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Current Clinical Landscape of Immunotherapeutic Approaches in... 339
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the number of CD8+T lymphocytes inside the tumor tissue and in close proximity to
tumor cells (Feig et al. 2013; Carstens et al. 2017; Balli et al. 2017).
Dysfunctionality and exhaustion of intratumoral CD8
+
CTLs include loss of
effector function, expression of coinhibitory receptors such as PD-1, T-cell
immunoglobulin, and mucin domain 3 (TIM-3), and lymphocyte-activation gene
3 (LAG-3), and alterations to the transcriptional profile. In a pancreatic cancer
model, IL-18 receptor signaling controls tumor-reactive CD8
+
T lymphocyte
exhaustion by activating the IL-2/STAT5/mTOR pathway (Lutz et al. 2023).
3 Immunotherapeutic Approaches to Pancreatic Cancer
3.1 Oncolytic Virus Therapy (OVT)
OVT is a novel kind of immunotherapy in which a virus, after infecting and lysing a
cancer cell, stimulates or triggers an immune response in the patient by releasing
tumor antigens into the bloodstream (Nisar et al. 2022). The effectiveness and
specificity of oncolytic viruses make it a desirable treatment strategy. Different
oncolytic DNA and RNA viruses are now being researched and used to treat various
cancer types. These viruses’ genetic makeup allows them to infect cancer cells
(Lou 2003; Cerullo et al. 2012). T-VEC, a Herpes simplex virus (HSV), is the first
oncolytic virus that the US Food and Drug Administration (FDA) has authorized for
treating metastatic melanoma (Kaufman et al. 2015; Pol et al. 2016). The T-VEC
virus has the gene encoding GM-CSF genetically integrated (Fig. 2) (Kaufman et al.
2015). T-VEC showed significant lytic effects in vitro against many tumor cell lines,
including melanoma and pancreatic cancer cells (Toda et al. 2000; Kaufman et al.
2015). Additionally, in vitro and in vivo, NV1020 (r7020) and G207 (two types of
Fig. 2 Principles and mechanism of action of T-VEC oncolytic virus therapy in pancreatic cancer.
GM-CSF Granulocyte-macrophage colony-stimulating factor, DC Dendritic cell, HSV-1 Herpes
simplex 1, T-VEC Talimogene Laherparepvec. (This figure was created by Biorender.com)
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herpes simplex oncolytic viruses) efficiently infect and destroy human pancreatic
cancer cells. NV1020 was first designated as a vaccine against HSV-1 and HSV-2
infection for humans (McAuliffe et al. 2000).
Upregulated KRAS levels, a hallmark of PDAC, improve the oncolytic ability
of the Bovine Herpesvirus-1 against lung cancer (Cuddington and Mossman 2014).
An effective oncolytic virus against KRAS-mutant lung adenocarcinoma is
Coxsackievirus Type B3 (Deng et al. 2019). HSVs demonstrated enhanced proliferation compared to adenoviruses, whereas other oncolytic viruses revealed
unchanged behavior under hypoxia in malignant cells. Oncolytic viruses have
varying adaptabilities under hypoxia in cancerous cells (Hay 2005). Pancreatic
cancers are characterized by hypoxia, a key component of the PDAC environment
(Yuen and Díaz 2014). Combining a HIF-1α inhibitor with the H-1 oncolytic
parvovirus in pancreatic cancer boosted anti-tumor response and accelerated apoptosis (Cho et al. 2015).
An E1B gene deletion adenovirus called ONYX-015 (dl1520) is specifically used
in head and neck cancer and pancreatic cancer clinical studies. Indeed, the gene that
codes for the protein E1B, which may bind to and deactivate the pro-apoptotic
protein p53, has been deleted in ONYX-015 (Heise et al. 1997; Mulvihill et al. 2001;
Hecht et al. 2003). Hence, these viruses may cause p53-mediated apoptosis
in healthy cells, but they can persist in cancer cells that typically inactivate p53
(Kaufman et al. 2015).
VCN-01 is an oncolytic adenovirus. It was engineered to replicate in cancer cells
that have a defective RB1 pathway, produce hyaluronidase to accelerate viral
intratumoral dissemination, and enable the extravasation of chemotherapy and
immune cells into the tumor. VCN-01 demonstrated anticancer effects that were
enhanced after being combined with chemotherapy in PDAC animals. The production of hyaluronidase by VCN-01 destroyed tumor stroma and enhanced the delivery
of several therapeutic drugs, including chemotherapy and therapeutic antibodies
(Bazan-Peregrino et al. 2021). The findings of a clinical trial demonstrated that
intravenous administration of VCN-01 for treating patients with PDAC is possible
and is linked with predictable and controllable adverse events. The tolerability
profile of intravenous VCN-01 has been shown to be favorable (Garcia-Carbonero
et al. 2022 ).
HF10 is an HSV-1-derived oncolytic virus that has unde rgone spontaneous
mutation and can exert a substantial anti-tumor impact on cancers without harming
normal tissue. Locally advanced pancreatic cancer was treated safely with HF10
direct injection in combination with erlotinib and gemcitabine (Hirooka et al. 2018).
3.2 Adoptive Cell Transfer Therapy
Cancer patients may benefit from adoptive cellular therapy, a kind of immunotherapy that employs their own T cells and other immune system cells to combat the
disease. Patients’ immune cells are often collected, expanded, and even genetically
modified to better combat cancer. With the FDA’s approval of CAR T-cell therapy
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for certain patients with blood malignancies, this field has expanded greatly in recent
years. Manipulated T lymphocytes can detect tumor cells based on their unique
molecular signatures (Rosenberg et al. 2008; Morotti et al. 2021; Bear et al. 2021). In
the following, we will delineate these immunotherapeutic approaches.
3.2.1 Tumor-Infiltrating Lymphocyte (TIL) Therapy
The effectiveness of immunotherapy in treating metastatic melanoma has led to its
use against other cancers. A promising treatment paradigm is TIL therapy, which
employs the patient’s own TILs after surgical removal of the malignancy and
subsequent expansion of these cells in vitro before reinfusion. Twenty percent of
individuals with metastatic melanoma experienced a favorable response that lasted
more than 3 years after receiving this treatment (Rosenberg et al. 2011). Infiltration
of CD3
patients with gastrointestinal malignancies (Rusakiewicz et al. 2013). Patients with
PDAC that had CD4
+
T lymphocytes is linked to improved progression-free survival (PFS) in
+
and CD8+T lymphocytes had a considerabl y better prognosis
and a higher 5-year survival (Fukunaga et al. 2004; Ino et al. 2013; Sideras et al.
2014). A study indicated that expanded TILs from pancreatic tumors are functional
and have the ability to recognize pancreatic cancer-related antigens (tumorassociated antigens [TAAs] and tumor-specific antigens [TSAs]). Additionally,
blockade of the PD-1 receptor, activation of the 4-1BB (CD137) receptor, and
enrichment of CD8
+
T cells are all successful techniques for increasing TIL production and tumor reactivity (Hall et al. 2016). According to a meta-analysis, PDAC
patients’ long-term oncological prognoses are substantially correlated with certain
subsets of TILs, particularly CD3
+
, CD8+, and FOXP3+T cells (Orhan et al. 2020).
Two clinical trials are now in recruiting state, which are going to deploy TIL therapy
in patients with metastatic PDAC (NCT01174121 and NCT03935893).
3.2.2 Genetically Modified T Cells
TCR-Engineered T-Cell Therapy
TCR-engineered T cells are the result of the ex vivo engineering of T cells to express
TCRs specific for TSAs or TAAs. TCRs are able to identify peptides presented by
major histocompatibility complex (MHC) class I and II (Shafer et al. 2022; Baulu
et al. 2023). In hopes of developing TCR T-cell therapy that is both safe and
effective, the selection and screening of appropriate antigens are a crucial step.
The ideal antigen would include epitopes that were displayed on MHC class I
molecules on the surface of cancerous cells and would also be expressed
homogenously and selectively (Baulu et al. 2023). Two suitable targets for TCR
T-cell therapy of pancreatic cancer are MSLN and G12D. A phase I clinical trial
investigates the effectiveness and safety of autologous MSLN-specific TCR T cells
in patients with stage IV pancreatic cancer (NCT04809766).
A patient with metastatic PDAC was treated with autologous TCR-engineered
T cells. These manipulated T cells clonally express two allogeneic HLA-C*08:02–
restricted KRAS G12D. Significantly, the patient’s visc eral metastasis regressed (72%
overall partial response). Also, the therapeutic response continued for 6 months.
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Additionally, six months following the T-cell transfer, the modified T cells composed
more than 2% of all T cells that were circulated in the peripheral circulation (Leidner
et al. 2022). KRAS mutations are common in cancers. The most prevalent mutation of
KRAS is a single amino acid change called G12D, which is reported in various
malignancies, including PDAC (Zhang et al. 2022b;Melief2022).
CAR T-Cell Therapy
CAR T-cell therapy, which employs genetically modified T lymphocytes to target
cancer antigens, represents an exciting new frontier in tumor treatment (Fig. 3). While
CAR T-cell therapy has shown impressive clinical outcomes for treating particular
subgroups of B-cell leukemia or lymphoma, various obstacles prevent it from being
widely used to treat solid tumors and hematological malignancies. Life-threatening
toxicities, poor anti-tumor effectiveness, antigen escape, restricted trafficking, and
limited tumor penetration are all obstacles to successful CAR T-cell treatment.
Moreover, CAR T-cell functionality is significantly modified by interactions with
the host and TME (Sterner and Sterner 2021). The absence of appropriate TSAs is a
Fig. 3 A clinical overview of chimeric antigen receptor (CAR) T cells production, manipulation,
and how these cells attack cancerous cells. (This figure was created by Biorender.com)
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key barrier to the successful cellular immunotherapy of PDAC, particularly CAR
T-cell therapy. Schäfer et al. identified CD318, TSPAN8, and CD66c among
371 antigens as target candidates for CAR T-cell-based immunotherapy of PDAC
(Schäfer et al. 2021). Tables 1 and 2 summarize information on CAR T-cell therapy in
preclinical and clinical trial settings. In the following, suitable therapeutic targets for
CAR T-cell therapy of pancreatic cancer are highlighted.
B7H3 (CD276) B7H3 is a cell surface-expressed immune checkpoint molecule
with an immuno-inhibitory effect by dampening T-cell activation and NK cell
cytotoxicity. The fact that B7H3 is expressed at u nusually high levels in many
cancers but at low levels in healthy tissues makes it a promising new target for
CAR T-cell therapy (Seaman et al. 2017; Liu et al. 2021; Yan et al. 2023). Mice
treated with B7H3 CAR T cells demonstrated completed survival and no adverse
effects (Du et al. 2019), whereas in vitro studies indicated that these cells strongly
suppressed pancreatic ductal cancer cells (Du et al. 2019;Huetal.2022). The
administration of B7H3 CAR T cells (TAA06) in patients with neuroblastoma,
malignant melanoma, lung cancer, and colorectal tumor has been authorized in
clinical studies (NCT05190185 and NCT05562024).
Human Epidermal Growth Factor Receptor 2 (HER2) Simply put, HER2 is a
transmembrane glycoprotein that plays a pivotal role in cell proliferation and
differentiation at both the embryonic and adult stages of development. Inhibiting
apoptosis, inducing neovascularization, and enhancing cell motility are all ways in
which HER2 facilitates tumor development, proliferation, and metastasis (Yan et al.
2023). The remission of metastatic PDAC is mediated by CAR T-cell therapy with
potential safety (Raj et al. 2019). In a phase I trial, the safety and durability of HER2
CAR T cells for treating pancreatic tumors were proven (Feng et al. 2018).
Epidermal Growth Factor Receptor (EGFR) The transmembrane protein known
as the EGFR binds to members of the extracellular EGF family of proteins. Up to
90% of patients with PDAC have a detectable level of EGFR (Yeo et al. 2022). The
median overall survival (mOS) of all 14 patients treated with anti-EGFR CAR
T cells was 4.9 months, indicating the safety and efficacy of this therapy for patients
with metastatic pancreatic cancer (Liu et al. 2020).
Carcinoembryonic Antigen (CEA) Tumor antigen CEA, a tumor-associated glycoprotein, is continually generated by aggressive gastrointestinal cancers. The effectiveness of CEA-specific CAR T cells in conjunction with recombinant human IL-12
(rhIL-12) in treating various solid tumors was assessed. In vivo data demonstrated
that when anti-CEA CAR T cells are combined with rhIL-12, they greatly increase
their anti-cancer efficacy, as measured by growth inhibition of the pancreatic tumor
cell line AsPC-1, compared to CEA CAR T-cell treatment alone (Chi et al. 2019).
Furthermore, as a possible target for PDAC, CEACAM7 (also known as CGM2) is a
member of the CEA family of proteins expressed only in the colon and the pancreas.
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et al.
(2018)
(2020)
(2018)
et al.
(2018)
(2019)
Participants with
pancreatic cancer Phase NCT identifier Reference
Clinical outcomes
Combination
CAR’s structure and
Molecular
Table 1 Clinical evidence of CAR T-cell therapy in pancreatic cancer
(=number of patients)
PR=2, SD=3, PD=2 7 I NCT02541370 Wang
therapy
Nab-paclitaxel
+Cyclophosphamide
stimulatory domains
+Human CD137+CD3z
target
CD133 Anti-CD133 ScFv
PR=4, SD=8, PD=2 16 I NCT01869166 Liu et al.
PR=0, SD=0, PD=2 2 I NCT01935843 Feng et al.
Nab-paclitaxel
+Cyclophosphamide
Nab-paclitaxel
+Cyclophosphamide
– SD=2, PD=1 6 I NCT01897415 Beatty
+CD8a+CD137+CD3z
+CD137+CD3z
1BB+CD3z
EGFR Anti-EGFR ScFv
HER2 Anti-HER2 ScFv+CD8a
MSLN Anti-MSLN ScFv+4-
Cyclophosphamide – 5 I NCT02159716 Haas et al.
1BB+CD3z
MSLN Anti-MSLN ScFv+4-
EGFR Epidermal growth factor receptor, HER2 Human epidermal growth factor receptor 2, MSLN Mesothelin, ScFv Single-chain variable fragment, PR Partial
response, SD Stable disease, PD Progressive disease
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Table 2 Ongoing clinical trials of CAR T-cell therapy in pancreatic cancer
Molecular target Combination therapy
CCT301-59 – 18 I NCT03960060
CCT303-406 – 15 I NCT04511871
CD22 Autologous aPD-L1
CD70 Cyclophosphamide
CEA – 75 I NCT02349724
Claudin18.2 – 110 I, II NCT04404595
Claudin18.2/
CD19/BCMA/
GPC3
EGFR – 40 I, II NCT03182816
EpCAM – 60 I, II NCT03013712
EpCAM/
TM4SF1
GD2 – 100 I, II NCT02992210
HER2 – 220 I NCT04650451
MSLN – 18 I NCT03323944
MUC-1 – 9 I, II NCT03633773
PSCA Rimiducid 151 I, II NCT02744287
CEA Carcinoembryonic antigen, EGFR Epidermal growth factor receptor, EpCAM Epithelial cell
adhesion molecule, GD2 Disialoganglioside, TM4SF1 Transmembrane 4 L Six Family Member
1, HER2 Human epidermal growth factor receptor 2, MSLN Mesothelin, MUC-1 Mucin-1, PSCA
Prostate stem cell antigen, BCMA B-cell maturation antigen, PD-1 Programmed cell death protein
1, PD-L1 Programmed death-ligand 1, CAR Chimeric antigen receptor, GP3 Glypican 3
armored anti-CD22 CAR T
cells
+Fludarabine+Aldesleukin
– 40 I, II NCT04348643
– 5 I NCT02850536
PD-1 monoclonal antibody
+Chemotherapy
Fludarabine
+Cyclophosphamide
– 72 N/A NCT04151186
Pembrolizumab 48 I NCT04660929
– 45 I NCT03740256
– 30 I NCT02706782
– 40 I, II NCT03030001
Participants with
pancreatic cancer Phase NCT identifier
30 I NCT04556669
124 I, II NCT02830724
123 I NCT03874897
18 N/A NCT03302403
Remission in xenograft tumors is mediated by CEACAM7-specific CAR T cells,
which can selectively kill antigen-expressing cancerous cells (Raj et al. 2021).
Mesothelin (MSLN) CAR T cells can be manipulated to recognize MSLN, a cell
surface antigen involved in tumor invasion that is expressed at low levels in
mesothelial tissues, but at high levels in mesothelioma, PDAC, ovarian cancer,
lung cancer, and breast cancer (Yan et al. 2023). Tomar et al. have developed highly
effective anti-MSLN hYP218 CAR T lym phocytes with augmented tumor
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infiltration and persisten ce for treating solid tumors. In pancreatic cancer (KLM-1)bearing mice, rechallenging treated animals with KLM-1 tumor cells elicited antitumor immunity due to the survival of hYP218 CAR T cells (Tomar et al. 2022). The
treatment of patients with metastatic PDAC by concomitant targeting MSLN and
CD19 with CAR T cells was safe and well-tolerated (Ko et al. 2020 ). The effectiveness of MSLN-specific CAR T cells was proven in orthotopic human pancreatic
cancer animal models (Lee et al. 2022). A combination of MSLN-redirected CAR
T cells and TNF-α/IL-2-armed oncolytic adenoviruses leads to tumor shrinkage in
mice engrafted with highly aggressive PDAC (Watanabe et al. 2018).
Disialoganglioside (GD2) GD2 is localized on the outer cell membrane and forms
part of the immunological identity of mammalian cells; nevertheless, it does not
often trigger an immune response. Targeting the GD2 molecules with CAR T cells
directed against this molecule is possible since GD2 is expressed by many embryonal malignancies, including brain tumors, but is seldom expressed in normal
cells (Yan et al. 2023). A clinical trial investigated the effectiveness and safety of
GD2-specific CAR T cells in patients with solid tumors, probably including pancreatic cancer (NCT02992210).
Natural Killer Group 2D (NKG2D) The activating receptor NKG2D, present
in numerous immune effector cells, plays a crucial function in tumor
immunosurveillance. MHC I chain-related molecules A and B (MICA and MICB)
are two of the eight NKG2D ligands (NKG2D Ls). Six cytomegalovirus UL16binding proteins (ULBP1-6) are also other ligands. In contrast to their high expression levels in cancer cells, NKG2DLs are either missing or expressed at low levels in
healthy tissues (El-Gazzar et al. 2013; Fernández et al. 2015). The NKG2D receptor
is a promising target for malignant neoplasm immunotherapy. Thus far, NKG2Dspecific CAR T cells have been used to treat hematologic and solid tumor patients.
Researchers assessed the viability and safety of NKG2D-specific CAR T cells,
finding that their ability to proliferate and persist in vivo was limited. Gao and
colleagues have knocked down the 4.1R gene in NKG2D-specific CAR T cells,
enhancing the function of CAR T cells against pancreatic carcinoma (Gao et al.
2021).
Epithelial Cell Adhesion Molecule (EpCAM) The type I transmembrane glycoprotein EpCAM is overexpressed in carcinomas such as colon, stomach, PDAC, and
endometrial malignancies. It has been linked to the Wnt/β-catenin signaling pathway, whose activation is thought to lead to poor T-cell infiltration in various human
malignancies (Yan et al. 2023). Several clinical trials are registered to use EpCAMspecific CAR T cells in patients with pancreatic cancer (NCT04151186 and
NCT03013712).
Mucin-1 (MUC-1; CD227) The transmembrane mucin glycoprotein MUC-1 is
highly expressed at the apical surface of epithelial cells. The differentially glycosylated
form of MUC-1 is overexpressed in more than 80% of human pancreatic
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adenocarcinomas. Overexpression of MUC-1 is linked to bleak prognosis and augmented metastasis. Besides, MUC-1 promotes chemoresistance in pancreatic cancer
cells by upregulation of multidrug resistance genes (Nath et al. 2013). Anti-MUC-1
CAR T cells demonstrated target-specific cytotoxicity and effectively controlled tumor
growth in xenograft models of pancreatic cancer (Posey Jr. et al. 2016). Three clinical
trials were registered to use MUC-1-specific CAR T cells in patients with pancreatic
cancer (NCT02587689, NCT05239143, and NCT04025216).
CD133 Hematopoietic and epithelial cells both express the transmembrane glycoprotein CD133. In addition to being strongly expressed in PDAC cancer stem cells
(CSCs), CD133 has been discovered in various malignancies, including hepatocellular and gastric carci nomas (Yeo et al. 2022). In a phase I clinical trial, 7 patients
with PDAC received CD133-specific CAR T cells. Patients received cyclop hosphamide and nab-paclitaxel before receiving CAR T-cell infusion. Overall, there were
3 cases of disease stabilization, 2 cases of partial remission, and 2 cases of disease
development (Wang et al. 2018).
Prostate Stem Cell Antigen (PSCA) PSCA was first reported as a 123-amino-acid
glycophosphatidylinositol-anchored surface glycoprotein with an unidentified function that was substantially expressed in prostate cancers but had minimal basal
expression in the prostate epithelium, urinary bladder, kidney, esophagus, stomach,
and placenta. Subsequent research proved its increased expression in many human
cancers, including pancreatic cancer, but its absence in healthy pancreas. In a
humanized mouse model of pancreatic cancer, PSCA-specific CAR T cells induce
tumor elimination (Abate-Daga et al. 2014).
CAR-NK Cell Therapy
NK cells, which constitute 5–10% of peripheral blood lymphocytes, are a crucial
element of the innate immune system and play a pivotal role in our first-line defense
against infections and tumor cells. NK cells eliminate aberrant cells, such as those
damaged by viruses or cancer. NK cells are distinguished from T lymphocytes by the
expression of CD56 and CD16 on their surfaces rather than TCR and CD3. NK cells
are further split into two primary subsets based on the level of CD56 and CD16
expression: CD16
fraction predominantly present in the peripheral blood, and CD16
less mature and more immunoregulatory subset located in tissues (Basar et al.
2020; Myers and Miller 2021; Daher and Rezvani 2021; Laskowski et al. 2022).
There is a lack of decent information on CAR NK cell therapy against pancreatic
cancer. However, in an orthotopic mouse model of human PDAC, radiation therapy
was more effective when combined with CAR NK immunotherapy targeting
ROBO1 (Xia et al. 2019). Moreover, in a mous e model of pancreatic cancer, a
combination of CAR NK cells targeting MSLN and cyclic guanosine
monophosphate–adenosine monophosphate ([cGAMP]; a STING agonist) inhibited
tumor development and increased survival (Da et al. 2022). Furthermore, two
clinical trials are registered to use ROBO1 and MUC-1-specific CAR NK cells in
+
CD56
dim
, which represents a more developed and cytotoxic
-
CD56
bright
,a
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patients with pancreatic cancer (NCT03941457 and NCT02839954). PSCA has
recently been heralded as a target candidate for CAR NK cell immunotherapy of
pancreatic cancer. Results indicate the therapeutic effectiveness of PSCA-specific
CAR NK cells in human metastatic PDAC models without evidence of systemic
toxicity, giving reliable justification for clinical advancement in the future (Teng
et al. 2022 ).
Cytokine-Induced Killer (CIK) Cell Therapy
As a recent development in the area of cancer immunotherapy, CIK cell therapy is a
combination of therapeutic approaches centered on contr olling and co-opting a
patient’s cells to cure diseases. In vitro-grown T lymphocytes known as CIK cells
have two significant subgroups that make them distinct from other T lymphocytes. A
broad range of MHC-unrestricted anti-tumor activity may be elicited by the first
subset, which has a CD3
cancers. The second group, which has the phenotype CD3
+
CD56+phenotype, against both solid and hematologic
+
CD56-, more closely
resembles typical T cells (Meng et al. 2017). Adoptive transfer of CIK cells has
shown significant efficacy and safety for treating cancer, as evidenced by the longer
life of patients with various tumor types (Schmidt-Wolf et al. 1991; Takayama et al.
2000; Gammaitoni et al. 2013; Wang et al. 2014, 2015; Schmeel et al. 2015). CIK
cell therapy is more effective in preventing cancer recurrence and improving
patients’ prognosis when used in combination with chemotherapy (Wu et al. 2008;
Li et al. 2012; Pan et al. 2014). Furthermore, CIK cell therapy, according to research,
is effective in killing CSCs in both animal models and human patients (Gammaitoni
et al. 2013 ; Sangiolo et al. 2014).
The use of CIK cells as a second-line therapy for advanced pancreatic cancer has
recently been explored, and the results achieved have been promising, both when
used alone and in combination with other therapies. Patients receiving CIK cells with
gemcitabine-refractory advanced pancreatic cancer had a mOS of 6.2 months in a
phase II clinical study (Chung et al. 2014). Patients with gemcitabine-resistant
advanced pancreatic cancer who received CIK cell therapy plus S-1, an oral
fluoropyrimidine derivative, had a mOS of 6.6 months, which was longer than the
mOS of patients receiving S-1 alone (6.1 months) (Wang et al. 2013). OS is
improved in patients with advanced pancreatic cancer after CIK cell therapy
(Wang et al. 2016).
3.3 Immune Checkpoint Blockade (ICB)
A successful ICB approach, the foremost of which, is ipilimumab, which was
licensed in 2011, has led to emerging immunotherapy as a new mainstay of cancer
treatment. ICB prevents or reverses acquired peripheral tolerance to cancer antigens
by blocking receptors and ligands implicated in pathways that attenuate T-cell
activation, such as CTLA-4, PD-1, and PD-L1 (Fig. 4) (Korman et al. 2022).
Table 3 provides clinical trials of immune checkpoint inhibitors and immunomodulatory agents for treating pancreatic cancer.
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