Durham et al. tested the effectiveness of GITR Ligand Fusion Protein (GITRL-FP) monotherapy in the immunogenic, self-priming CT26 tumor model and found that it promotes expansion of antigen-specific T cells, depletion of Treg cells, tumor clearance, and generation of a lasting CD8+ T cell memory response. In the non-self-priming TC-1 model, no GITRL-FP anti-tumor effects were observed unless accompanied with an E7-targeting vaccine.
BACKGROUND: The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations. METHODS: We explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy. In TC-1, GITRL-FP was also combined with concurrent administration of an E7-SLP vaccine. We evaluated tumor growth inhibition by tumor volume measurements as well as changes in CD8 T cell populations and function including cytokine production using flow cytometry. Additionally, we interrogated how these therapies resulted in tumor antigen-specific responses using MHC-I dextramer staining and antigen-specific restimulations. RESULTS: In this study, we demonstrate that a GITR ligand fusion protein (GITRL-FP) is an effective modulator of antigen-specific CD8 T cells. In a CT26 mouse tumor model, GITRL-FP promoted expansion of antigen-specific T cells, depletion of regulatory T cells (Tregs), and generation of long-lasting CD8 T cell memory. This memory expansion was dependent on the dose of GITRL-FP and resulted in complete tumor clearance and protection from tumor rechallenge. In contrast, in TC-1 tumor-bearing mice, GITRL-FP monotherapy could not prime an antigen-specific CD8 T cell response and was unable to deplete Tregs. However, when combined with a vaccine targeting E7, treatment with GITRL-FP resulted in an augmentation of the vaccine-induced antigen-specific CD8 T cells, the depletion of Tregs, and a potent antitumor immune response. In both model systems, GITR levels on antigen-specific CD8 T cells were higher than on all other CD8 T cells, and GITRL-FP interacted directly with primed antigen-specific CD8 T cells. CONCLUSIONS: When taken together, our results demonstrate that the delivery of GITRL-FP as a therapeutic can promote anti-tumor responses in the presence of tumor-specific CD8 T cells. These findings support further study into combination partners for GITRL-FP that may augment CD8 T-cell priming as well as provide hypotheses that can be tested in human clinical trials exploring GITR agonists including GITRL-FP.
Author Info: (1) Department of Translational Medicine, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA. (2) Department of Translational Medicine, MedImmune, One Medimmune Way, Gaithers
Author Info: (1) Department of Translational Medicine, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA. (2) Department of Translational Medicine, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA. (3) Department of Infectious Disease and Vaccines, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA. (4) Department of Oncology, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA. (5) Department of Translational Medicine, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA. (6) Department of Infectious Disease and Vaccines, MedImmune, One Medimmune Way, Gaithersburg, MD 20878 USA.
