Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery.

Abstract

Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a CAR containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvβ3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvβ3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was codelivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues.

• Authors: Xinping Fu, Armando Rivera, Lihua Tao, Xiaoliu Zhang
• Journal: International journal of cancer (Int J Cancer) Vol. 133 Issue 10 Pg. 2483-92 (Nov 15 2013) ISSN: 1097-0215 [Electronic] United States
• PMID: 23661285 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 UICC.

Chemical References

• Antigens, Neoplasm
• Integrin alphaVbeta3
• Mutant Chimeric Proteins
• Receptors, Antigen

Topics

• Amino Acid Sequence
• Animals
• Antigens, Neoplasm (biosynthesis, genetics)
• Blood Vessels (pathology)
• Cell Line
• Cell Line, Tumor
• Human Umbilical Vein Endothelial Cells (pathology)
• Humans
• Integrin alphaVbeta3 (metabolism)
• Male
• Melanoma, Experimental (blood supply, metabolism, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Mutant Chimeric Proteins (biosynthesis, genetics)
• Nanoparticles (administration & dosage)
• Neovascularization, Pathologic (drug therapy, genetics, metabolism, pathology)
• Receptors, Antigen (metabolism)
• T-Lymphocytes (immunology, physiology)