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About the Editor
https://t.me/med1917
Nima Rezaei, MD, PhD, Professor Nima Rezaei
gained his medical degree (MD) from Tehran University
of Medical Sciences and subsequently obtained an MSc
in Molecular and Genetic Medicine and a PhD in
Clinical Immunology and Human Genetics from the
University of Sheffield, UK. He also spent a short-term
fellowship of Pediatric Clinical Immunology and Bone
Marrow Tr ansplantation in the Newcastle General Hospital. Prof. Rezaei is now the Full Professor of Immunology and Vice Dean of Research and Technologies,
School of Medicine, Tehran University of Medical
Sciences, and the co-founder and Head of the Research
Center for Immunodeficiencies. He is also the Founder
of Universal Scientific Education and Research Network
(USERN). Prof. Rezaei has already been the Director
of more than 100 research projects and has designed
and participated in several international collaborative
projects. Prof. Rezaei is the editor, editorial assistant,
or editorial board member of more than 40 international
journals. He has edited more than 50 international
books, has presented more than 500 lectures/posters in
congresses/meetings, and has published more than 1200
scientific papers in the international journals.
xixi
Interdisciplinary Approach
https://t.me/med1917
in Gastrointestinal Cancers
Khashayar Danandeh, Maryam Balibegloo, and Nima Rezaei
Abstract
Since the first studies around the cancers and their burden, gastrointestinal
(GI) cancers have been responsible for considerable rates of mortality and
morbidity through the years. They have remained incurable in many subtypes
despite significant development in diagnosis and therapies since their first-ever
diagnosis in the early nineteenth century. GI-related cancers constituted about
36% of all cancer-related deaths in 2020. GI system includes longitude sites from
the mouth to the anus with a variety of functions and features. Colorectal, gastric,
K. Danandeh
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran
Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific
Education and Research Network (USERN), Tehran, Iran
M. Balibegloo
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran
Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific
Education and Research Network (USERN), Tehran, Iran
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network
(USERN), Chicago, IL, USA
N. Rezaei (*)
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran
Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific
Education and Research Network (USERN), Tehran, Iran
Department of Immunology, School of Medicine, Tehran University of Medical Sciences,
Tehran, Iran
e-mail: rezaei_nima@tums.ac.ir
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2022_12
Published online: 30 August 2022
1
2 K. Danandeh et al.
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liver, esophageal, pancreatic, and gallbladder cancers are the six major GI
malignancies, in descending order regarding their incidence rates in 2020, worldwide. Recently, a better understanding of the genetic, epigenetic, and biology of
GI cancers has resulted in improved survival. Nevertheless, despite specific
biomarkers, biosensors, and selective para-clinic and laboratory data used in the
diagnostic approach, early diagnosis is challenging. Interdisciplinary studies over
immune-related cells and their interactions with gene expression and mutation in
the tumor microenvironment have recently added new insights into the diagnosis
and treatment. Although the combination of chemotherapy, immunotherapy, and
biological drugs provided a better survival rate than in the past, annual deaths are
among the most lethal cancers. Studies and experiments around GI cancers, their
causes, and optimal therapies are actively continuing.
Keywords
Chemotherapy · Gastrointestinal cancers · Immunoediting · Immunotherapy
1 Introduction
Cancer has remained a significant issue in human society throughout the world.
Considering all gastrointestinal (GI) cancers together, they have been reported to be
the leading cause of cancer-related deaths with the highest incidence, worldwide in
2020. Additionally, colorectal cancer (CRC) is the third most prevalent cancer being
responsible for the third most cancer-related deaths, as well in men. In women, CRC
is the second most common with the third-highest cancer-related deaths. Furthermore, gastric cancer is the third cause of cancer- related death globally (Sung et al.
2021).
In addition to the long longitude of the GI tract, including the mouth, oropharynx,
esophagus, stomach, liver, pancreas, biliary system, small intestine, and colorectum,
a large number of epithelial cells could increase the risk of cancer in this major
system. Some risk factors can play a significant role in the incidence of GI cancers
acting synergically such as adiposity (Murphy et al. 2018;O’Sullivan et al. 2018),
frequent alcohol consumption (Scherübl 2020; Yoo et al. 2021), and tobacco use
(Chen and Haber 2021). Meanwhile, dysbiosis of the gut microbiome may contribute to GI malignancy susceptibility (Weng et al. 2019).
The human immune system reacts to cancerous cells in two ways: by responding
to tumor-specific antigens (TSA) (molecules specific to cancer cells) or tumorassociated antigens (TAA) (molecules expressed differentially by cancer cells and
normal cells) (Finn 2008). Recent studies have demonstrated that immunity can
enhance cellular and molecular changes, inhibit or limit tumor expansion, and
modify tumor immunogenicity (Grivennikov et al. 2010). By a process known as
“cancer immunoediting”, a functional immune system may prevent, regulate, and
shape/promote cancer (Mittal et al. 2014). Dendritic cells (DCs), as one of the main
antigen-presenting cells (APC) initiating the cancer-immunity cycle, play an
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essential role in the modulation of innate and adaptive immune responses (Wculek
et al. 2020 ).
Esophagus and gastric cancers, being among the deadliest GI malignancies, have
poor prognosis by routine chemo/radiotherapy strategies. Nevertheless, novel
immunotherapies by targeting programmed cell death-ligand 1 (PD-L1) in addition
to defects in mismatch repair (dMMR) genes resulting in microsatellite instability
(MSI-H) phenotype make a new gate to these poor prognosis cancers (Vrána et al.
2019). Immunology provides a chance for scientifically driven treatment develop-
ment. The introduction of immune checkpoint inhibitors (ICIs) such as antibodies
against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death
1 (PD-1), and PD-L1 has developed a framework for cancer immunotherapy
(Andrews et al. 2019).
2 Primary Tumor Sites and Types of Gastrointestinal Cancers
GI cancers are on the list of most common primary tumors and malignancies and
they play a role in secondary and metastatic tumors. Different studies have classified
GI cancers in different ways based on various factors such as anatomic tumor sites
and upper and lower GI cancers, gene expression patterns, mutations, molecular
biomarkers, and cancer staging. Based on the GI circulation, the whole GI tract is
divided into two major parts: the lower and upper GI tract . The ligament of Treitz,
also known as the suspensory ligament of the duodenum, is the anatomic territory
that distinguishes upper and lower blood supply, so the cancer sites above the
ligament of Treitz are defined as upper GI cancers, including esophagus and gastric
cancers. The rest below the ligament, named lower ones, includes the duodenum,
liver, gallbladder, and colorectum (DiGregorio and Alvey 2020). Specific gene
alteration, expression, and distinct molecular landmarks have been recognized
through the years. Esophageal, gastric, and CRC are the primary malignancies
classified more in this category due to a higher proportion of morbidity and mortality. Specific genes are recognized in esophag eal, gastric, and CRCs including
vascular endothelial growth factor (VEGF), human epidermal growth factor receptor
2 (HER2), and epidermal growth factor receptor (EGFR) (Fakhri and Lim 2017).
3 History of Gastrointestinal Cancers
Cancer always has been a severe regret of general and health care society since it was
discovered. Moreover, GI cancers, as one among the highest-burden malignancies,
had a long history of diagnosing and therapies until today. Initiating from the most
upper part, esophageal cancer history goes back to ancient Chinese and Islamic
clinicians. In the middle of the nineteenth century, diagnosis improved so fast;
Vincenz Czerny (1842–1916) accomplished the first successful cervical esophageal
excision for cancer in 1877. Then in 1913, the first successful esophagectomy for
cancer was performed by Tohru Ohsawa (1882–1984) (Karamanou et al. 2017).
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Gastric or stomach cancer has been misdiagnosed in many cases through the earlier
part of the nineteenth century due to lack of direct examination. One of the most
historically contributed mortality which clarified a gastric cancer-related death was
Napoleon Bonaparte’s in 1821. He had the symptoms of a vague syndrome and
progressive epigastric pain. Finally, benign and malignant gastric ulcers were only
characterized by J. Cruveilhier in 1835. Nevertheless, great clinicians and scientists
like Avicenna have recognized gastric-related symptoms and gastritis since the
seventeenth century or even much sooner. Between the late nineteenth and early
twentieth centuries, clinicians and experts recognized the principal risk factors of
these cancers well. Direct examination of mucosa occurred by developing and
progression of autopsy and endoscopy. Besides the detection of gastric and duodenal
ulcers and Helicobacter pylori (H.Pylori) infection in many cases, many studies
proved the significant role of smoking, excessive alcohol consumption, and their
synergistic effect (Santoro 2005; Graham 2014).
The description of the pancreatic islets was named after Paul Langerhans in 1869
for the first time. Scattered evidence has been found regarding pancreatic neoplasms,
but pancreatic-related diseases remained unknown and incurable for many years.
Indeed, the very first insights into acute pancreatitis were obtained from Reginald
H. Fitz, a pathologist who explained the clinical features of acute pancreatitis in
1889. Because of being unknown, lack of direct observations, and challenging
accessibility, pancreas cancers were explored later than other GI cancers. Near the
late twentieth to early twenty-first centuries, diagnosis improved by the development
of para-clinic and laboratory data (Rustgi 2013; Navarro 2016). The investigations
on heredity and primary CRCs began in the late nineteenth century by Dr. Aldred
Warthin (Schlussel et al. 2014 ). Further genetic development and studies so far
helped to recognize the hereditary nonpolyposis CRC (HNPCC) well and described
a complete definition of CRC in the late twentieth century (Lynch et al. 1993; Matsui
et al. 2000 ).
4 Epidemiology of Gastrointestinal Cancers
GI cancers are almost always placed in the top list of global cancer incidence and
prevalence, with more than one-fourth of cancer population cases. According to the
GLOBOCAN 2020 study which estimated 36 kinds of cancers in 186 countries all
around the world, colon, stomach, liver, rectu m, and esophagus cancers are in the top
ten cancers with a higher incidence. The term Human Development Index (HDI),
defined by the United Nation’s 2019 Human Development Report, can demonstrate
the relation between high HDI regions and major risk factors such as adiposity and
smoking or alcohol consumption for GI cancers (Programme 2019). The incidence
of GI cancers varies significantly by geography, with colon cancers being more
common in Europe and Northern America. Norway and Hungary are the countries
with the highest incidence rates of colon cancers compared to all countries in females
and males, respectively. Rectal cancer is also distributed with almost the same
pattern. HDI is effective in both the incidence and prevalence of CRCs. According
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to recent studies, those countries with high or very high HDI are the leading regions
for CRCs. Unsuitable diet, obesity, and higher rates of smoking and alcohol users are
the main problems in high HDI countries (Dizdar and Kılıçkap 2019; Sung et al.
2021). Colon cancer is the top among all other GI cancers, with nearly 20% of the
whole GI-related new cases. Gastric, liver, rectal, esophageal, pancreatic, gallbladder, and anus cancers follow colon cancer in descending order (Lu et al. 2021; Sung
et al. 2021 ).
In contrast, stomach and liver cancer incidences are higher in Asia and/or Africa
(Sung et al. 2021). Smoking, alcohol, infections, hereditary factors, nutrition, and
obesity are major risk factors for GI malignancies. Changes in lifestyle and environmental variables and medical developments all have an impact on the epidemiology
of GI malignancies (Dizdar and Kılıçkap 2019). In addition, the 5-year prevalence of
all GI cancers showed that Japan had the highest rate in the whole world by 785 per
100,000 people (Fereidouni et al. 2020).
5 Mortality and Morbidity of Gastrointestinal Cancers
According to World Health Organization (WHO) estimates, cancer is the primary or
second major cause of death even after excluding patients with the age of 70 and
over in more than 110 countries over 183 in 2019, and one of the five top causes in
other nations (Bray et al. 2021). The health care system suffers a lot from the GI
cancer burden. CRC accounts for about 25% of GI-related mortalities. The other
top-five ones in descending order are liver (23%), gastric (21%), esophagus (15%),
and pancreatic (13%) cancers (Sung et al. 2021). CRC is responsible for the world’s
second cancer-related mortality with about 9% of all cancer deaths, with nearly one
million deaths in 2020. Meanwhile, liver (third), stomach (fourth), esophagus
(sixth), and pancreas (seventh) cancers are the next lethal ones with 8%, 8%, 5%,
and 5% of all estimat ed mortalities in 2020, respectively.
Eastern regions of Asia and Europe are responsible for the most GI-related
morbidity and mortality worldwide. Mongolia had the highest age-standardized
mortality rates in both sexes for all GI cancers with 130.1 deaths in every 100,000
people (Fereidouni et al. 2020; Sung et al. 2021). However, there is a strong
relationship between morbidity and mortality and specific risk factors of every GI
cancer. For instance, CRC associated with diet, alcohol use, and smoking increased
in the modern lifestyle and justified the burden raised in high HDI regions.
According to their subsites, stomach cancers are divided into two primary types:
cardia (upper part) and non-cardia (lower part). The main risk factor of non-cardia
stomach cancer is H.Pylori infection, accounting for nearly all occurrences. However, investigations have revealed two different causes for gastric cardia cancers;
some have named H.Pylori infection as the main reason. Nevertheless, others linked
it to the excess body weight and gastroesophageal reflux disease (GERD) injuries,
with adenocarcinoma-like properties.
A major kind of primary liver cancer is hepatocellular carcinoma (HCC),
constituting almost 80% of cases. Chronic hepatitis B (HBV) or C virus (HCV)
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infection, aflatoxin-contaminated foods, high alcohol consumption, obesity, type
2 diabetes mellitus, and smoking are the key risk factors for HCC, for which China
has the highest burden. The two major histologic subtypes are squamous cell
carcinoma (SCC) and adenocarcinoma. High alcohol consumption, heavy smoking,
and dietary components and behaviors are the main causes of SCC. For adenocarcinoma, excess body weight, Barrett’s esophagus, and GERD play key roles (Sung
et al. 2021 ).
6 Interdisciplinary Approach in Gastrointestinal Cancers
6.1 Interdisciplinary Approach in the Diagnosis
of Gastrointestinal Cancers
One of the most challenging issues around GI cancers is early diagnosing, which is
still not feasible in many cases. Despite science and technology development and
many confirmed molecular or laboratory biomarkers and other para-clinic data in
different kinds of GI cancer diagnoses, the mortality and 5-year survival rates have
remained concerning. Also, early-stage GI cancers have no distinct symptoms, so it
gives the opportunity to cancerous cells to move up into advanced and late poor
prognosis stages. Optimal diagnosis methods are unavailable, and accessible ways
have low specificity and sensitivity, such as detecting occult blood in the stool or
carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) as two
main biomarkers for diagnosing and follow-up monitoring. Serologic tests are
commonly used to diagnose a few cancers. The best example is α-fetoprotein
(AFP) which is mainly used for diagnosing HCC. Imaging data like computed
tomography scan (CTS), endoscopic retrograde cholangiopancreatography
(ERCP), and endoscopic ultrasound are chosen methods for additional
investigations. CRC is the most diagnosable GI-rela ted cancer among all GI
malignancies, with 95% of 5-year survival in early-stage diagnosis, while pancreatic
cancer with nearly 5% is the worst (Nannini et al. 2020). Endosonography (EUS)
and CTS are two para-clinic assessment ways that give data for the staging of
malignancies according to tumor node metastasis (TNM) classification. TNM
staging classification can give clear guidance for further treatment plans; however,
the prominent blind spot of this kind of staging is the final report. The final reports of
imaging data are strongly dependent on the radiology experts and professionals,
which increases the risk of bias and incorrect diagnosis (Cho 2015). There was a
long history of investigating DNA and RNA biomarkers or some inherited molecular
markers of genes such as CDH1 gene (encoding epithelial cadherin, E-cadherin) or
IL-1 gene. Furthermore, recognized GI cancer-related immune checkpoints and their
ligands are playing a crucial role in diagnosis and targeted immunotherapy (Radhika
et al. 2016). Epigenetic changes were the constant part of all cancers, including GI
cancers. Improper DNA methylation is the most common alteration in GI cancers.
Besides, histone and non-coding RNA modifications are both known as GI-related
epigenetic changes. There are several reports of aberrant DNA met hylation in blood
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and fecal DNAs in CRCs. The observation showed that in gastric cancer with the
EBV (Epstein-Barr virus) and H.Pylori infections, as two common risk factors, there
is a strong association between DNA promotor methylation and these risk factors.
Through the progression of neoplasms in Barrett’s esophagus, hypermethylation of
CDKN2A gene in addition to methylation of promotor in APC and ESR1 has been
detected. In pancreatic cancer, especially ductal adenocarcinomas, as the most
common subtype among all the others, NTPX2, SARP2, RPRM, and LHX1 have
been detected with significant epigenetic changes. Furthermore, wrong DNA methylation has been observed in biliary tract cancers such as cholangiocarcinoma as the
most prevalent subtype. The various methylation levels in TFPI2, NPTX2, and
CCND2 genes have been discovered in cholangiocarcinoma. In the group of genes
(CDH1, CDKN2A, GSTP1, RASSF1A, RUNX3, and WIF1), hypermethylation of
DNA is happened in HCC compared to healthy tissue (Vedeld et al. 2018). The use
of electrochemical nano biosensors for biomarkers miRNA 106A in the early
detection of GI cancer has already been described (Richardson et al. 2001). Nextgeneration sequencing technology has had some footprints as a novel method
through the years. Generation of Sanger sequencing, Maxam Gilbert sequencing,
and whole-genome sequencing (WGS) data analysis provided opportunities for early
diagnosis in some difficult situations and lighted hopes for improved survival. WGS
analysis demonstrated that integrated data with specific DNA genes such as BRCA1,
BRCA2, and PALB2 could precisely target the malignancies. MINT25, PRDM5, and
GDNF are also found in gastric cancers with high sensitivity and specificity. In
esophagus SCC, TFF1 methylation was reported as a potential early-diagnose
biomarker compared to the intact tissue. CD1D is one of the most potential genes
for diagnosing and comparing intact and cancerous tissue with acceptable sensitivity
and specificity. However, the main problem of epigenetic examination is time, at
least weeks to months lasts, to prepare the report of genetic data (Watanabe et al.
2009; Neelapu and Surekha 2016; Nakagawa and Fujita 2018).
The primary goal for any cancer is the earliest possible diagnosis to decrease
mortality and morbidity rates. Emerging biomarkers, biosensors, and computational
technologies are focused as most likely methods for early diagnosis. Moreover,
genetic and immune-related factor interactions are inseparable during cancer progression. These factors can play a momentous role in early diagnosis after many
failures by available methods. The suppression of the p53 gene and the expression of
CD44 aberrant transcripts are both frequent phenomena that can be used to diagnose
cancer (Tahara 1995). Gene expression/mutation can be a two-edged sword; for
instance, COX-1 is found in most tissues and is assumed to be responsible for
maintaining low levels of prostanoids. Nevertheless, COX-2 is an instant reaction
gene strongly inducible at sites of inflammation and is overexpressed in some
malignancies (Wang and DuBois 2018). Autophagy is one of the leading processes
during cancer growth; although it can be an inhibitor in the early stages, it helps the
cancer progress in the late phases. Detecting microRNAs (miRNAs) as a non-coding
regulatory RNA in tumor cells associated with the autophagy process in GI cancers
is a novel possible diagnosing biomarker (Pourhanifeh et al. 2020). HER2 is found in
the gastroesophageal junction. Mutations in the ERBB2 gene cause HER2
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overexpression, which leads to early-stage carcinogenesis. The MET, also known as
hepatic growth factor (HGF), is a receptor tyrosine kinase that stimulates many
signaling pathways. Activation of signaling cascades such as the HGF/c-Met signaling cascade has been identified as a prognostic and predictive marker for gastric
cancer. PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are immunological checkpoints regulating cellular brakes on T lymphocytes and acting as a
predictor biomarker for GI cancers. PD-1 biomarker overexpression detection is a
predictive immune checkpoint for some GI cancers (Bramhachari and Neelapu
2020). Also, advanced studies over epigenetic data in GI cancers with CRC as top
priority demonstrated a group of promising genes that could predict the early stages
of GI cancers. Epigenetic changes by DNA promoter methylation are detected in
novel genes, including CDO1, ZNF331, and ZSCAN18, with a higher correlation
with DCLK1 for CRCs (Marie Vedeld et al. 2015).
6.2 Interdisciplinary Approach in the Treatment
of Gastrointestinal Cancers
6.2.1 Approved Therapies
Immunotherapy has developed and altered cancer treatment plans during recent
years, yet remained disappointing for GI cancers. The implication of immunotherapy
in cancer treatment is based on the idea that cancer cells impair regulatory T-cellmediated immunosuppression as one of their key immune evasion mechanisms.
Tumor cells can utilize various strategies to evade the immune system. Tumors can
decrease cytotoxic T-cell activity by manipulating cytokines pathways that increase
T regulatory cells and myeloid-derived suppressor cells. All the processes result in
CD4 and CD 8 T cells being suppressed since they would not be able to identify
foreign antigens anymore. MHC class expression can also be lost, causing T
lymphocytes to lose their ability to identify them. Tumors can increase the expression of immune checkpoint molecules like PD-L1, causing peripheral T-cell exhaustion and malignant cell apoptosis inhibition. The discovery of immune-based therapy
changed the trends in treatment and prognosis in a promising way. A vast amount of
immunotherapy plans hold on the patients in different levels of cancers; interleukin
(IL)-2-activated lymphocytes, tumor-specific reactive CD8+ T-lymphocyte transfer,
DC vaccines, non-specific biological response modifiers (OK432,9 lentinan,10
PSK11), and TAA-derived peptides. All of these therapies have been effective in
contributed cases (Hazama et al. 2018; Golshani and Zhang 2020).
Immune Checkpoint Blockade
ICIs have been conventional immunotherapy for GI cancers since their first successful response in melanoma in 2011. In 2013, they were used in GI cancers for the first
time and showed many effective results in the patients. Immune checkpoint
molecules, of which PD-1 and CTLA-4 are the most well-studied ones, interact
with APCs and other cell types to prevent T cells from becoming overactive. PD-1 is
a CD28 family member that modulates the immune system by being expressed on
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activated T cells, B cells, and myeloid cells. When PD-1 is activated by its ligand
PD-L1, inhibitory signals are transmitted to T cells, resulting in the establishment of
peripheral tolerance. Pembrolizumab, nivolumab, and camrelizumab are three popular ICI agents examined in different trials on esophagus cancers; in addition, all
these drugs are approved by the Food and Drug Adm inistration (FDA) for GI
cancers. Statistics demonstrated a significant benefit in survival compared to routine
chemotherapy, especially in SCC. Both pembrolizumab and nivolumab prolonged
survival in advanced gastric cancer compared to chemotherapy alone. The CRC
predictor biomarkers, MSI-H/dMMR, also can be targeted by these anti-PD-1
antibodies and enhance survival significantly (Lu et al. 2020). Seventeen patients
with non-CRC dMMR GI malignancies were treated with pembrolizumab in a phase
II study. The study showed an objective response rate of 47% with four participants
reaching a complete response. However, there was not any clinical activity regarding
objective response rate in those with proficient MMR (pMMR). It is explained as
those with dMMR develop neo-antigens in response to genomic alterations which
are being identified by the immune system (Le et al. 2015).
CD73 and Adenosine Receptor Subtype
After significant development in immune-related treatment strategies for GI cancers,
anti-PD-1 and anti-CTLA-4 became one of the vastly used treatment plans with or
without chemotherapy and adjuvant therapies. Molecular studies demonstrated that
during the cancer progression and metastasis, CD73 and adenosine receptor subtype
(A2AR) are actively expressed compared to the normal tissue. Advanced studies on
targeting CD73 and A2AR by blocking the process significantly enhanced the
efficacy of anti-PD-1 and anti-CTLA-4 therapy. Furthermore, it even stopped and
slowed the progression of cancer growth and metastasis efficient ly. The results
around cellular immunotherapy were controversial. However, chimeric antigen
receptor (CAR)-T therapy as an adoptive T-cell therapy with antigens like EGFR,
HER2, CEA, and MUC1 has provided some excellent survival improvement in GI
cancers, especially in CRC (Ma et al. 2019 ).
Cancer Vaccination
Cancer vaccination has been used to generate an antitumor immune response that
can eradicate a tumor and offer continuous monitoring to prevent its regrowth in a
variety of tumor forms. Autologous, peptide, viral vector, and DC vaccines have all
been recruited in GI-related cancers in the last decade. Autologous vaccines are
made from cells taken directly from a patient’s tumor and, by definition, cover all
relevant TAAs. Autologous tumor cells, as opposed to single-peptide vaccinations,
can prevent tumor escape by eliciting adaptive immunity against several tumor
antigens. On the other hand, whole tumor cell vaccines have demonstrated minimal
therapeutic benefit since the majority of antigens are found in normal cells, and the
immune response elicited is not unique to cancer cell s. The justification for using
peptide vaccines is based on discovering and synthesizing antigenic epitopes
obtained from TAA or TSA that are 8–11 amino acids long. Peptide vaccines can
elicit particular T cells that fight TSA, and they can be used with adjuvants to boost
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