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Preclinical/
clinical reference
(2013), Sanford
et al. (2013)
(2016)
(2020), Lin et al.
(2020)
(2020), Lin et al.
(2020)
(2014)
(2014)
(2019)
(2019), Grauel
et al. (2020)
(2019), Steele
et al. (2021)
Molecular target/
drug Cellular target Combination therapy Participants Phase NCT identifier
40 I,II NCT03496662 Mitchem et al.
Gemcitabine+Nab-
paclitaxel
Nivolumab 20 I NCT04477343 Steele et al.
MDSCs
CCR2/BMS-813160 M-MDSCs Nivolumab+
CXCR2/SX-682 PMN-
132 I NCT03329950 Hegde et al.
- 24 II NCT04536077 Hegde et al.
Conventional
FLT3L and CD40
Pembrolizumab
DCs
agonists/ CDX-301
and CDX-1140
10 II NCT02754726 Sherman et al.
112 I,II NCT03520790 Sherman et al.
+Chemotherapy
paclitaxel
Nivolumab+Albumin-
168 II NCT03563248 Murphy et al.
bound paclitaxel
+Cisplatin+Gemcitabine
ATR2/Losartan CAFs FOLFIRINOX
165 II NCT04390763 Huang et al.
+Nivolumab
+Radiotherapy+Surgery
+Gemcitabine+Nab-
TGF-β/NIS793 CAFs Spartalizumab (PDR001)
10 I NCT04581343 Biffi et al.
paclitaxel
paclitaxel+Gemcitabine
CAFs Spartalizumab+Nab-
IL-1β/Canakinumab
(ACZ885)
Targeting
Therapeutic
Table 6 Active clinical trials of immunotherapies based on targeting myeloid cells and cancer-associated fibroblasts in pancreatic cancer
immunosuppressive
approach
myeloid cells
Reprogramming
DCs
Targeting CAFs VDR/Paricalcitol CAFs Gemcitabine+Nab-
Inhibiting TGF-β
activity
Inhibiting IL-1β
signaling
derived suppressor cell, PMN-MDSC Polymorphonuclear myeloid-derived suppressor cell, ATR2 Angiotensin II receptor, DC Dendritic cell, VDR Vitamin D
receptor, FLT3L Fms-related receptor tyrosine kinase 3 ligand, TGF-β Transforming growth factor beta, IL-1β Interleukin-1 beta
CCR2 C-C Motif chemokine receptor type 2, CXCR2 C-X-C Motif Chemokine Receptor 2, CAF Cancer-associated fibroblast, M-MDSC Monocytic myeloid-
360 P. Farhangnia et al.
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et al. 2020). However, anti-CD40 mAb APX005M (sotigalimab) did not improve
clinical outcomes in a phase II trial, indicating that T-cell-priming function related to
anti-CD40 mAb in human PDAC might not represent its fundamental mechanism of
action (O’Hara et al. 2021). In mice treated with the nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) modulator LCL-161, macrophages that
phagocytize and kill pancreatic tumor cells were described. This was accomplished
by reprogramming macrophages to produce lymphotoxin from T cells (Roehle et al.
2021; Hosein et al. 2022).
CD47, often known as the “don’t eat me” ligand, is expressed on cancer cells and
can impede phagocytosis by engaging signal regulatory protein-α (SIRP-α)on
macrophages. However, blocking CD47 by itself has minimal impact on most
solid tumors because it does not provide a prophagocytic response (Chao et al.
2010; Weiskopf et al. 2013; Sockolosky et al. 2016; Feng et al. 2019). Alterations in
the pivotal carbon metabolism of macrophages are evoked by stimulation with a
CpG oligodeoxynu cleotide, an agonist for the TLR9. These changes make it conceivable for macrophages to engage in anti-cancer activities, including engulfing
+
CD47
cancer cells (Liu et al. 2019).
Signal transduction by colony-stimulating factor 1 receptor (CSF1R) in
macrophages may be a worthwhile therapeutic target for reprogramming the
immunosuppressive milieu in human PDAC tumors and improving the therapeutic
effectiveness of immunotherapy. TAMs are eliminated from pancreatic tumors when
the CSF1/CSF1R signaling pathway is blocked, and the remaining macrophages are
reprogrammed to enhance anti-tumor immunity. The CSF1/CSF1R blockage
improves anti-tumor interferon responses, boosts CTL infiltration, and prevents
tumor growth (Zhu et al. 2014).
3.5.2 Targeting CAFs
Most chemokines that attract myeloid cells come from activated fibroblasts. A
renewed interest in broadly targeting subgroups of fibroblasts or their secreted
products has emerged despite failing to target PDAC CAFs (Hosein et al. 2022).
mAbs directed against TGF-β have a wide range of effects on immune responses,
including a reduction of intratumoral fibroblasts, a lowering of CD8
sion, and a lessening of myeloid cell infiltration (Mariathasan et al. 2018; Huang
et al. 2019; Grauel et al. 2020). A phase II clinical trial is now assessing the
effectiveness of combining gemcitabine, nab-paclitaxel, and PD-1 inhibitor
(spartalizumab) with an anti-TGF-β mAB (NIS793) in patients with PDAC
(NCT04390763). Furthermore, nivolumab (anti-PD-1 mAb) and chemoradiotherapy
(FOLFIRINOX [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus stereotactic body radiotherapy [SBRT] ) are now being investigated in advanced PDAC, and
the angiotensin II receptor antagonist (losartan) is thought to have a role in reducing
TGF-β expression (Murphy et al. 2019). Vitamin D may also promote quiescence in
fibroblasts (Hosein et al. 2022). In this regard, for patients with advanced PDAC,
two phase II trials are now recruiting participants: one combining paricalcitol
with gemcitabine and nab-paclitaxel (NCT03520790) and the other combining
nivolumab with gemcitabine, paclitaxel, and cisplatin (NCT02754726).
+
T-cell repres-
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The macrophages and granulocytes in PDAC vigorously produce IL-1β, which
has pleiotropic effects on the TME, including promoting the development of inflammatory CAFs, which in turn generate IL-6 and have been shown to promote an
immunoregulatory microenvironment and tumor cell longevity (Biffi et al. 2019;
Steele et al. 2021). PDAC tumor cells may also generate IL-1β, and blocking IL-1β
has synergistically favorable effects with blocking PD-1 in preclinical studies (Das
et al. 2020). A phase I trial is now evaluating the effectiveness of gemcitabine and
nab-paclitaxel in combination with the IL-1β-blocking mAb (canakinumab) and the
PD-1-blocking mAb (spartalizumab; NCT04581343).
Cancer cell s and CAFs both have high levels of expression of the prolyl isomerase PIN1 (Koikawa et al. 2021). Several oncogenic pathways are promoted by PIN1,
which controls the conformational change in the phosphorylated Serine/ThreonineProline motif (Yeh and Means 2007; Zhou and Lu 2016). Therefore, blocking PIN1
with drugs has been considered to be an effective approach to combating cancer
(Koikawa et al. 2021; Liu et al. 2022). Several small molecule drugs, including
all-trans retinoic acid (ATRA), arsenic trioxide, juglone, AG17724, KPT-6566, and
sulfopin, have been found as PIN1 inhibitors and have been applied or repurposed to
study PIN1 functions in oncogenesis (Liu et al. 2022). Promising results are shown
in the phase I clinical trial of chemotherapy with ATRA for patients with metastatic
PDAC (Kocher et al. 2020). In PDAC models, the addition of ATRA to arsenic
trioxide or sulfopin treatment induces a quiescent CAF state and reduces the forming
of adhesions or fibrous connective tissue within the tumor. Furthermore, PIN1
inhibition results in decreased degradation of the gemcitabine plasma membrane
transporter (ENT1), increasing chemosensitivity, and it may synergize with immunotherapy (Dubiella et al. 2021; Koikawa et al. 2021). Subcutaneous and orthotopic
pancreatic cancer models showed decreased tumor development when treated with
DNA-barcoded micellular system encapsulating the PIN1 inhibitor AG17724, antiFAPα mAb, and T CD8
+
lymphocytes-recruiting DNA aptamer (Liu et al. 2022).
Placental growth factor (PlGF) is a member of the VEGF family and is mainly
expressed in the placenta (Chau et al. 2017). Improvements in survival were
observed in animal models of intrahepatic cholangiocarcinoma after blocking
PlGF, which enriched quiescent CAFs and decreased desmoplasia (Aoki et al.
2022). PlGF enhances murine liver fibrosis and promotes tumor angiogenesis,
improving cancer cell metastasis and invasion (Kim et al. 2022). PlGF is upregulated
by chemotherapy, which directly triggers CAFs to generate the extracellular matrix
(ECM) in PDAC. Using a combinatorial therapeutic strategy and the VEGF decoy
receptor, targeting CD141
+
CAFs with atezolizumab (an anti-PD-L1 mAb)-directed
PlGF/VEGF inhibition enhances the efficacy of chemotherapy in pancreatic cancer
(Kim et al. 2022 ).
3.5.3 Reprogramming Dendritic Cells
While efforts to revitalize exhausted T cells have shown some success in pancreatic
cancer, it is still unclear whether endogenous T-cell depletion or a lack of T-cell
priming is the primary problem in patients with PDAC (Vonderheide 2018; Hosein
et al. 2022). Cross-presenting type 1 conventional dendritic cells (cDC1s) are
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essential for priming tumor-specific CD8+T lymphocyte responses, as shown by
studies in mice, but they are in insufficient abundance in pancreatic cancer (Hegde
et al. 2020; Lin et al. 2020). PDAC mouse models had significantly fewer CD103
cDC1s than lung adenocarcinoma mouse models. Mouse models of PDAC have
been sensitized again to CD40 agonist antibody and radiation therapy after receiving
FMS-like tyrosine kinase 3 ligand (FLT3L) treatment, which increases the number
of intratumoral cDC1s (Hegde et al. 2020). Early-stage clinical studies with the
CD40 agonist antibody CDX-1140 in conjunction with FLT3L (CDX-301) in
PDAC and other solid tumors are now underway. Results will soon reveal whether
or not the treatment is safe and effective (NCT04536077 and NCT03329950).
DC function may also be altered by tumor cells and TME intrinsic factors. By
inhibiting cross-priming of T cells, DCs invaded by tumor cells may, for instance,
promote β-catenin signaling. Tumor-infiltrating DCs synthesize retinoic acid
through vitamin A metabolism (Guo et al. 2019). Accumulation of lactic acid occurs
during active glycolysis in cancer and stromal cells. Additionally, activated DCs
have a greater need for glucose and generate more lactate (Peng et al. 2021). An
increase in lactate levels in the TME has been shown to impede the activation and
antigen presentation of DCs. The DC phenotype may be influenced by the lactic acid
produced by the cancer cells, which can contribute to tumor evasion (Gottfried et al.
2006).
Tumor-derived molecules, including triglycerides, cholesterol esters, and fatty
acids, inhibit DC cross-presentation of tumor antigens by downregulating the production of peptide-MHC class I complexes (Cao et al. 2014; Xiang et al. 2023).
Compared to DCs from tumor-free mice and healthy humans, a significant percentage of DCs in tumor-bea ring mice and people with cancer have high levels of
triglycerides (Herber et al. 2010). Upregulation of scavenger receptor A led to
enhanced absorption of extracellular lipids, which led to lipid buil dup in DCs.
High-lipid DCs were unable to deliver TAAs or trigger allogeneic T lymphocytes.
The functional activity of DCs was restored by pharmacologically normalizing lipid
abundance using an inhibitor of acetyl-CoA carboxylase, which significantly
increased the efficacy of cancer vaccines (Herber et al. 2010).
DCs ingest pieces of tumor cells and display antigenic peptides on MHC class I
and II. DCs stimulate naïve CD8
+
and CD4+T lymphocytes by expressing
co-stimulatory ligands and upregulating CCR7 after activation (Dougan et al.
2019). Damage-associated proteins, such as adenosine triphosphate (ATP) or
HMGB1, produced by dying tumor cells, are essential for this process. However,
DCs may be activated by the demise of tumor cells; the subsequent phagocytosis of
tumor cell fragm ents also initiates regulatory processes in DCs that impede their
interaction with T cells. Exposing DCs to microbial products that stimulate TLR
signaling, such as the v iral nucleic acid mimicking pIpC or CpG DNA, may
circumvent this regulatory function, which is why innate immune adjuvants are
being included in vaccination approaches. Targeted agents that influence DNA
replication and repair pathways may also activate the STING pathway, which then
triggers the generation of type I interferon and, in turn, boosts DC activation (Hosein
et al. 2022; Chamma et al. 2022). For instance, in animal models of pancreatic
+
Current Clinical Landscape of Immunotherapeutic Approaches in... 363
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cancer, STING agonist treatment increases inflammation in the immune milieu and
lowers tumor burden (Jing et al. 2019).
3.5.4 Targeting Immunosuppressive Myeloid Cells
Regulation of neutrophil and monocyte cell migration to the PDAC microenvironment is known to be critically dependent on the chemokine receptors CXCR2 and
CCR2 and their ligands (Nywening et al. 2018). Depletion or specific interruption
with neutrophil trafficking may reduce the PDAC burden in mice. However, such
approaches cannot be perpetuated over the long term (Stromnes et al. 2014; Steele
et al. 2016; Chao et al. 2016). In PDAC mice models, the CD11b agonist reduces
accumulation of most myeloid cell types and has a substantial synergy with PD-1
blockade (Twyman-Saint Victor et al. 2015). PDAC tumor burden was decreased in
mice treated with CCR2 inhibitors that selectively targeted circulating monocytes
(Mitchem et al. 2013). A study determined the optimal oral dosage of the CCR2
inhibitor PF-04136309 for use in a phase II trial in combination with the chemotherapy regimen FOLFIRINOX. This combination therapy was safe and well-tolerated
in patients with PDAC. Findings revealed that monocytes are retained in the BM of
CCR2 inhibitor-receiving patients, which correlated with a significant decrease in
circulating monocytes and M-MDSCs in the TME. This was followed by remarkable
decreases in the primary tumor burden, which allowed 39% of the group to undergo
surgery (Nywening et al. 2016). However, PF-04136309 in combination with
nab-paclitaxel/gemcitabine induced significant pulmonary toxicity and did not
show a favorable signal (Noel et al. 2020 ). Combining BMS-813160 (a selective
CCR2/5 dual antagonist), nivolumab plus chemotherapy is being tested in an earlystage clinical trial in patients with PDAC (NCT03496662).
4 Conclusion
All in all, the paradigm shift prompted by immunotherapy is altering how we
perceive cancer treatment. Immu notherapy is now being used in clinical settings
for various solid cancers. Several standard treatments have failed to benefit patients
with PDAC; however, immunotherapy has shown promising outcomes. This chapter
highlighted an extensive spectrum of immunotherapies , including OVT, adoptive
cell transfer therapy including TCR-engineered T cells therapy, CAR T-cell therapy,
CAR NK cell therapy, and CIK cells, ICB and immunomodulators, cancer vaccines,
and immunotherapeutic strategies based on targeting myeloid cells. As immunotherapeutic strategies for treating and managing PDAC hopefully develop, logical efforts
to enhance patients’ quality of life must also be prioritized. Several tri als using
immunotherapy strategies have had dismal results in PDAC. Although the low
success rate has several causes, immunosuppres sive TME is a major contributor.
Current immunotherapies should be enhanced and refined to address this significant
challenge. There should also be further research into the efficacy of new immunotherapy targets found in preclinical studies, which should be validated through
human clinical trials.
364 P. Farhangnia et al.
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