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benefit are urgently needed. The spotlights are now on new immunotherapy approaches, since it is an
unexplored and growing landscape and has been applied successfully in other types of cancer. There are
many evidences showing that pancreatic cancer generates antitumor immune responses, suggesting that
immunotherapies can be a promising alternative for those patients . As already known, pancreatic cancer
[75]
creates an immunosuppressive tumor microenvironment with mucin overexpression. To overcome this
immunosuppressive microenvironment, Banerjee et al. have developed a nanovaccine using recombinant
[76]
fragments of MUC4, a highly expressed mucin which contributes to cancer aggressiveness, and immunized
KPC mice. When compared to control group, the immunized mice exhibited a slower tumor growth kinetics
and a greater accumulation of CD8+ and CD4+ T cells. The suppression of tumor progression caused by the
immunization points the MUC4 nanovaccine to be a potential immunotherapy for pancreatic cancer.

Another potential immunotherapy approach resulted from the study in which they administered AMD3100
(plerixafor) in KPC mice. AMD3100 is an inhibitor of chemokine receptor CXCR4, a CXCL12 receptor. The
inhibition of CXCR4 by the AMD3100 contributes to a fast T cell accumulation in regions of the tumor
and acted together with the immunological checkpoint antagonist, α-programmed cell death 1 ligand 1, to
reduce cancer cells .
[77]
Five main categories for immunotherapy applied to pancreatic cancer have been described : (1) checkpoint
[78]
inhibitors/immune modulators. This strategy aims to modulate immune system through inhibitory or
stimulatory signals, such as inhibition of CD28 family receptors, which controls T cell responses, modulating
the immune cytotoxic response, restoring or increasing the cytotoxic antitumor activities of T cell ; (2)
[79]
therapeutic vaccines. In these cases, occurs a patient’s active immunization with tumor specific antigen.
This vaccine will trigger T cells and increase its activity against the tumor ; (3) adoptive T cell transfer. An
[80]
adoptive T cell transfer is a kind of transfusion therapy that infuses mature T CD8+ specific cells in patients.
These cells target surface proteins in tumor tissue, which are used to T CD8+ cells docking and eliminate
cancer cells through granzyme and perforin secretion ; (4) monoclonal antibodies. This approach is a
[81]
passive immunization using antibodies against the same cancer molecule epitope, created to target specific
tumor antigens, which enhance the cancer cells recognition by phagocytes and T CD8+ cells improving
its elimination; (5) cytokines use. The cytokines such as IL-10 and IL-17B are used to regulate tumor
microenvironment, aiming to suppress the cancer cells property to express immunosuppressive cytokines
that stop the immune activation against the cancer cells .
[78]

Even though many encouraging results have been obtained for other types of cancer [82-84] , none of these
treatments showed significant efficiency when applied as pancreatic cancer therapy [85,86] . Currently, although
there are many ongoing trials for immunotherapy, therapeutic vaccines are the most cutting-edge clinical
therapy applied as pancreatic cancer immunotherapy. Concerning to vaccines as immunotherapy category,
the most advanced studies to date are those conducted with whole-cell vaccines and granulocyte-macrophage
colony-stimulating factor (GM-CSF) vaccines.

THERAPEUTIC VACCINE IMMUNOTHERAPY WHOLE-CELL VACCINES
Algenpantucel - L is an irradiated, live combination of two human allogeneic pancreatic cell lines that
express the murine enzyme α-1,3-galactosyl transferase. This enzyme performs the addition of α-galactosyl
epitopes on surface proteins and glycolipids of such cell lines. The human cells do not express murine alpha-
gal epitopes and these cells inoculation induce a hyperacute rejection of the vaccine pancreatic allograft
cell. The hyperacute rejection results in the fast activation of antibody-dependent cell-mediate cytotoxicity.
These processes will also stimulate the host immune system to eliminate endogenous pancreatic cancer
cells [78,87] . Hardacre et al. in 2013 performed a multi-institutional, open-label phase II trial to evaluate the
[88]
use of algenpantucel-L in addition to standard adjuvant chemotherapy and chemoradiotherapy setting for
resected pancreatic cancer patients (NCT00569387). In this study 70 patients were treated with gemcitabine