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Page 2 of 17 Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90
[2]
the second leading cause of cancer-related deaths in the United States by 2030 . It is estimated that 57,600
Americans will be diagnosed with pancreatic cancer and more than 47,050 will die of the disease in 2020
[1]
making it the most lethal malignancy of all major cancers . Most patients present with unresectable or
metastatic disease leading to an abysmal 5-year-overall survival (OS) rate of only 7%. Even when surgery
[3]
is feasible in 15%-20% of the patients, the 5-year survival remains only about 10% . Current front-line
treatment options include traditional chemotherapies that only provide modest survival benefits.

Gemcitabine was considered the backbone of management for metastatic PDAC as it provided a survival
[4]
benefit as well as alleviation of symptoms compared to fluorouracil (5-FU) . Many trials after this
failed to show improvement from this integral study in 1997. Various combination treatments have been
explored since then to see if any headway could be made in the treatment of this lethal disease. Notably,
combination treatments with epidermal growth factor receptors (EGFR) as well as anti-vascular endothelial
growth factors (VEGF) did not produce clinically meaningful results [4-6] . Additionally, combination
treatments exploring gemcitabine with various cytotoxic agents including the addition of oxaliplatin,
5-FU, capecitabine, and irinotecan failed to demonstrate a statistically significant OS advantage [7-10] . Two
chemotherapy combination regimens have shown superiority in patients with metastatic disease since
then. In the PRODIGE/ACCORD and MPACT trials, FOLFIRINOX and gemcitabine plus nab-paclitaxel,
respectively, showed an OS benefit at the cost of increased toxicity [11,12] . OS has improved with the addition
of chemotherapy in the adjuvant setting as well, however, there is much room for improvement [13,14] . Despite
the improvement noted in these trials, pancreatic cancer is highly chemo-resistant and patients who
[15]
respond will inevitably develop resistance to these therapeutic modalities . Based on this historical data,
providers can attempt treatment with varying success, but there is still a dire need to develop newer agents
and incorporate newer strategies to improve outcomes in pancreatic cancer.

Recently, immunotherapy has revolutionized cancer care and has garnered approval in many different solid
tumors, including melanoma, lung cancer, and urothelial cancers, among others . Therefore, it has been
[16]
of great interest to explore the role of various immunotherapies in PDAC. Overall, results in this realm
have been disappointing to date, reflecting the non-immunogenic and complex tumor microenvironment
of PDAC. To overcome these challenges, therapeutic vaccines, combination treatments, adoptive T cell
transfer, as well as immunomodulators are being explored. With the emerging use of immunotherapy and
immunomodulators, the scope of this review is to present the current data on these agents as well as focus
on the advancements in the treatment of PDAC.

MECHANISMS OF CHEMORESISTANCE AND TUMORIGENESIS
Pancreatic cancer is highly resistant to chemotherapy and radiotherapy, making treatment less
effective compared to other solid tumors. The dense desmoplasia surrounding the pancreatic tumor
microenvironment (TME) plays a major role in immune modulation and chemotherapy resistance.
Pancreatic TME is comprised of the tumor and its surrounding stroma. The development and progression
of PDAC is associated with the interplay of inflammatory cells, mediators, pancreatic stellate cells
(PSCs), and the extracellular matrix (ECM) that gives rise to the tumor micro environment favoring
tumorigenesis [17,18] [Figure 1].

PSCs are part of normal pancreatic stroma and involved in vitamin A storage, exocrine/endocrine
[19]
secretion, phagocytosis and maintenance of pancreatic stroma . In PDAC, the malignant cells secrete
transforming growth factor beta-1 (TGFβ-1), fibroblast growth factor-2 (FGF2), sonic hedgehog and
platelet derive growth factor (PDGF) that drive PSC proliferation and increase ECM deposition leading
to desmoplastic reaction [19,20] . The PSCs also contribute to the chemo resistance by actively entrapping
[21]
gemcitabine in their cytoplasm lessening the effect of gemcitabine on pancreatic cancer cells . Dense ECM
deposition is thought to promote proliferation, chemoresistance, and limit T-cells accumulation near cancer