Abstract 70: Effect of aging on the antitumor activity of GITRL-Fc
Authors: Park Angie Inkyung , Srivastava Minu K. , Yun Rui , Pokorny Jenny , Yu Janice , Axelrod Fumiko , Gurney Austin 
Published: August 2018

Mouse tumor models have been successfully used to generate preclinical data for numerous clinical programs including immunotherapy. Preclinical in vivo studies are typically carried out using young mice (often less than 2 months old) to generate efficacy data, predictive biomarker and pharmacodynamic markers. In notable contrast, the majority of human cancer occur in adult and older patients. It has become increasingly clear that the immune system of young and old mice is quite different with regards to the relative abundance and functionality of different cell populations. Data generated using young mice could provide a distorted assessment of the potential activity of immuno-oncology drugs in the clinic. Therefore, we tested the activity of GITRL-Fc protein in both young and old mice (&gt;9 months). Previously using extensive young mice experiments, we have shown that GITRL-Fc promoted a robust antitumor immune response and enhanced tumor-specific T-cell responses, particularly of the Th1 type, and also led to a reduction in Treg-mediated immunosuppressive activity. Compared to young mice, tumors grew faster in older mice, and peripheral blood of older tumor-bearing mice has fewer T cells and NK cells. The total MDSC population was increased in the blood and spleen of old tumor-bearing mice, with a significantly higher number of G-MDSCs in the blood. On the other hand, old mice had reduced “antigen-presenting cells” (macrophages/dendritic cells expressing MHCII) in the blood. Furthermore, splenocytes from old mice had impaired production of IL-2. GITRL-Fc significantly inhibited tumor growth in both older and younger mice. However, efficacy was more pronounced in young mice, which frequently exhibited complete tumor regression. There were fewer tumor-infiltrating immune cells with less CD8 T and NK cells in older mice compared to young mice, consistent with faster tumor growth. Interestingly, GITR expression in CD8 T cells in old mice was lower compared with young mice at the tumor site. In old mice, GITRL-Fc (mIgG2a) was still able to deplete Tregs in tumor and increase Tregs in the spleen as has been previously shown with GITRL-Fc in young mice. On the other hand, GITRL-Fc deficient in effector function (mIgG2a (N297A)) did not deplete Tregs in the tumor but did retain some antitumor growth activity, indicating a role for GITR signaling in the mechanism of efficacy by GITLR-Fc. In conclusion, the results demonstrate the potential for the aging of the immune system to impact the efficacy observed with immunotherapy agents and highlight the potential benefits of conducting efficacy studies with both young and older mice.

Citation Format: Angie Inkyung Park, Minu K. Srivastava, Rui Yun, Jenny Pokorny, Janice Yu, Fumiko Axelrod, Austin Gurney. Effect of aging on the antitumor activity of GITRL-Fc [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 70.