extracellular
fluids [55]. They play a crucial role in the progression of BC and are involved in the
stimulation of tumour angiogenesis, the reorganisation of the stroma, and the
promotion of tumour growth and create the tumour microenvironment (TME) [58].
Studies showed that exosome contents reassemble with cancer [54], thereby offering
hope for lowering
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malignant cell activity and enhancing cancer imaging, prognosis [55], and liquid biopsy [53].
In addition, the expression pattern of exosomal microRNAs (miRNAs) correlates with the
degree of tumour malignancy and prognosis. Therefore, circulating exosome-encapsulated
miRNAs present an early prognostic biomarker for BC [58]. Any quantitative signs that
reveal the presence or potential of malignancy or forecast tumour behaviour or prognosis
are referred to as biomarkers [59]. Studies showed that the presence and the number
of axillary node metastases are the most significant prognostic biomarkers in cases of
BC. The ER marker is one of the BC prognostic biomarkers that is now available [60].
Currently, the multiple reaction monitoring (MRM) assay has been evolved to detect BC
biomarker peptides in serum samples [61]. miRNAs and exosomes are new diagnostic
and therapeutic biomarkers for BC patients [57,59]. Some biomarkers for BCB (breast
cancer bone) metastases include CST1/2/4/6, PLAU, PLAT, COL6A1, and PLOD2. The
advancement of technology, such as deep sequencing, lent advantages over conventional
biomarkers by being non-invasive [59]. Proteins such as ER, ERR, Her2, Ki67, CEA, and
TSGF and miRNAs such as miR-10b, miR-21, miR-145, and miR-155 are examples of distinct
BC biomarkers [57].
The treatment of cancer has always been a challenge for the scientific community.
The following paragraphs briefly describe some of the strategies developed over time to
treat BC.
One of the most advanced strategies for the treatment of BC involves the use of
nanoparticles (NPs). They are an efficient means to deliver medications targeting malignant
cells [62], with improved pharmacokinetics and pharmacodynamics [63] and reduced side
effects [64]. For example, a liposomal nanoformulation of Doxorubicin was shown to
display action with significantly reduced side effects. Catechols, gallol, and their
derivatives are used to construct nanomaterials [65], with the use of polymers, to
deliver conjugated or encapsulated drugs [66]. Gold, silver, and iron oxide NPs are
thermally stable, low in toxicity, compact, and effective in BC treatment [11]. In
addition, magnetic NPs are also being studied as promising materials for prospective
nanopharmaceuticals [67]. Neoadju- vant treatment is an effective treatment strategy for
inoperable locally advanced BC [68]. In patients with non-metastatic BC and axilla
tumours, neoadjuvant therapy is used to de-escalate the extent of surgery [69], thereby
minimising unnecessary surgeries and mas- tectomies [70]. In order to fix, add, or repress
a gene, the genetic material must be first administered through a vector to the target
cells. Gene therapy is less toxic than conventional medicine and helps to target tumour
cells without harming normal cells [71].
Radiotherapy (RT) exerts local action [72] and represents one of the most effective
non-surgical treatment modalities [73]. Whole breast irradiation, also known as WBI,
is frequently carried out following a breast-conserving surgery [29], i.e., intraoperative
radiation therapy (IORT), which is a therapeutic strategy that accomplishes surgery and
adjuvant RT in a single treatment [29].
The dynamic relationship between tumour cells and the immune system involves
three key stages: elimination, equilibrium, and escape [74]. Immunotherapy (IT) is a
strategy that works by stimulating and recruiting a patient’s immune system against the
tumour cells [75–77]. Various IT approaches include tumour-targeting antibodies, adoptive
T-cell therapy, vaccines, and immune checkpoints [60]. Glycoprotein mucin-1 (MUC-1)
was one of the first BC-associated antigens to be identified [78]. In order to evaluate the
cell–cell interactions, the use of bioengineering tools such as optical microscopy and a
microphysiological in vitro system was accomplished [79]. IT, however, can negatively
affect the foetus or impede a future desired pregnancy [80].
The use of combination therapy may give a new hope for BC treatment [81,82]. It is a
promising therapeutic approach that involves folate ligands in conjunction with chemother-
apeutic drugs and small interfering RNAs (siRNAs) [83]. A study undertaken by Ma et al.
reported the beneficial effects of a combination of Trastuzumab and Everolimus in patients
with ER+/HER2-HER mutant BC [84]. It reported a boost in the survival rates of patients
by up to 35%. Some examples of combination approaches include the combinations of any
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of the following therapies: immunotherapy, molecular-targeted therapy, cell cycle man-

agement, cell signalling pathway regulation, monoclonal antibodies, and antibody–drug
conjugates [60].
Thermal ablation (TA) therapy exerts its action by destroying the entire tumour using
heat, through needle-like applicators [85]. It results in minimal invasion without damaging
the adjacent vital structures [86,87] and, thus, is a safe and effective alternative to surgical
resection in early-stage treatment of BC [88]. This advancement resulted in
percutaneous TA techniques, viz., radiofrequency ablation, microwave ablation,
cryotherapy [89], and cryoablation [90,91]. Another method is radiofrequency ablation
(RFA), which entails in- serting a metal electrode into the breast and connecting it to a
radiofrequency generator that outputs 200 W at 400–800 KHz. [91]. The tumour tissue is
burned at temperatures (50 ◦C) high enough to cause necrosis [92]. Microwave (MW)
ablation is a recent advancement in the field that involves heating malignant tissue with
MW energy to cause cell death [91]. The goal of hyperthermic therapy is to kill tumour
cells by inducing a series of metabolic changes, such as apoptosis in the tumour tissue
by heating it to high temperatures [93]. The use of magnetic nanoparticles (MNPs) such
as iron oxide nanoparticles (IONPs), in an alternating magnetic field results in magnetic
hyperthermia. The technique utilises two types of magnetic nanoparticles: magnetic
alloy nanoparticles (MANPs) and magnetic metal oxide nanoparticles (MMONPs) [94].
They are site-specific and are classified as whole-body hyperthermia, regional
hyperthermia, and localised hyperthermia depending on the site of application [95].
In addition, modern medicine emphasises the prevention and treatment of cancer
with natural nutritional components [96]. This includes the use of flavonoids, phenolic
compounds, and some dietary sources that effectively exhibit anticancer activity [96–99].
For example, quercetin prevents free radicals from impairing low-density lipoproteins and
is useful against cancer [96]. Luteolin [99] and resveratrol proved to modulate various
signaling pathways involved in the proliferation of cancerous cells and are established as
anticancer agents [100]. Some naturally occurring constituents such as the c-3 fatty acids
and phytoalexin found in grapes; epigallocatechin gallate, a polyphenolic compound found
in herbs such as Oldenlandia diffusa and Ziziphus jujube [98]; and Silibinin, a major component
of Silymarin that is obtained from the seeds of milk thistle, Silybum marianum [97], can
be used in the treatment of BC. Pomegranate, Punica granatum, can also be used against
different type of cancers [101].
3. Vaccine Therapy in BC
3.1. Introduction
Vaccines have long protected humans from communicable and non-communicable
diseases [102]. Therefore, conventionally, the word “vaccine” is usually related to the fight
against infectious diseases. Vaccines exert their action by stimulating immune
responses. This is achieved by inoculating a healthy individual with
attenuated/detoxified bacteria, viruses, or extracted toxins [103].
The immune system works to keep living things in a state of equilibrium by the
process called immune surveillance [104]. The method by which tumour cells circumvent
the immune system has been extensively explored and has been successfully established
over the past few years. Such efforts led to the conclusion that cancer immunoediting is
the strategy employed by the tumour cells towards immune evasion [105,106]. It may be
caused by TME-antigen-mediated antitumour immunological responses. A number of tools
for cancer immunotherapy were developed, which include antibodies, peptides, proteins,
nucleic acids, and immune-competent cells such as dendritic cells and T-cells [103]. Cancer
immunotherapies are now considered the fourth treatment method [107,108], used either
alone or in combination [60]. The therapy was initially utilised by William B. Coley in 1891,
to treat sarcoma patients with Coley’s toxin [109].
The available vaccines for cancer immunotherapy can be divided into two basic types,
the prophylactic and the therapeutic vaccines [110,111]. The former induces immunological
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memory by vaccinating healthy people [112], to prevent morbidity from a certain malig-
nancy [113], and can be a cost-effective preventive measure [114]. The latter boosts
immune systems in people detected with cancer [103]. The therapeutic cancer vaccine
prevents the growth of advanced malignancies or relapsed tumours that are resistant to
standard treatments [112]. Based on the structure and the content, the vaccines are further
classified into the cell vaccines, the peptide vaccines and the nucleic acid vaccines [103].
The criteria necessary to be fulfilled to achieve vaccination requires a target
antigen on tumour cells to stimulate the immune response, a vector to deliver the vaccine-
derived antigen to the immune system, an adjuvant to boost immunological stimulation,
and an appropriate monitoring tool [115]. These are discussed in detail in the subsequent
sections.
3.2. Concepts in Designing of a Breast Cancer Vaccine (BCV)

3.2.1. Immunoediting
The immune system constantly changes as BC progresses. The process is called
immunoediting, which comprises three steps: elimination, equilibrium, and escape. During
elimination, the tumour cells stimulate the innate immune system (which along with
the adaptive immune response can recognise and remove early altered tumour cells)
through the activation of macrophages, natural killer cells (NK-cells), and dendritic cells
(DCs), in turn activating the tumour-targeted T-lymphocytes. The equilibrium phase
initiates in the case of a cancer subclone colony surviving the host’s immunity. This
stage creates a delicate balance between cancer growth and the immune system’s defence
function, making it difficult to totally remove the tumour cells, though their progression
is severely limited [116]. However, it results in the formation of cancer cells with
decreased immunogenicity, epigenetic alterations, and genetic instability [117], thus
making them capable of escaping the immune detection and destruction [118]. Such cells
that escape the immunological pressure finally enter the third stage of immunoediting,
where the immune system barely puts any restraints on the progression of the modified
tumour cells as in Figure 1 [119].
Figure 1. The process of immunoediting carried out by cancer cells.

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3.2.2. Immune Surveillance

Effector immune cells must directly recognise tumour antigens from tumour cells
or indirectly from antigen-presenting cells (APCs), via the major histocompatibility
complex (MHC) on the cell surface, to initiate an immune response. CD8+ and CD4+ T-
cells are critical to the immunoediting process and help separate the non-self epitopes
of the tumour cells expressed by MHC class I and MHC class II molecules from the
normal self-antigens [120,121]. Tumour-specific antigens (TSAs) and tumour-associated
antigens (TAAs) [122] are examples of tumour antigens. These include germ-line antigens,
tissue dif- ferentiation antigens, and overexpressed antigens, exemplified by the melanoma-
associated antigen, the carcino-embryonic antigen (CEA), and HER2 and MUC-1,
respectively [123]. Many of the tumour antigens employed in immunotherapy are
expressed in normal tissues as well. However, tumour cells overexpress these antigens
[122].
3.2.3. Immune Suppression

Tumour cells successfully inhibit the host’s immune system, both locally and sys-
temically, from evading immune surveillance [124]. It is well-established that there is
predominance of the immunosuppressive effect with advancement of the disease. This
results in a gradual transition from the elimination phase to the escape phase [125]. During
this process, there is an alteration of the number of cells around TME and the lymph nodes
in the vicinity of the tumour tissue. First are regulatory T-cells (Treg cells). There is en-
hancement in the proliferation of Treg cells brought about by transforming growth factor-β
(TGF-β) [126], while cytotoxic T-lymphocytes (CTLs) are greatly reduced, as interleukin-2
preferably binds to Treg cells. The antitumour response is, thus, weakened by a reduction
in the number of CTLs [127] and NK-cells [128] in TME (Figure 2). Treg cells function to
downregulate the dendritic cell co-stimulatory markers, viz., CD80 and CD86, necessary for
the priming of CTLs [129], which, in turn, function to eliminate any abnormal-
phenotype- expressing cell. Second are tumour-associated macrophages (TAMs). TAMs
release inhibitory cytokines including IL-10 and TGF-β to suppress CTL activity and the
production of IL-12 [130]. Third are the myeloid-derived suppressor cells (MDSCs).
During the shift, these cells start appearing in the peripheral blood as well [131]. Tumour
cells also activate immunological checkpoint receptors such as cytotoxic T-lymphocyte
antigen-4 (CTLA-4) and programmed cell death receptor-1 (PCDR-1) [132]. PCDR-1
blocks programmed cell death ligand-1 (PCDL-1).
Therefore, in patients with diverse malignant tumours, the tumour-infiltrating lym-
phocytes (TILs) and the tumour-specific T-lymphocytes show high amounts of PCDR-1.
The involvement of PCDL-1/PCDR-1 by tumour cells prevents the elimination of T-cells,
thereby causing their dysfunction and, ultimately, cell death. In contrast, the cytokines that
create an immunosuppressive milieu help to further promote tumour growth [133].
3.2.4. Identification of the Antigen for BC Immunotherapy

Numerous tumour antigens, which are expressed in healthy cells but are overexpressed
in tumour cells, are employed in BC immunotherapy. They include HER2, p53 (tumour
protein 53), MUC1, carcinoembryonic antigen (CEA), telomerase reverse transcriptase
(hTERT), and carbohydrate antigens [78]. Due to their widespread expression in the
majority of tumour types, some of these antigens are known as universal tumour antigens.
An example of this class is hTERT [134]. All the potential antigens that are used in the
creation of vaccines for the management of BC are briefly discussed in the following section.
Human Epidermal Growth (HER2) Receptor 2

HER2 is a tyrosine kinase that regulates cell proliferation and survival. The
oncogene for HER2 is located on chromosome number 17q12. In cases where BC is
HER2-positive, an amplification of 15–20% in the expression of HER2 is found. This is
responsible for triggering the growth and progression of tumour cells [135]. HER2 is
linked to a more severe form, a higher risk of recurrence, and a higher mortality rate.
The first drug to be
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established as a HER2 blocker was Trastuzumab [136], which has been validated for the
treatment of patients with HER2+ BC [137,138].
Figure 2. Immune-suppression by tumour cells.
Tumour Suppressor p53 Protein (p53)

The gene encoding p53 is located on chromosome number 17 [139]. It plays a vital
role in the maintenance of DNA integrity and the prevention of cancer. Under normal
physiological conditions, when a cell’s DNA is damaged, there is an induction of the p53
protein that causes arrest of the cell cycle. This allows cells to repair themselves, but, if
the damage is too severe, the cells apoptise and are rejected. In a variety of cancer
forms,
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mutations in the p53 gene (mtp53) takes place [140]. However, mtp53 is less frequently
found in BC [141], though it has high significance in the diagnosis and prognosis of TNBC,
with almost 70%–80% of cases displaying mtp53 [142].
Mucin1 (MUC1)
The MUC1 gene is encoded by chromosome 1q21. It is a high molecular weight
transmembrane glycoprotein that functions as a physical barrier to protect the
epithelial layer of cells from environmental exposure. It forms the epithelial lining of the
respiratory and GI tracts, mammary glands, pancreas, liver, and kidneys. MUC1 is a poly-
morphic type I member of the mucin family. It is overexpressed in about 90% of human
BC due to genetic alterations and the dysregulation of transcription [143,144]. MUC1 is also
aberrantly glyco- sylated [145], which exposes various antigens, thereby generating a new
set of antibodies that can prove beneficial in the diagnosis of cancer [146].
Carcinoembryonic Antigen (CEA)

The CEA is a glycoprotein that is encoded by human chromosome 19q13.2. This
antigen is an important serum biomarker for the detection of cancer and plays a vital
role in the prognosis and diagnosis of BC. It is found elevated in patients with metastatic
BC, especially with bone metastasis [147,148]. Several studies suggested the significance of
CEA and CA15-3 levels in predicting BC patients who can be operated on at an early stage
[149].
Human Telomerase Reverse Transcriptase (h-TERT)

The gene encoding h-TERT, a catalytic subunit of the telomerase, is encoded on chro-
mosome 5p15.33. This ribonucleoproteic enzyme is responsible for synthesising telomeres,
which, in turn, maintain the chromosomal length. The ultimate result is cellular immortali-
sation [150]. Studies suggested their vital role in the development of cancer. It was found
that in most forms of cancer, the reactivation of telomerase takes place in a dependent or an
independent manner. The enzyme ensures the stability of chromosomes, thus bypassing
senescence. TERTp is the promoter region of TERT. Mutations in the TERT gene support
carcinogenesis with variable frequencies, which takes place through the healing of the
telomere’s length, thus expanding the life of cells. TERTp was established as a tool to
characterizes the type of cancer [151] and, thus, is helpful in the diagnosis and prognosis of
the disease [152].
3.3. Design Approaches of a BCV

The optimisation of vaccine schedules and administration methods is a component of
a vaccination strategy. Based upon the platforms and formulations, BCVs can be broadly
classified as peptide- and protein-based [153], carbohydrate antigen-based, whole-cell-
based, gene-based [154], and fusion-based vaccines [155]. However, irrespective of the type,
all vaccines are dependent on the autologous immune system recognising a specific antigen
to exert a therapeutic effect. Moreover, the use of an adjuvant is essential, as it helps to
increase the antigen immunogenicity, thereby controlling the immune response [156].
3.3.1. Peptide- and Protein-Based Vaccine (PV)

In this class of BCVs, the MHC class I restricted peptide epitopes are used to stimulate
the immune response against a tumour antigen as shown in Figure 3 [157]. The injected
peptide stimulates immune effector cells to find and kill cancer cells [158]. Some short
amino acid peptides are preferably used, as they are cheap, stable, and easy to
synthesise and modify and display low immunogenicity [159]. However, a vaccination
cannot be given to patients with a non-common human leukocyte antigen type, since each
peptide is confined to a specific HLA subtype.
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Figure 3. Mechanism of a peptide-based BCV.
MHC class I binding peptides poorly stimulate CD4+ helper T-cells and also, in turn,
limit their ability to activate CD8+ cytotoxic T-cells, resulting in a transitory immunological
response. According to Pallerla et al., long peptides are capable of containing many
MHC class I and class II epitopes, thus helping to partially overcome this difficulty. Such
peptides containing 23–45 amino acids may improve T-cell activation through processing
and presentation [154]. The success of the peptide-based BCV can be seen from its entry
into phase I/II of clinical trials [160].
Diagnostics 2023, 13, 10 of
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The entire tumour antigen protein or a truncated portion of it, wherein the
sequence of amino acids is substantially longer than that of peptides, is used to create
protein-based vaccines [161]. It is not HLA-restricted and allows for the absorption,
processing, and presentation of a variety of MHC class I and class II peptide epitopes
[162]. However, the presenting method may be less effective, and the lack of a precise
marker makes it difficult to estimate how well such vaccine types would work [163]. A
number of clinical trials (Table 1) are currently in the pipeline to test the efficacy of
vaccines pertaining to BC [162].
Table 1. Clinical trials in the field of breast cancer vaccines.
NCT Number Antigens/Biological Clinical Phase

NCT00854789 E75 and GM-CSF I
NCT00892567 Her-2/neu; CEA and CTA I
NCT02019524 E39 and J65 peptides I
NCT04270149 ESR1 peptide vaccine I
NCT04521764 Helicobacter pylori neutrophil-activating protein I
NCT00343109 HER-2/neu II
NCT02348320 Personalised polyepitope DNA vaccine I
NCT02018458 LA TNBC; ER+/HER-BC I/II
NCT04348747 Anti-HER2/HER3 DC vaccine; Pembrolizumab II
NCT02061423 HER-2 pulsed DC vaccine I
NCT01730118 AdHER-2/neu DC vaccine I
NCT00524277 HER2-derived peptide GP2; GM-CSF II
NCT01479244 HER2-derived peptide E75; GM-CSF I/II
NCT01570036 HER2-derived peptide E75; GM-CSF; Trastuzumab II
NCT00140738 HER; AS 15 I/II
NCT02061332 HER; DC vaccine II
NCT00399529 HER2; GM-CSF; Cyclophosphamide; Trastuzumab II
NCT01479244 HER2-derived peptide E75; GM-CSF III
3.3.2. Carbohydrate Antigen-Based Vaccine (CAV)

Immune cells can discriminate between improperly expressed carbohydrate antigens
in tumour cells. This makes the carbohydrate antigen a prime candidate for inclusion
in cancer vaccination. An example includes the expression of a unique disaccharide
carbohydrate, Sialy-Tn (STn), on the cell surface of cancer cells, including BC cells, which is
connected to MUC-1 [164]. According to Munkley (2016), immunisation with STn
results in tumour regression and prolongation of survival time. Thus, it could be
beneficial in the development of a cancer vaccine [165].
3.3.3. Whole Tumour Cell-Based Vaccine (WTCV)

One of the conventional approaches in the development of a cancer vaccine is the
stimulation of the immune response by the use of whole tumour cells or the products
obtained from tumour cell lysis. A WTCV induces a polyvalent immune response, since
it is based on a pool of unknown antigens created by autologous or allogeneic tumour
cells [166]. Sometimes, the enhancement of the antigen-presenting ability of the WTCV
is achieved through engineered tumour cells that are capable of releasing cytokines or
expressing co-stimulatory molecules. The drawback of the WTCV is that it contains
endogenous cellular antigens, which can result in an autoimmune response. A
systematic procedure for creating the WTCV is, however, lacking [167].
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3.3.4. Dendritic Cell-Based Vaccine (DCV)

Upon migration into the lymph nodes, a diverse population of APCs, called DCs,
effectively absorb antigens to process and present them to CD4+ and CD8+ T-cells. DCs
can also stimulate NK-cells and B-cells. DC-based vaccines typically use ex vivo
generated DCs that were transfected to express tumour antigens or are loaded with
tumour antigens. In a review by Butterfield et al., the use of antigens, such as complex
tumour lysates and several MHC class I and class II peptides, and monocytes and CD34+
progenitor cells for the purpose of DCV preparation was discussed [57]. The technical
challenge that arises while developing DC-based vaccines was because of the distinct
process of ex vivo DC maturation [168].
3.3.5. Gene-Based Vaccine

The strategy for a gene-based vaccine involves a plasmid that carries the DNA
encoding the cancer antigen. This form of vaccine can be used to activate both a non-
specific innate immunity and an adoptive immunity specific to an antigen. Due to its
simplicity, safety, and cost-effectiveness, this approach is regarded as one of the most
practicable methods for cancer immunotherapy. However, it suffers from limitations
such as a lack of plasmid uptake and ineffective antigen expression, thus presenting
insufficient immunogenicity [162]. To overcome this demerit, various approaches were
undertaken. One of the approaches was to make the vaccine self-replicating. This utilised the
RNA replicase encoding gene [169]. RNA-based medications have the potential to be
effective pharmacological regulators against cancer cells by altering the expression of
particular proteins. These characteristics help to increase specificity and reduce the chance
of off-target impacts [153].
3.3.6. Fusion Vaccine

This strategy employs the fusion of autologous DCs and autologous whole tumour
cells. It involves the cytoplasm of both cell types to be fused together without their
nuclei doing so. This preserves their ability to function as individual cells. With the
fusion, the formed vaccine can express and process a wide range of recognised and
unrecognised tumour antigens [170]. Studies and trials found a favourable response by
patients with metastatic BC towards this fusion vaccine, in terms of its potent antitumour
effects [154,171].
3.4. Adjuvants Used in Design of BCVS

Adjuvants are combined with the antigen and are essential in the case of low immuno-
genicity. They help to increase the immunogenicity of the antigen and thus, trigger, the
immune response, particularly in the elderly [156]. Most adjuvants work by decreasing
antigen release, encouraging antigen absorption and presentation by APCs, and
boosting the growth of DCs and macrophages [172]. Traditional adjuvants, such as
alum, mostly stimulate type-2 T-helper cell-dependent humoral immunity in prophylactic
vaccinations for infectious diseases rather than type-1 T-helper cell responses that
directly destroy tumour cells [173]. A common adjuvant in BCV is a secreted cytokine,
called granulocyte- macrophage colony-stimulating factor (GM-CSF). It was
demonstrated to promote the proliferation and activation of DCs as well as the
maturation of myeloid cells such as granulocytes and macrophages [174,175]. Clinical
trials of many GM-CSF-containing BCVs revealed measurable immune responses. The local
administration of GM-CSF to melanoma patients increases the probability of the antigen
immune response after vaccination. Studies found GM-CSF suppresses T-cell responses
and produces inhibitory MDSCs. However, elaborative research is needed to discover the
role of GM-CSF as an adjuvant for cancer vaccines. DNA-based cancer vaccines also use
recombinant viral vector adjuvants (Figure 4).
Recombinant viral vectors, which commonly carry antigens, contain different levels of
pattern recognition receptor (PRR) and toll-like receptor (TLR) ligands that activate
DCs and boost immune response. TLR agonists activate CD8+ T-cells and prevent T-cell
exhaus- tion. The vectors contain other sequences that can compete with the targeted
antigen motif, which is the main drawback of this adjuvant. However, adjuvant effects
vary depend-
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ing on vaccination formulation, targeted tumour antigens, immunisation schedule, and

mode of administration, making adjuvant comparisons difficult [176]. Moreover, adjuvant
optimisation tests for BCV are crucial.
Figure 4. Diagrammatic representation of vector-based vaccines.
3.5. Routes of BCV Administration

A good vaccine for cancer should be capable of efficiently transferring antigens to
autologous APCs. For this purpose, various strategies are preferred. HER2 peptide-
based vaccines are usually intradermally administered and exhibit an enhanced rate of
response. This is probably due to the widespread network of DCs. Low intradermal
peptide doses are safe and trigger specific responses by antigen T-cells in most healthy
human subjects [177–179]. Several BCVs were tested for their immune response induction
efficiency via subcutaneous injection [180]. However, a large dose of antigen at the site
of injection may cause severe reaction and sporadic sterile abscesses, which may
require vaccine discontinuation or a dosage reduction [175]. Vectors or plasmids are
injected through various routes in the case of the administration of a DNA-based
vaccine, of which the intramuscular route of administration was found to display the most
effective immune response [181]. Some DC-based immunisations must be given
intravenously to directly stimulate lymph node T-cells [157].
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3.6. Clinical Trials of BCVs

In preliminary studies, certain BCVs were successful in eliciting discernible
immune responses and showing good tolerance. However, most of them showed
appreciable clinical advantages in the ensuing Phase 3 trials. Recently, the NeuVax TM
vaccine (developed by Galena Biopharma, a US-based biotechnology company), which is
administered with Leukine® for the disease condition of BC with intermediate to low
HER2 expression, was granted a Special Protocol Assessment for its Phase 3 trial
(Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer) [182]. The
Theratope® and Enhanzyn™ vaccines are some of the vaccines that were withdrawn from
the clinical trial enrolment [183]. A brief summary of the vaccines in clinical trials is
listed in Table 1.
3.7. Combinational Therapy of BCVs

Immune checkpoint blockers (ICB) have changed the approach towards the treatment
of cancer. As far as BC is concerned, ICBs were already proven to be effective in treating
metastatic TNBC [184]. The addition of ICB to Trastuzumab, however, was linked to
additional side events and did not provide a clinically substantial improvement in the
progression-free survival for HER2-positive metastatic BC [185]. Combining the vaccination
with ICB to combat cancer tolerance is a trending research approach in the field [186].
As previously stated, ICB blocks inhibitory receptors such as PCDR-1/PCDL-1 and CTLA-
4 to enable the effector immune cells to kill tumour cells. According to certain
preclinical research, when T-cells are activated by tumour vaccines, the inhibitory receptor
expression on the cell surface also increases. One of the underlying reasons is the enhanced
interferon- γ (IFN-γ), which is released by tumour-specific T-cells. IFN-γ up regulates the
expression of PCDL-1 on the tumour cells and APCs. PCDL-1 initially helps to prevent the
body’s immune responses from being too amplified [187,188]. Therefore, the
immunosuppressive impact that reduces the antitumour immunity elicited by vaccines is
likely to be relieved by an injection of ICB [189]. A promising approach that has the
potential to improve and lengthen the course of the immune response and effectively
produce considerable clinical benefits is the combination of the BC vaccination with ICB.
Additionally, combining cancer vaccinations with recognised medicines could also
increase efficacy.
The research suggests that some HER2-derived peptide vaccines [190] and anti-HER2
monoclonal antibodies may function synergistically [191]. Studies show a connection
between chemotherapy/radiation therapy and immune-related cell death. When these
medicines are applied in conjunction with cancer vaccines, it might create a long-lasting
immune response. Consistently, it would be worth investigating the effects of
integrating cancer vaccination with chemotherapy [192,193], hormone therapy
[194,195], targeted therapy [196,197], and radiation therapy [198,199].
3.8. Challenges Faced during the Course of Development of BCVs

Despite the several advantages associated with cancer vaccines, there are
numerous challenges accompanying cancer vaccination strategies. Firstly, the
development of tolerance towards the antigen, which results in lowered immune
response. Secondly, the heterogenicity of the tumour type brings in some diverse intrinsic
and extrinsic pressures, which, in turn, result in a detrimental effect on the antitumour
vaccination processes. In addition, some genetic and non-genetic mechanisms play a role in
defining the heterogenicity of cancerous cells, thus affecting the immune response.
Moreover, the immune invasion mechanism was found to be a major hurdle in the
efficacy of a vaccine. This requires potential alternative strategies to improve
antitumour immunity [200]. Some developed vaccines were found to display poor
immunogenicity when used alone. Therefore, the next generation of adjuvants may be
used [201]. A key point during the development of an anticancer vaccine is the
aftermath, in the form of immunological responses. Thus, it is necessary to recognise the
immune modulatory pathway, and test and validate the disease-specific cancer
vaccination [202]. Cancer immune interaction is also governed by the concomitant use
of a drug.
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4. Recent Patents Filed/Granted on Cancer Treatment and Diagnostics

This review also encompasses the patents filed/granted at the USPTO during 2018–
2022, as shown in Table 2 [203–240]. The patents present advancements in diagnostic
technologies as well as in cancer therapeutics.
Table 2. Some patents related to cancer diagnosis and treatment filed/granted in the past five years.
S. No. Patent Number Date of Publication Invention Disclosed

This invention disclosed the antigenic specificity of the T-cell
1. US 2022/0195008 A1 23 June 2022 receptor (TCR) for the melanoma antigen family. The
polypeptide in the functional portion of the TCR was found to
carry amino acid sequences of length 16–21 [203].
This invention described an immune cytokine that is a conjugate
and an immunomodulatory antibody. It comprised an
2. US 2022/0193199 A1 23 June 2022 interleukin15-containing polypeptide, which is an IL-15Ra sushi
domain-containing polypeptide. The immunomodulatory
antibody- or antigen-binding fragment was said to be capable of
binding PD-1 and PD-L1/L2 [204].
A pharmaceutical combination comprising a CDK inhibitor and
3. US 2022/0193079 A1 23 June 2022 an antihormonal agent that regulates the P13K/Akt/m TOR
pathway or a pharmaceutically acceptable salt was discussed in
the patent [205].
This invention disclosed the compositions and methods of
generating an RNA chimeric-antigen receptor of transfected T-cells
4. US 2022/0170012 A1 22 June 2022 for use in adoptive therapy for cancer. The method modified the 5′
end of the RNA or its 7-methyl guanosine cap by the addition of
the 5′-end of the eukaryotic messenger, soon after the initiation of
the transcription [206].
Methods for reducing the cytotoxicity of chemotherapeutic agents
towards non-cancer cells and increasing their cytotoxicity towards
5. US 2022/0184111 A1 16 June 2022 cancer cells were described in this patent. The patent gave details
regarding the administration of an effective amount of the agent to
achieve the inhibition of CD47 signalling for an effective
chemotherapeutic agent [207].
This patent disclosed a method for the treatment of a solid
6. US 2022/0185892 A1 16 June 2022 tumour through the administration of an effective quantity of
some
anti-LAG-3 and anti-PD1 antibodies that carry the CD-R1, -R2, and
-R3 domains of the chain [208].
This invention discussed a method for detecting a tumour
7. US 2022/0186323 A1 Jun16, 2022 marker, which, in turn, indicated the presence of a cancer. The
marker may be a sample of nucleic acid. The sample was then
amplified by polymerase chain reaction, thereby enriching the
nucleic acids for the detection of genomic regions [209].
A treatment method for enhancing the efficacy of a therapy for
8. US 11,291,723B2 5 April 2022 cancer in humans and animals was presented in this invention.
This treatment was selective in killing or reducing the growth of the
target cell by using the enzyme- Cas nuclease. It was also related to
cell populations, system, arrays, cells, RNA, and other means
affecting the therapy [210].
This patent disclosed cancer immunotherapy relating to
9. US 2022/0040278 A1 10 February 2022 tumour-associated T-cell peptide epitopes. The presence of
peptides on the tested tissue sample biopsies helped to diagnose
cancer. This patent also gave methods, such as antibody detection
or spectrometry, for analysing peptides [211].
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Table 2. Cont.

This invention discussed a method to detect the inactivation of the
DNA homologous recombination pathway, which helped to detect
10. US 2022/0010385 A1 13 January 2022 the BC gene, BRCA, or placental alkaline phosphatase, PALP (also
called FANCN), inactivation, which was probably due to a somatic
mutation or a mutation in the germ cell line [212].
An expression of a set of genes as thera-prognostics for the
disease-free survival of cancer patients was disclosed in this
11. US 11,220,715B2 11 January 2022 invention. It gives the use of a paraffin-embedded biopsy
material that is compatible with different methods of tumour
tissue harvest [213].
This invention mentioned the methods to determine the presence
or absence of a cancer type in an animal. The procedure
12. US 2022/0003792 A1 6 January 2022 determined the concentration of lipid amounts in a sample, which
was obtained either from a detected cancer or a treated individual’s
body fluid, using the mass spectrometric technique [214].
This patent gave details regarding the identification and analysis of
some polynucleotide adaptors, which include cell-free nucleic acids,
13. US 11,085,084B2 10 August 2021 from sample cancer patients. It also included their detection,
diagnosis, and prognosis [215].
A pharmaceutical composition that could be utilised for the
treatment of patients diagnosed with HER2-positive BC was
14. US 2021/0145835 A1 20 May 2021 addressed. The pharmaceutical substance disclosed was
(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H pyrazolo [3,4-d]
pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one [216].
This invention described the administration of a therapeutically
effective quantity of N-((4,6-
dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5-(ethyl
15. US 2021/0137936 A1 13 May 2021 (tetrahydro-2H-pyran-4-yl) amino)-4-
methyl-4′-(morpholino-methyl)-[1,1′-biphenyl]-3-carboxamide
hydrobromide. The compound was a polymorph and exhibited
an X-ray powder diffraction pattern with characteristic peaks
[217].
This patent related to methods for the evaluation of the diagnosis of
cancer in a patient. The patient may be subjected to some therapy.
16. US 10,991,448B2 27 April 2021 The attributes that were measured included the degree of mutation,
transcription and translation levels, protein, and interaction. Thus,
a probabilistic pathway gave a comparative graph representing the
cellular processes [218].
This invention was related to the collection of live tumour cells
using a collecting probe, where the procedure involved placing the
17. US 10,987,037 B2 27 April 2021
probe in a living organism. The probe used was composed of guide
wire carrying a binding surface with an optically sensitive dye and
an atraumatic tip at the distal end [219].
A method for the treatment of patients with metastatic BC that
would extend the progression-free survival of the subjects under
18. US 2021/0093715 A1 1 April 2021
treatment was disclosed. The therapeutic regime consisted of an
effective dose of a chemotherapeutic agent and an anti-VEGF
antibody [220].
This invention disclosed a method for the treatment of BC with
19. US 2021/0047429 A1 18 February 2021
an effective amount of HER2 antibody and a taxane derivative
[221].
This patent described a method for the treatment of patients
diagnosed with HER2-positive BC. The method involved the
20. US 2021/0040216 A1 11 February 2021 administration of a therapeutic amount of an antagonist
of programmed cell-death (PCD) protein-1 combined
with Trastuzumab and Pertuzumab [222].
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Table 2. Cont.

Certain methods, devices, and kits to be used for the detection of
biomarkers in cancer patients were disclosed in this patent. The
21. US 10,907,214B2 2 February 2021 treatment involved a secretory phospholipase A and a hydrolysable
cisplatin-containing liposome. It also discussed the use of a
microarray device with an oligonucleotidic probe to assess the
responsiveness of the patient [223].
The compositions and procedures for treating cancer with chimeric
antigen receptor-modified cells were included in the invention. An
22. US 2020/0385484 A1 10 December 2020
antigen-binding domain, a transmembrane domain, a
co-stimulatory signalling region, and a CD3 zeta signalling domain
may all be present in the antigen [224].
This invention provided methods for use in the adoptive
immunotherapy of diagnosed cancer patients. It gave the
23. US 10,858,626B2 8 December 2020 composition, which consisted of specific tumour infiltrating
lymphocytes, tyrosine-protein kinase-2 receptor, and a vascular
endothelial growth factor recepto inhibitor [225].
This invention gave the methods for the treatment of an
24. US 2020/0246275 A1 6 August 2020 individual with cancer, which comprised the administration of a
therapeutically effective amount of a nanoformulation of some
taxanes with albumin and a Bcl-2 inhibitor such as ABT-263 [226].
This invention described a combination therapy consisting of
antagonists of PCD-1 and lymphoma kinase for use in the
25. US 10,695,426B2 30 June 2020 treatment of cancer. The treatment consisted of monoclonal
antibody with variable regions of seq. ID nos. 13 and 15 with a
heavy chain and a light chain [227].
An immunotherapeutic strategy for cancer was discussed in this
26. US 2020/0157177 A1 21 May 2020 invention. It described the use of tumour-associated T-cell peptide
epitopes in combination with certain other associated peptide
molecules bound to the major histocompatibility complex [228].
This invention claimed that methods and compositions enhance the
27. US 10,633,441B2 28 April 2020 immune system response towards cancers. It related antigen
receptors that selectively target human mesothelin [229].
This patent gave methods for immune response induction in cancer
28. US 2020/0101102 A1 2 April 2020 patients using Toll-like receptor-9 agonists being administered
intratumourally [230].
This invention disclosed the composition and methods of making
antibodies and carrier proteins to be used as cancer therapeutic
29. US 10, 596, 112B2 24 March 2020 agents. It also discussed a lyophilisation procedure for nanoparticle
formulation that contained albumin, antibodies, and some drug
such as Paclitaxel [231].
A molecular diagnostic test for cancer was presented in this
invention. The test was based on the detection of DNA damage and
30. US 10, 378, 066B2 13 August 2019
the repair mechanism and was capable of determining cancer in
clinically responsive or non-responsive patients [232].
This invention related to immunotherapeutics obtained from
pluripotent stem cells to generate some phenotypical,
31. US 10, 370, 452B2 6 August 2019 functionally expandable T-cells. The cells could be used to target
a specific antigen, thereby enhancing the cytotoxic potential,
antitumour activity, and, thus, the survival of the patient [233].
This patent disclosed some pharmaceutical compositions and their
preparation methods. The composition was said to be useful in
32. US 10, 344, 096B2 9 July 2019
inhibiting metastasis using receptor tyrosine kinase-like orphan
receptor1 antibodies (ROR1-antibodies) [234].
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Table 2. Cont.

This invention described surface-engineered human T-lymphocytes
33. US 10, 266, 592B2 23 April 2019 for augmenting the immune response. The designed molecules
helped mediate cellular immunotherapy and, thus, were an
effective strategy to treat cancer [235].
The use of proteins, peptides, and nucleic acids such as
34. US 10, 213, 499B2 26 February 2019 immunotherapeutic agents, either alone or in combination, was
presented. The peptides could either be peptide epitopes or bound
to molecules such as the major histocompatibility complex [236].
This invention reported substituted pyrazino [2,3-b] pyrazines as
35. US 10, 167, 290B2 1 January 2019 inhibitors of mammalian target of rapamycin (mTOR) kinase.
These compounds are used for the treatment of diseases such as
cancer, inflammation, or neurogenerative disease [237].
This patent explored the use of certain cells such as
immune-responsive cells, natural killer cells, T-lymphocytes,
and
36. US 10, 124, 023B2 13 November 2018 regulatory T-cells, which were capable of expressing an
antigen-binding receptor in the activation of immune cells. These
were single-chain variable fragments that bound to the antigens
with immunosuppressive activity, thereby reducing the suppressive
action of the antigen [238].
Certain novel compositions and methods to diagnose and treat
37. US2018/0222997 A1 9 August 2018 solid tumours by the use of antibodies were described. It was
said that the antibody was specifically bound to the extracellular
domain of the human Frizzled (FZD) receptors, thereby
inhibiting growth of tumour cells [239].
This invention described the methods and systems for determining
38. US 9, 920, 366B2 20 March
genetic variants and detecting double-stranded DNA [240].
2018
5. Conclusions
Breast cancer (BC) is one of the most prevalent diseases worldwide. However, ad-
vancements in science and technology have aided the development of methods for BC
diagnosis. They have also transformed the way BC is treated. As far as BC therapeutics
are concerned, a revolution was introduced by the use of the immune system as an
instrument. This led to the development of several promising BCVs, including
preventive, therapeutic, and fusion vaccines. Even though many strategies have been
employed to date, developing a cancer vaccine still remains challenging. The major
challenges faced when creating a cancer vaccine include inadequate immunogenicity,
tumour heterogeneity, poor antigen identification, and the health consequences.
An overview of the approaches for diagnosing BC, related treatments, vaccines, and
patents was included in the article to provide leads for future research. Thus, with the
advancements in research tools and new technologies, cancer vaccines may soon be a
reality.
Author Contributions: Conceptualization, S.K.S. and G.N.F.; Software, G.N.F. and H.F.; Resources,
S.K.S., G.N.F. and H.F.; Writing-original draft preparation, G.N.F. and H.F.; Writing, review and
editing, S.K.S., G.N.F. and H.F.; Supervision, S.K.S. All authors have read and agreed to the
published version of the manuscript.
Funding: No funding was received for preparation of this manuscript.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
2175
List of Abbreviations
AI artificial intelligence
APCs antigen-presenting cells
BC breast cancer
BCV breast cancer vaccine
CAD computer aided diagnosis
CAV carbohydrate antigen-based vaccine
CEA carcino-embryonic antigen
CT computed tomography
CTLA-4 cytotoxic T-lymphocyte antigen-4
CTLs cytotoxic lymphocytes
DCIS ductal carcinoma in situ
DCs dendritic cells
DCV dendritic cell-based vaccine
ER estrogen receptor
FDGePET/CT 18F-fluorodeoxyglucose positron-emission tomography
FZD receptors human Frizzled
GM-CSF granulocyte-macrophage colony-stimulating factor
HER2 human epidermal growth receptor2
h-TERT telomerase reverse transcriptase
ICB immune checkpoint blockers
IDC infiltrating ductal carcinoma
IFN-γ interferon-γ
ILC invasive lobular carcinoma
IORT intraoperative radiation therapy
IT immunotherapy
LCIS lobular carcinoma in situ
MANPs magnetic alloy nanoparticles
MDSCs myeloid-derived suppressor cells
MHC histocompatibility complex
MIAS Mammographic Image Analysis Society
miRNAs exosomal microRNAs
MMONPs magnetic metal oxide nanoparticles
MNPs magnetic nanoparticles
MRI magnetic resonance imaging
MRM multiple reaction monitoring
mTOR kinase mammalian target of rapamycin kinase
mtp53 mutation in the p53 gene
MUC-1 mucin-1
MW microwave
NK-cells natural killer cells
NPs nanoparticles
p53 tumour protein 53
PALP placental alkaline phosphatase
PCD programmed cell death
PCDL-1 programmed cell death ligand-1
PCDR-1 programmed cell death receptor-1
PET positron emission tomography
PR progesterone receptor
PRR pattern recognition receptors
PV peptide and protein-based vaccine
RFA radiofrequency ablation
ROR1-antibodies receptor tyrosine kinase-like orphan receptor1 antibodies
siRNAs small interfering RNAs
STn Sialy-Tn
TA thermal ablation
TAMs tumour-associated macrophages
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TCR T-cell receptor

TGF-β transforming growth factor-β
TILs tumour-infiltration lymphocytes
TLR toll-like receptors
TME tumour microenvironment
TNBC triple-negative breast cancer
Treg cells regulatory T-cells
TSA tumour-specific antigens
WTCV whole tumour cell-based vaccine
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diagnostics

Vaccines in Breast Cancer: Challenges and Breakthroughs

Keywords: breast cancer; diagnostics; biomarkers; therapeutics; vaccine strategies; antigens;

of the following therapies: immunotherapy, molecular-targeted therapy, cell cycle man-

3.2. Concepts in Designing of a Breast Cancer Vaccine (BCV)

Figure 1. The process of immunoediting carried out by cancer cells.

3.2.2. Immune Surveillance

3.2.3. Immune Suppression

3.2.4. Identification of the Antigen for BC Immunotherapy

Human Epidermal Growth (HER2) Receptor 2

Figure 2. Immune-suppression by tumour cells.

Tumour Suppressor p53 Protein (p53)

Carcinoembryonic Antigen (CEA)

Human Telomerase Reverse Transcriptase (h-TERT)

3.3. Design Approaches of a BCV

3.3.1. Peptide- and Protein-Based Vaccine (PV)

Figure 3. Mechanism of a peptide-based BCV.

Table 1. Clinical trials in the field of breast cancer vaccines.

NCT Number Antigens/Biological Clinical Phase

3.3.2. Carbohydrate Antigen-Based Vaccine (CAV)

3.3.3. Whole Tumour Cell-Based Vaccine (WTCV)

3.3.4. Dendritic Cell-Based Vaccine (DCV)

3.3.5. Gene-Based Vaccine

3.3.6. Fusion Vaccine

3.4. Adjuvants Used in Design of BCVS

ing on vaccination formulation, targeted tumour antigens, immunisation schedule, and

Figure 4. Diagrammatic representation of vector-based vaccines.

3.5. Routes of BCV Administration

3.6. Clinical Trials of BCVs

3.7. Combinational Therapy of BCVs

3.8. Challenges Faced during the Course of Development of BCVs

4. Recent Patents Filed/Granted on Cancer Treatment and Diagnostics

S. No. Patent Number Date of Publication Invention Disclosed

S. No. Patent Number Date of Publication Invention Disclosed

S. No. Patent Number Date of Publication Invention Disclosed

S. No. Patent Number Date of Publication Invention Disclosed

TCR T-cell receptor

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