Azd8853: A Novel Antibody Targeting Gdf15 For Immunotherapy Refractory Tumors.

Abstract Immunotherapy has revolutionized patient care, however, the majority of patients with cancer still do not benefit from this treatment modality. This is due to many factors, including a complex tumor microenvironment (TME) that has too few functional effector cells and/or the presence of many inhibitory cells. Understanding how to remodel the TME to potentiate productive immunity against cancer cells is an active area of research. Growth and Differentiation Factor 15 (GDF-15) is a member of the TGF-beta superfamily that is overexpressed by many solid tumors and is implicated in dampening immune responses. The present study was aimed at understanding the role of GDF-15 in tumor immune biology. We show that GDF-15 can inhibit the differentiation and activation of human monocyte-derived dendritic cells (DCs) and prevent T cell activation. Furthermore blockade of GDF-15 by AZD8853, an anti-GDF15 monoclonal antibody, can restore these activities in vitro. Tumors derived from GDF15 knock-out syngeneic cell lines, Renca and MC-38, show 2-3 fold increases in T cells and activated DCs in the TME as compared to tumors derived from isogeneic parental cells. Treatment of mice with anti-GDF15 mAb leads to substantial anti-tumor activity in anti-PD-L1 refractory LL/2 and MBT2 syngeneic tumors with 50% of the animals showing complete tumor regressions. Coupled with this anti-tumor activity, we show that after 2 doses of anti-GDF15 mAb there is an increase in both activated T cells and DCs in the TME. Depletion of T cells, using anti-CD4 and anti-CD8, in mice ablates the anti-tumor activity observed with anti-GDF15 mAb treatment. These results suggest that inhibition of GDF15 by AZD8853 may be an attractive therapeutic strategy for patients with solid tumors that have high expression of GDF15. Citation Format: Elaine Hurt, Suneetha Thomas, Kathy Mulgrew, Stephen Blackmore, James Moynihan, Fiona Cusdin, Roger Dodd, Peter Cariuk, Anna Sigurdardottir, Emily Brannigan, Claire Dobson, Rakesh Kumar, Mark Cobbold. AZD8853: A novel antibody targeting GDF15 for immunotherapy refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1828.