Format

Send to

Choose Destination
ACS Nano. 2017 Sep 26;11(9):8690-8706. doi: 10.1021/acsnano.7b01786. Epub 2017 Aug 28.

Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer.

Author information

1
Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, ‡Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, §Carolina Center for Genome Sciences, and ∥UNC & NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

Abstract

Pancreatic tumors are known to be resistant to immunotherapy due to the extensive immune suppressive tumor microenvironment (TME). We hypothesized that CXCL12 and PD-L1 are two key molecules controlling the immunosuppressive TME. Fusion proteins, called traps, designed to bind with these two molecules with high affinity (Kd = 4.1 and 0.22 nM, respectively) were manufactured and tested for specific binding with the targets. Plasmid DNA encoding for each trap was formulated in nanoparticles and intravenously injected to mice bearing orthotopic pancreatic cancer. Expression of traps was mainly seen in the tumor, and secondarily, accumulations were primarily in the liver. Combination trap therapy shrunk the tumor and significantly prolonged the host survival. Either trap alone only brought in a partial therapeutic effect. We also found that CXCL12 trap allowed T-cell penetration into the tumor, and PD-L1 trap allowed the infiltrated T-cells to kill the tumor cells. Combo trap therapy also significantly reduced metastasis of the tumor cells to other organs. We conclude that the trap therapy significantly modified the immunosuppressive TME to allow the host immune system to kill the tumor cells. This can be an effective therapy in clinical settings.

KEYWORDS:

CXCL12; PD-L1; allograft model; pancreatic ductal adenocarcinoma; trap protein

PMID:
28809532
PMCID:
PMC5961942
DOI:
10.1021/acsnano.7b01786
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center