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Tumor-specific crosslinking of GITR as costimulation for immunotherapy.
J Immunother. 2010 Nov-Dec; 33(9):925-34.JI

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 1.2 μM 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-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.

Authors+Show Affiliations

Division of Oncology, University Hospital Zürich, Zürich, Switzerland. christoph.renner@usz.chNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20948444

Citation

Burckhart, Tanja, et al. "Tumor-specific Crosslinking of GITR as Costimulation for Immunotherapy." Journal of Immunotherapy (Hagerstown, Md. : 1997), vol. 33, no. 9, 2010, pp. 925-34.
Burckhart T, Thiel M, Nishikawa H, et al. Tumor-specific crosslinking of GITR as costimulation for immunotherapy. J Immunother. 2010;33(9):925-34.
Burckhart, T., Thiel, M., Nishikawa, H., Wüest, T., Müller, D., Zippelius, A., Ritter, G., Old, L., Shiku, H., & Renner, C. (2010). Tumor-specific crosslinking of GITR as costimulation for immunotherapy. Journal of Immunotherapy (Hagerstown, Md. : 1997), 33(9), 925-34. https://doi.org/10.1097/CJI.0b013e3181f3cc87
Burckhart T, et al. Tumor-specific Crosslinking of GITR as Costimulation for Immunotherapy. J Immunother. 2010 Nov-Dec;33(9):925-34. PubMed PMID: 20948444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor-specific crosslinking of GITR as costimulation for immunotherapy. AU - Burckhart,Tanja, AU - Thiel,Markus, AU - Nishikawa,Hiroyoshi, AU - Wüest,Thomas, AU - Müller,Dafne, AU - Zippelius,Alfred, AU - Ritter,Gerd, AU - Old,Lloyd, AU - Shiku,Hiroshi, AU - Renner,Christoph, PY - 2010/10/16/entrez PY - 2010/10/16/pubmed PY - 2011/5/25/medline SP - 925 EP - 34 JF - Journal of immunotherapy (Hagerstown, Md. : 1997) JO - J. Immunother. VL - 33 IS - 9 N2 - 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 μM 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-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. SN - 1537-4513 UR - https://www.unboundmedicine.com/medline/citation/20948444/Tumor_specific_crosslinking_of_GITR_as_costimulation_for_immunotherapy_ L2 - http://dx.doi.org/10.1097/CJI.0b013e3181f3cc87 DB - PRIME DP - Unbound Medicine ER -