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A homing system targets therapeutic T cells to brain cancer

Authors :
Samaha, Heba
Pignata, Antonella
Fousek, Kristen
Ren, Jun
Lam, Fong W.
Stossi, Fabio
Dubrulle, Julien
Source :
Nature. September, 2018, Vol. 561 Issue 7723, p331, 7 p.
Publication Year :
2018

Abstract

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.Therapeutic T cells bearing ligands engineered to optimize adhesion and transmigration through the blood-brain barrier can be targeted to brain tumours.<br />Author(s): Heba Samaha [sup.1] [sup.2] [sup.3] [sup.4] , Antonella Pignata [sup.2] [sup.3] [sup.4] , Kristen Fousek [sup.2] [sup.3] [sup.4] [sup.5] , Jun Ren [sup.6] , Fong W. Lam [sup.4] [sup.7] [...]

Details

Language :
English
ISSN :
00280836
Volume :
561
Issue :
7723
Database :
Gale General OneFile
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
edsgcl.572956960
Full Text :
https://doi.org/10.1038/s41586-018-0499-y