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each patient. A vaccine that targets TSAs needs to be personalized to the individual patient. However, TSAs
such as MUC1 or KRAS which is expressed by more than 90% of PDAC cells are an exception to this rule.
Currently there are a number of vaccines targeting shared antigens and patient specific antigens that are
under investigation. Examples of TAAs expressed by PDAC cells include EGFR family, carcinoembryonic
antigen (CEA), mesothelin, VEGF family, and Wilms’ tumor 1 (WT-1); however, since they may also be
expressed by normal cells, off-target toxicity can occur [65,66] .

Whole cell vaccines
GVAX is the most extensively evaluated whole cell vaccine consisting of two human allogeneic pancreatic
tumor cells lines irradiated to release antigens. It is also genetically engineered to release granulocyte-
[67]
macrophage colony-stimulating factor (GM-CSF) at the vaccination site . Dendritic cells are attracted to
GM-CSF site where they phagocytose antigens released from apoptotic PDAC cells. These dendritic cells
then travel to draining lymph nodes, present tumor antigens found in vaccine PDAC cell lines to effector
T-cell and activate them.

In an early phase clinical trial, GVAX demonstrated improved disease-free survival (DFS) in PDAC
[68]
patients who displayed delayed-type hypersensitivity responses to autologous tumor cells . In a
phase II trial of 60 patients with resected PDAC, GVAX was studied in combination with chemoXRT.
Results demonstrated a DFS of 17.3 months with an OS of 24.8 months, and induction of mesothelin-
specific CD8+ T cells was seen in those treated with GVAX, which correlated with DFS . Another
[69]
trial studied GVAX in the neoadjuvant setting where patients received cyclophosphamide and GVAX
prior to pancreaticoduodenectomy. Surgical resection samples from these patients were noted to have
novel vaccine-induced upregulation of PD-1/PD-L1 pathways in the intratumoral tertiary lymphoid
aggregates . In the metastatic setting, GVAX has also been studied with or without ipilimumab in
[62]
patients that were refractory to gemcitabine-based therapy. This study enrolled 15 patients in each arm
and results showed a median OS of 3.6 months vs. 5.7 months (P = 0.072) for single agent ipilimumab
[70]
versus combination ipilimumab with GVAX . Currently, there are ongoing phase I and II clinical trials of
GVAX in various combinations with nivolumab and urelumab (NCT02451982), nivolumab and radiation
therapy (NCT03161379), ipilimumab, nivolumab and CRS-207 (Listeria based vaccine) (NCT03190265),
pembrolizumab and radiation therapy (NCT02648282), pembrolizumab and IMC-SC4 (NCT03153410).

Another whole cell vaccine is Algenpantucel-L which contains two irradiated allogeneic PDAC tumor cell
lines transfected to express alpha-1, 3-galactosyltransferase epitopes, a cell surface carbohydrate. A phase
III IMPRESS trial comparing chemoXRT + algenpantucel-L vs. chemoXRT alone in the adjuvant setting
showed no improvement in OS. Unfortunately, no further trials are planned at this time due to limited
[71]
clinical benefit .
Bacterial-based vaccines
Vectors based on bacteria, including Listeria monocytogens, salmonella, Lactobacillus Plantarum, and
Bacillus Calmette-Guerin, have been studied as they can elicit both innate and adaptive immune responses
to TAAs. The bacterial vectors are modified to express specific antigens and elicit potent CD8+ and CD4+
responses via MHC I and MHC II antigen processing pathways. CRS-207, a live attenuated listeria vaccine
genetically modified to secrete mesothelin was studied in combination with GVAX [72,73] . In a phase II trial
with metastatic PDAC patients, GVAX with cyclophosphamide (Cy/GVAX) was compared to Cy/GVAX
followed by CRS-207. The Cy/GVAX plus CRS-207 arm showed an OS benefit of 6.1 months vs. 3.9 months
in the Cy/GVAX alone arm . It was also noted that patients who elicited mesothelin specific CD8+ T-cell
[74]
responses also had longer OS. However, a more recent phase IIb trial in which previously treated patients
with metastatic PDAC who failed > 2 lines of chemotherapy were randomized 1:1:1 to receive Cy/GVAX
+ CRS 207 (arm A), CRS-207 (arm B), or a physician’s choice of singe-agent chemotherapy (arm C),