Interest in GITR as a target for cancer immunotherapy developed from reports showing that agonist anti-GITR antibodies (the rat monoclonal DTA-1 and goat polyclonals) could overcome self-tolerance and reverse in vitro Treg suppression. Originally, both groups attributed this to direct effects on Tregs; however, it was subsequently shown with the use of GITR?/? T cells that GITR ligation worked primarily by making Teffs resistant to Treg suppression. GITR can also be modulated through the therapeutic use of GITR-L; however, most evidence in murine models suggests that this approach works best when combined with tumor antigen vaccination and not as monotherapy. Boczkowsk et al. observed that vaccination with DCs expressing melanocyte differentiation antigen TYRP-2 provided only a short delay in tumor growth after B16 cancer challenge. When combined with DCs engineered to secrete either a GITR-L-Fc fusion protein or DTA-1, cancer survival was enhanced to 50%. Likewise, combining DNA vaccines encoding tumor antigens from the CMS5 sarcoma with DNA encoding GITR-L dramatically delayed tumor growth.
Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Current opinion in immunology. 2012;24(2):217-224.