Tumor-specific crosslinking of GITR as costimulation for immunotherapy

Burckhart, Tanja and Thiel, Markus and Nishikawa, Hiroyoshi and Wüest, Thomas and Müller, Dafne and Zippelius, Alfred and Ritter, Gerd and Old, Lloyd and Shiku, Hiroshi and Renner, Christoph. (2010) Tumor-specific crosslinking of GITR as costimulation for immunotherapy. Journal of immunotherapy, Vol. 33, H. 9. pp. 925-934.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/dok/A6006663

Downloads: Statistics Overview


Activation of murine glucocorticoid-induced tumor necrosis factor-related receptor (mGITR) by its natural ligand (GITRL) or antiGITR agonist mAb enhances T-cell responses, inhibits regulatory T-cell (Treg)-mediated suppression and induces tumor immunity in a variety of murine tumor models. However, systemic administration of these costimulatory agents can lead to global T-cell activation and autoimmunity. To specifically manipulate the T-cell compartment in the tumor microenvironment we propose to target the tumor infiltrating T cells with a bispecific mGITRL fusion protein. For that purpose, mGITRL is linked to a single-chain antibody targeting fibroblast activation protein (FAP) as FAP expression is restricted to cancer-associated fibroblasts (CAFs) found in the stroma of epithelial cancers. AntiFAP-mGITRL fusion protein forms dimers and binds to murine GITR with 1.2 M affinity and to murine FAP with 4.5 nM. The construct is able to costimulate CD8+ and CD4+ effector T cells resulting in increased proliferation, IFN- and IL-2 production. This costimulatory effect is enhanced when the fusion protein is bound to a FAP-positive cell line mimicking FAP CAFs. In suppression assays, membrane-bound antiFAP-mGITRL is 100-fold more effective in overcoming Treg-mediated suppression than unbound fusion protein. These studies suggest that targeted tumor therapy with antiFAP-mGITRL fusion protein could induce tumor rejection while minimizing autoimmune side effects.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cancer Immunology and Biology (Zippelius/Rochlitz)
UniBasel Contributors:Zippelius, Alfred
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Lippincott Williams & Wilkins
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
Last Modified:19 Jul 2013 07:43
Deposited On:19 Jul 2013 07:35

Repository Staff Only: item control page