Combined delivery of a TGF-β inhibitor and an adenoviral vector expressing interleukin-12 potentiates cancer immunotherapy.

Abstract

Cancer immunotherapy appears to have a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-β (TGF-β), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-β inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-β inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene. In addition, it significantly delayed growth of B16 melanoma xenografts in mice and increased animal survival. Mechanistic studies showed that this combination therapy enhanced anti-tumor immune response by activating CD4+ and CD8+ T cells, natural killer cells and interferon-γ secretion in the tumor microenvironment.

STATEMENT OF SIGNIFICANCE:

To weaken immune resistance of tumors and simultaneously strengthen tumors' immune responses, we synthesized a structurally simple, low-toxic but functional polymer β-cyclodextrin-PEI to encapsulate a hydrophobic TGF-β inhibitor SB-505124 and to complex adenovirus vectors expressing IL-12. This is the first report demonstrating that combining TGF-β inhibitor with IL-12 could provide effective immunotherapy against melanoma by the sustainable release of SB-505124 and the effectible transduction of IL-12 gene in tumor cells. The rational delivery system presented a comprehensive and valued platform to be a candidate vector for co-delivering hydrophobic small-molecule drugs and therapeutic genes for treating cancer, providing a new approach for cancer immunotherapy.

• Authors: Jiayu Jiang, Yuandong Zhang, Ke Peng, Qin Wang, Xiaoyu Hong, Hanmei Li, Gerui Fan, Zhirong Zhang, Tao Gong, Xun Sun
• Journal: Acta biomaterialia (Acta Biomater) Vol. 61 Pg. 114-123 (10 01 2017) ISSN: 1878-7568 [Electronic] England
• PMID: 28483693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• 2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride
• Antineoplastic Agents
• Benzodioxoles
• Imidazoles
• Pyridines
• Transforming Growth Factor beta
• beta-Cyclodextrins
• Interleukin-12
• Polyethyleneimine
• betadex

Topics

• Adenoviridae (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzodioxoles (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Movement
• Combined Modality Therapy
• Drug Delivery Systems
• Female
• Genetic Vectors (administration & dosage)
• Imidazoles (administration & dosage, pharmacology)
• Immunotherapy
• Interleukin-12 (therapeutic use)
• Melanoma, Experimental (immunology, pathology, therapy)
• Mice, Inbred C57BL
• Neoplasm Invasiveness
• Neoplasms (immunology, therapy)
• Polyethyleneimine (chemistry)
• Pyridines (administration & dosage, pharmacology)
• Transduction, Genetic
• Transforming Growth Factor beta (antagonists & inhibitors)
• beta-Cyclodextrins (chemistry)