Tumor-specific crosslinking of GITR as costimulation for immunotherapy Journal Article

Authors: Burckhart, T.; Thiel, M.; Nishikawa, H.; Wüest, T.; Muller, D.; Zippelius, A.; Ritter, G.; Old, L.; Shiku, H.; Renner, C.
Article Title: Tumor-specific crosslinking of GITR as costimulation for immunotherapy
Abstract: 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 1.2μM affinity and to murine FAP with 4.5nM. The construct is able to costimulate CD8++ and CD4 + effector T cells resulting in increased proliferation, IFN-γ 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. Copyright © 2010 by Lippincott Williams & Wilkins.
Keywords: controlled study; protein expression; unclassified drug; drug efficacy; nonhuman; binding affinity; neoplasm; cd8+ t lymphocyte; lymphocyte proliferation; t lymphocyte; animal cell; mouse; animal tissue; interleukin 2; cancer immunotherapy; protein; regulatory t lymphocyte; hybrid protein; gamma interferon; cd4+ t lymphocyte; fibroblast; stroma; cytokine production; effector cell; lymphocytic infiltration; autoimmune disease; glucocorticoid induced tumor necrosis factor receptor; tumor rejection; protein cross linking; drug protein binding; costimulation; tumor microenvironment; fibroblast activation protein; glucocorticoid-induced tumor necrosis factor-related receptor ligand; regulatory t-cell; dimer; fibroblast activating protein antibody glucocorticoid induced tumor necrosis factor related receptor ligand fusion protein; cancer associated fibroblast
Journal Title: Journal of Immunotherapy
Volume: 33
Issue: 9
ISSN: 1524-9557
Publisher: Lippincott Williams & Wilkins  
Date Published: 2010-11-01
Start Page: 925
End Page: 934
Language: English
DOI: 10.1097/CJI.0b013e3181f3cc87
PROVIDER: scopus
PUBMED: 20948444
Notes: --- - "Export Date: 20 April 2011" - "CODEN: JOIME" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Gerd Ritter
    166 Ritter
  2. Lloyd J Old
    519 Old