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major factor that predi cts the efficacy of ICIs is the presence of tumor-infiltrating
lymphocytes (TILs). Studies have shown that tumors with more TILs in their TME
have a more favorable outcome. In gastric and esophageal cancers, it’s been
suggested that the density of TILs is higher in the early stages compared to advanced
stages. This discrepancy may stem from the selection of less immunogenic cancer
cell clones through tumor progression (Jindal 2018). Nevertheless, nivolumab and
pembrolizumab have been approved in the United States and Europe for treating
advanced esophageal, gastric, and colorectal cancer with mismatch-repair-deficient
and microsatellite instability-high (dMMR/MSI-H) disease (De Mello et al. 2019;
Boukouris et al. 2022).
3.2 Tumor Antigen Vaccine Therapies
In this method, TAAs are transported to the patient’s body in different ways; in one
way, TAAs are introduced to APCs and expressed on their surface. The treated
APCs and co-stimulatory adjuvants are then transported to the patient’s body.
Another way is by inserting TAAs’ genes in the genetic material of viral agents
and injecting these vectors into the patient’s body. Patients can also receive TAAs in
the form of peptides accompanied by immunomodulatory agents to induce an
immune response (Chudasama et al. 2021). Promising results have been
demonstrated by combining vaccines with chemotherapy in GI cancers; however,
there are still many challenges related to vaccine therapy such as immune tolerance
of TME and low specificity of TAAs in solid tumors (Rahma and Khleif 2011;
Chudasama et al. 2021).
3.3 Adoptive Cell Therapy (ACT)
This method is one of the primary passive immunization therapies. In this method,
T cells are collected from patients’ blood or tumor tissue, proliferated in large
numbers, and infused back into the patient’s body. TILs and CAR-T cells are the
two types of ACT (Dahiya et al. 2021).
4 CAR-T Cell Therapy
4.1 Anti-tumor Mechanism of CAR-T Cell Therapy
CAR-T cell thera py is one of the most innovative and promising cellular
immunotherapies rapidly evolving in the last decades (Dahiya et al. 2021). In this
method, T cells are first collected from the patient’s blood, then introduced to vectors
(viral or non-viral methods) carrying desired CARs genes, designed against the
patient’s tumor antigens. Subsequently, vectors transfer CAR genes to T cells to
express CARs on their surface. CAR-T cells are then proliferated to reach a
Immunotherapy in Gastrointestinal Cancer Focusing on CAR-T Cell Therapy 257
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therapeutic dose and are transfused to the patient (Zhang et al. 2016). In this way,
CARs are synthetic immunoreceptors consisting of an intracellular signaling
domain, a transmembrane d omain, a hinge, and an extracellular domain called
single-chain variable fragments (scFvs) (Lee et al. 2022). scFvs are the antigensensing components composed of two chains (heavy and light) of a high-affinity
monoclonal antibody (mAb) (Wang et al. 2013). Although numerous studies have
demonstrated the success rate of CAR-T cell therapy in hematologic malignancies,
the application of this method in solid tumors, including GI cancers, is limited by
several facto rs such as challenging infiltration of T cells to the tumor, their proliferation and steadiness in TME, and presence of diverse TAAs on solid tumor’s surface
(Bębnowska et al. 2020; Murad et al. 2021). Further, we discuss some of the most
studied TAAs in GI cancers targeted by CAR-T cells.
4.2 Targeted Antigens Expressed on GI Tumors
Mucin 1 (MUC1) is the first member of a high molecular weight glycoprotein
presenting on the apical surface of epithelial cells. MUC1 has three domains: an
extracellular domain protecting cells from the invasion of pathogens, a transmembrane domain, and an intracellular domain playing a role in signaling pathways
(Bose and Mukherjee 2020). Hyperglycosylated MUC1 presents abundantly on GI
cancer cells and correlates with metastasis and poor prognosis (Wang et al. 2016).
The hyperglycosylated state of MUC1 in GI cancers distinguishes them from MUC1
in normal cells, making them a suitable target for CAR-T cell therapy. For example,
tumor-associated MUC1 (tMUC) is overexpressed on roughly 85% of pancreatic
ductal adenocarcinoma (PDA). In this way, Yazdanifar et al. have achieved
promising results by designing CAR-T cells against tMUC1 (called TAB004derived CAR-T cells) in animal models of pancreatic ductal adenocarcinoma
(Yazdanifar et al. 2019).
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein
with intracellular and extracellular domains belonging to the adhesion molecule
family. Studi es have revealed that EpCAM overexpression on epithelial tumors’
surfaces plays a crucial role in tumor proliferation and metastasis (Bębnowska et al.
2020). EpCAM overexpression in GI cancer cells makes them a favorable target for
CAR-T cell therapy; in fact, there are some promising in vivo and in vitro studies
using CAR-T cell therapies against EpCAM in GI cancers such as gastric and
colorectal cancers (Zhang et al. 2019a; b; Li et al. 2021a; b).
Human epidermal growth factor receptor 2 (HER2) is a cell surface tyrosine
kinase and a member of the epidermal growth factor receptor (EGFR) family.
Binding of ligands to the extracellular domain of HER2 initiates pathways leading
to carcinogenesis, tumor proliferation, and metastasis. In this way, its overexpression
correlates with poor prognosis of various cancers, including GI cancers (Budi et al.
2022). In fact, in HER2-positive gastric and colorectal cancers, HER2-specific
CAR-T cells have completely eradicated the tumoral cells (Budi et al. 2022).
In addition, clinical trials have reported more than 50% survival rate by using
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HER2-specific CAR-T cells as an adjuvant in treating biliary tract and pancreatic
carcinoma (Siddiqui and Sardar 2021).
Carcinoembryonic antigen (CEA) is a glycoprotein involved in cell adhesion. It
is expressed by the luminal epithelium of the GI tract and lung. It is widely used as a
marker for cancer diagnosis, prognosis, and recurrence. CEA in CAR-T cell therapy
has attracted attention due to its different status in cancer cells compared to normal
cells. Unlike normal cells, which express CEA only on apical surfaces, cancer cells
express CEA all over their surface (Klein et al. 2017). The safety and efficacy of antiCEA-specific CAR-T cells in GI cancers, including gastric, pancreatic, and colorectal cancers, are being studied in clinical trials; however, the overall improvement in
the survival has been low compared to hematologic malignancies (Umut et al. 2021).
B7 family is a group of co-stimulatory or co-inhibitory proteins regulating T cell
response to tumor cells. Studies have shown various and controversi al expression
levels of B7 family members in the cancer cell, and their role in the prognosis of GI
cancers is not established yet (Sadelain et al. 2013). For instance, overexpression of
B7H6, a B7 family member, has been reported in gastrointestinal stromal tumors
(GISTs), playing as a ligand for the natural killer cell-activating receptor, NKp30.
B7H6 has also shown an antiapoptotic role, leading to tumor proliferation of
hepatocellular carcinoma. Subsequently, B7H6-specific CAR-T cells have resulted
in increased cytotoxicity and less tumor burden in some B7H6-positive cells (Brandt
et al. 2009; Chen et al. 2018). Also, in gastric cancer, higher expression of B7H6
correlates with a better prognosis (Li et al. 2020) (Table 2).
5 Side Effects and Limitations of CAR-T Cell Therapy
Despite the promising results of CAR-T cell therapy, this method is not the first-line
cancer treatment. This is partly due to some acute and chronic related toxicities,
which are life-threatening if not managed properly (Adkins 2019). Here we discuss
the most critical side effects and limitations that we face in this method.
5.1 Side Effects
Cytokine Release Syndrome (CRS) CRS, one of the most common CAR-T cellrelated adverse event, is a systemic inflammatory response to the high concentration
of cytokines. This syndrome occurs between the first day and the third week after
CAR-T cell infusion, manifesting as high-grade fevers, hypotension, hypoxia, and
even organ failure (Adkins 2019). The exact mechanism of CRS following CAR-T
cell therapy underlies the process by which CAR-T cells kill tumor cells. As we
mentioned earlier, the scFv of CAR-T cells is the site of detection and junction with
TAAs. Following this connection, CAR-T cells become activated and secrete
cytokines such as perforins, granzymes, interferon-γ (IFN-γ), and tumor necrosis
factor (TNF). Modified versions of CAR-T cells can also produce more cytokines
because of their co-stimulatory domain (Hay et al. 2017; an et al. 2021). Following
Immunotherapy in Gastrointestinal Cancer Focusing on CAR-T Cell Therapy 259
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Table 2 Antigens targeted by CAR-T cell therapy in gastrointestinal cancers
Antigen Other names
MUC1 episialin, PEM,
MSA, CA15-3,
KL6, DF3,
MAM-6, PUM,
CD227, PAS-0, and
CAM 123-6
EpCAM CD326 Preclinical,
HER2 ErbB2 Preclinical,
CEA -- Preclinical,
MUC1 mucin 1, EpCAM epithelial cell adhesion molecule; HER2 human epidermal growth factor
receptor 2, CEA carcinoembryonic antigen
Phase of
studies Cancers References
Preclinical,
clinical
clinical
clinical
clinical
Cholangiocarcinoma,
pancreatic cancer,
gastric cancer,
esophageal cancer,
hepatocellular
carcinoma, Gastric
cancer, breast cancer
Gastric cancer,
colorectal cancer,
pancreatic cancer
Pancreatic cancer,
biliary tract cancer,
gastric cancer,
colorectal,
esophageal cancer
Liver cancer,
colorectal cancer,
pancreatic
carcinoma, gastric
cancer
Posey Jr. et al.
(2016), DeSelm
et al. (2017),
Yazdanifar et al.
(2019), Zhang et al.
(2020), Supimon
et al. (2021), Zhai
et al. (2021)
Zhang et al. (2018a),
b), Ma et al. (2019),
Zhang et al. (2019a),
b), Zhou et al.
(2019), Li et al.
(2021a), b), Yang
et al. (2021), Staudt
et al. (2022)
DeSelm et al.
(2017), Feng et al.
(2018), Song et al.
(2018), Yu et al.
(2021)
Chmielewski et al.
(2012), Katz et al.
(2015),
Thistlethwaite et al.
(2017a),
et al. (2017), Zhang
et al. (2018a), b),
Chi et al. (2019),
Hombach et al.
(2019), Cha et al.
(2021), Fan et al.
(2021), Kumar et al.
(2021), Raj et al.
(2021)
b), Zhang
the cytokine release, immune and nonimmune cells such as epithelial cells get
activated and secrete more cytokines. A key cytokine in CAR-T cell-associated
CRS is IL-6 because its secretion depends on the connection between CAR-T cells
and tumor-specific macrophages (Hunter and Jones 2015). Targeting these cytokines
in the proper time and setting may improve the disease outcome.
Clinical manifestation of CRS depends on its stage. Mild CRS presents with fever,
fatigue, headache, rash, and myalgia, while severe CRS symptoms are tachycardia,
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hypotension, circulatory collapse, respiratory failure, and multi-organ failure (Chen
et al. 2019). Mild to moderate symptoms can be managed by supportive care, while
more severe cases may need immunomodulatory agents (Le et al. 2018).
Neurotoxicity Neurologic adverse effects may present 1–3 weeks after CAR-T cell
infusion (Gust et al. 2017). The pathogenesis of neurologic toxicity is not established
yet; however, it is believed that endothelial cell damage caused by inflammatory
cytokines may be one mechanism. In this way, it is shown that a high concentration
of cytokines such as TNF-alpha, IL-6, and IFN-γ could activate endothelial cells,
causing the production of a great amount of angiopoietin (Ang)-2 and von
Willebrand factor (VWF) (Kometani et al. 2014; Hu et al. 2016). Subsequently,
these two factors increase the permeability of the blood-brain barrier (BBB) and the
development of cerebral edema (Adkins 2019). Additionally, damaged BBB results
in leakage of inflammatory cytokines and CAR-T cells to brain tissue, supported by
the observation of these cells in cerebrospinal fluid (Mackall and Miklos 2017;
Johansson et al. 2021). Following the leakage of cytotoxic cells to the central
nervous system, these cells’ direct toxic effect on neural cells manifests as neurotoxicity. The clinical manifestation of neurologic effects varies, influenced by several
factors, including target antigen selection and infused cell dose (Gust et al. 2017).
Symptoms range from confusion, diminished attention, and disturbance in language
and writing to paralysis, seizure, or even death (Santomasso et al. 2018; Gajra et al.
2019). Furthermore, due to the inability of many immunomodulatory agents to cross
the blood-brain barrier, managing severe cases is more challenging and may be
limited to corticosteroids (Santomasso et al. 2018; Adkins 2019).
5.2 Limitations
Disease Relapse Besides the promising results of CAR-T cell therapy, reports of
the disease relapse in patients treated with this method have opened a new window
towards the immune system and CAR-T cell mecha nism. One mechanism proposed
for the disease relapse is antigen do wnregulation or antigen loss escape in the later
phase of treatment. In this way, studies have shown that relapsed tumor cells express
previously CAR-T cell-targeted antigens at lower or zero levels (Li et al. 2018). The
mechanism proposed for antigen loss is either by producing tumor cells phenotypically similar to the previous tumor type, only lacking the CAR-T targeted antigen, or
by the emergence of phenotypically different tumor cells genetically related to the
previous tumor cells (Majzner and Mackall 2018). Additionally, antigen loss escape
may be achieved by trogocytosis, defined as a phenomenon by which CAR-T cells
capture targeted TAAs and shift target antigens into their own cell, reducing the
number of expressed TAAs on targeted tumor cells (Hamieh et al. 2019). In contrast
to natural immune systems’ T cells, which recognize even low-expressed antigens,
CAR-T cells require a minimum expression level to detect antigens (Majzner and
Mackall 2018).
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Furthermore, antigen-positive relapse is an early phase cause of disease relapse,
stemming from inadequate removal of tumor cells. The most common factors
responsible for this type of relapse are poor quality and quantity of T cell collection,
inefficacious production of CAR-T cells, higher tumor burden, conditioning regimen
for T cell persistence, and the recipient’s immune system response (Nie et al. 2020).
One proposed strategy to overcome incomplete removal of tumors is to target
multiple antigens instead of one. This technique is more productive in solid tumors
expressing heterogeneous antigens (Bielamowicz et al. 2018).
On-Target, Off-Tumor Toxicities CAR-T cells target antigens overexpressed on
the tumor cells, but most of these antigens are not tumor-specific and are expressed
on normal tissues, as well. On-target, off-tumor toxicity occurs when normal cells,
along with tumor cells, are targeted by CAR-T cells. This complication is more
prevalent in solid tumors because, unlike hematologic tumors, which express only
specific TAAs, solid tumors overexpress heterogenous antigens that have lower
expression levels on healthy cells (Zhang et al. 2016). For example, a clinical
trial about the efficacy of CEACAM5-specific CAR-T cells in GI tumors by
Thistlethwaite et al. was prematurely terminated due to the progression of transient
and acute respiratory complications. The expression of CEACAM5 on lung epithelium was accused of this toxicity (Thistlethwaite et al. 2017a; b). Interestingly, using
low-affinity CAR-T cells has shown anti-tumor activity against overexpressed
antigens on tumor cells compared to their inactivity against norm al cells, which
express the same antigen at a normal level (Yang et al. 2020).
6 How to Improve the Safety of CAR-T Cell Therapy?
As we mentioned earlier, although CAR-T cell therapy is a highly potential technique in cancer treatment, several obstacles limit its administration in clinical
studies. In this way, scientists seek ways to reduce this method’s toxicity while
improving its specificity. Suicide gene switch, multi-target-antigen therapy, synthetic notch receptors, inhibitory chimeric antigen receptors, bispecific T cell
engager, and on-switch CAR are some examples (Yu et al. 2019). Here, we mention
two developing methods.
6.1 Immune Inhibitory Receptors
As we mentioned earlier, PD-1 and CTLA-4 play an important role as inhibitory
receptors in reducing and eliminating T cell responses (Curran et al. 2010). Inhibitory chimeric antigen receptors (iCAR) are CARs containing PD-1 and CTLA-4
inhibitory signaling domains, along with scFv designed to detect antigens specificto
normal tissue, not tumor cells. Designing T cells possessing both TAA-specific
CARs and iCAR has shown reduced off-tumor toxicity due to the initiation of
inhibitory signaling in CAR-T cells targeting normal cells (Fedorov et al. 2013).
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6.2 On-Switch CAR
An extracellular scFv, co-stimulatory domain, and a key downstream signaling
element together form the on-switch CAR. The CAR-T cells’ therapeutic activity
depends on the antigen’s recognition and the junction of a small priming molecule.
Small priming molecules control the time, region, and dosage of T cell activity to
relieve the toxicity. Furthermore, on- and off-switch CAR-T cell has been developed
by Jan et al., in which degradable tags are incorporated into CAR to initiate
lenalidomide or other thalidomide analog-induced CAR degradation (Jan et al.
2021).
7 Conclusion
Along with the remarkable success of different types of immunotherapies, scientists
are investigating tactics to increase these methods’ effectiveness. The most important immunotherapies in GI cancers are ICIs, vaccine-based therapies, and ACT,
including CAR-T cell therapy. CAR-T therapy has demonstrated significant efficacy
compared to conventional treatments; however, the success of this method in GI
cancers and other solid tumors compared to hematologic tumors is in its infancy.
Using the specific features of solid tumors, for example, designing multi-targeted
CAR-T cells against the more heterogeneous TAA s in solid tumors, has shown
promising results. More research is still needed to reveal solid tumors’ specific
features and design a more ef ficacious CAR-T cell with less toxicity.
Acknowledgment None.
Ethical Statement The manuscript does not contain clinical studies or patient data.
Conflict of Interest The authors declare that they have no conflict of interest.
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