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Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90 Page 9 of 17
[75]
showed Cy/GVAX + CRS-207 did not improve OS compared to chemotherapy . CRS-207 is now being
studied in combination with indoleamine 2, 3 dioxygenase-1 (IDO1) inhibitor and ICIs (NCT03190265,
NCT03006302).

Yeast-based vaccines
Yeast cells have also been used as vaccine vectors given their ability to elicit robust T cell responses. Yeast
cells can be genetically engineered to express TSAs. GI-4000 is a combination of four vaccines made up of
heat-inactivated S. cerevisiae expressing the three most common Ras mutations of human cancers. A phase
II randomized trial in which GI-4000 was given together with gemcitabine in PDAC showed a modest
[76]
OS benefit of 524 days vs. 444 days . Another phase I trial (NCT03552718) is evaluating a personalized
neoepitope yeast vaccine in patients with resected pancreas, liver and lung cancers.

Viral vector based vaccines
Another strategy to elicit T-cell response is using viral vectors modified to encode TAAs/TSAs. These
vectors include adenovirus (AdV), adeno-associated virus (AAV), vaccinia virus (VV), and alphavirus.
Phase I results were encouraging. However, a phase III trial with PANVAC-VF, a recombinant attenuated
vaccinia and fowlpox vector expressing CEA, MUC-1and immunostimulatory molecules ICAM-1,
B7.1 LFA-3, did not show statistical significance in overall survival . A phase I trial (NCT02432963) is
[77]
evaluating a combination of vaccinia virus expressing p53 (MVA-p54) and pembrolizumab in PDAC and
other solid tumors.

Peptide vaccines
Antigenic peptide vaccines are phagocytosed by dendritic cells and presented to T-cells to trigger a
response. Theses vaccines have the potential to be personalized to individual patients with improved
selection of immunogenic epitopes and have been shown to have some benefit in high risk melanoma
[78]
patients . In PDAC, despite demonstration of T-cell immune response by several peptide vaccines
(elpamotide-VEGFR2 vaccine, KIF202A-66-member of kinesin super family protein 20A, and RAS
peptide) in clinical trials, no OS benefit was observed [79-81] .

DNA-based vaccines
DNA vaccines contain a DNA plasmid that encodes for highly immunogenic TAA that are specific to a
patient’s PDAC including epitopes of mesothelin. After administration, the DNA plasmid is electroporated
into cells. The expressed neoantigens are taken up by antigen presenting dendritic cells to elicit T-cells
response. A phase I double blind, placebo controlled trial of VXM01, a DNA vaccine, in 71 patients with
advanced PDAC showed that it was well tolerated and led to activation of VEGFR2-specific cytotoxic
T-cells . A phase I DNA vaccine trial (NCT03122106) of resected PDAC patients is ongoing.
[82]
Dendritic cell-based vaccines
Dendritic cells are specialized antigen presenting cells that process antigens to prime T cells. They can
be loaded with tumor cell lysate and antigens, expanded ex-vivo and administered into patients [83,84] . Two
phase I trials with autologous dendritic cells pulsed with mutant KRAS peptides (NCT03592888) and
dendritic cells loaded with tumor cell lysate and RNA (NCT04157127) corresponding to the patient’s
specific tumor mutation and HLA type in resected PDAC patients are currently ongoing.

Adoptive T-cell therapy
Adoptive T-cell therapy is another area of interest in treatment of PDAC given its success in number of
[63]
hematologic malignancies . T-cells are genetically engineered to express chimeric antigen receptor (CAR)
which targets specific tumor antigens. The receptors are made up of an extracellular antigen recognition
domain to an intracellular signaling domain of CD28, 4-1BB, and other co-stimulatory molecules which