Page 368 - Read Online

Page 8 of 14 Pereira et al. J Cancer Metastasis Treat 2018;4:30 I http://dx.doi.org/10.20517/2394-4722.2018.13

Table 3. Therapeutic vaccines immunotherapy summary
Clinical trial Biological Intervention Phase Patient
Whole cell NCT01072981 Algenpantucel-L + Gemcitabine III ongoing Resected pancreatic cancer
vaccines NCT01303172 IMM-101 + Gemcitabine II completed Advanced pancreatic cancer
GM-CSF vaccines GVAX + CR207 Cy/GVAX + CRS207 II completed Metastatic pancreatic cancer
GM-CSF: granulocyte-macrophage colony-stimulating factor; Cy: cyclophosphamide

and 5-FU based chemoradiotherapy as well as algenpantucel-L. The median follow-up was 21 months, and
the one-year progression-free survival was 62% added to an 86% overall survival. Inoculation site pain and
local tissue induration were the common side events; however, the allogenic cells administration was safe,
and it proves to be a feasible combined approach. The results obtained from this phase II trial demonstrated
that this immunotherapy component may improve survival, and due to such optimistical results a multi-
institutional phase III study is ongoing (NCT01072981).

Another randomized phase II trial explored the safety and tolerability of an injectable immunomodulator from
heat-killed mycobacterium obuense (IMM-101) used in combination with gemcitabine. This study showed
that the administration of IMM-101 plus gemcitabine was safe and well tolerated as gemcitabine alone in
patients with advanced pancreatic cancer, moreover the results from this phase II trial suggested a beneficial
effect on overall survival which may support further evaluation of IMM-101 in a confirmatory study .
[89]

GM-CSF VACCINES
A recent phase II randomized multicenter study was conducted comparing cyclophosphamide (Cy)/GVAX
followed by CRS-207 with Cy/GVAX alone in patients with metastatic pancreatic cancer. Cy/GVAX is
composed of two irradiated GM-CSF-secreting allogeneic pancreatic cancer cell lines administered with
low-dose of Cy to hinder regulatory T cells. GVAX induces T CD8+ cells activity against a tumor associated
antigen named mesothelin that is over expressed in most pancreatic cancer cells. CRS-207 is a live-attenuated
Listeria monocytogene-gene expressing mesothelin that induces innate and adaptative immunity response.
The overall survival for the Cy-GVAX followed by CRS-207 was 6.1 months compared to 3.9 months of Cy-
GVAX alone. Stable disease rate of 31% and 1-year survival rate of 24% are encouraging results. Furthermore,
heterologous boost with Cy-GVAX and CRS-207 extended overall survival for pancreatic cancer patients
with minimal related toxicities [Table 3].
[90]

Worldwide efforts should be directed to identification and selection of specific antigens in order to
induce immune response against pancreatic cancer cells aiming to eliminate the immunosuppressive
microenvironment that this cancer produces. Appropriate selection of target antigens and combination of
treatment protocols are critical to enhance treatment efficacy, lowering related toxicities and as already
demonstrated improving the overall survival .
[91]

Regardless of the advances in pancreatic tumor biology knowledgment, mechanisms associated with the
tumor microenvironment remain poorly understood, highlighting that the distinct composition of pancreatic
tumor microenvironment could be a great barrier for immunotherapy success . As a consequence of newly
[92]
emerging information about tumor microenvironment, there was a shift in the cancer development concept
from a tumor cell-centered view to a complex tumor ecosystem, which led to the acceptance that cancer cells
interact with the extracellular matrix (ECM) and stromal cells [93,94] . A major component of the extracellular
matrix is hyaluronic acid (HA), a hydrophilic glycosaminoglycan that is produced in bulk by many pancreatic
cancer. Accumulation of HA in tumors is associated with malignancy and poor prognosis, because HA
polymers bind and trap water molecules in the ECM as a fluid gel that increases interstitial fluid pressure and
creates a physical barrier that restricts antibody and immune cells access the tumor. A pegylated recombinant
human hyaluronidase (PEGPH20) is an agent that degrades the hyaluronic acid and normalizes interstitial