Abstract 1637: ICOS agonism induces potent immune activation and anti-tumor response in non-clinical models

Inducible T-cell costimulator (ICOS) is a costimulatory receptor that is upregulated on activated CD4 and CD8 T cells and plays an important role in T cell survival, differentiation, regulation of memory and regulatory T cell pools and humoral responses. Preclinically, augmenting signaling through the ICOS pathway has been reported to induce anti-tumor activity and enhance responses to CTLA4 blockade. Here we present non-clinical data evaluating ICOS agonist antibody activity in human and mouse model systems using a different antibody for each species. GSK3359609 is a novel, selective anti-human ICOS agonist. GSK3359609 induces ICOS signaling through phosphorylation of intermediates in the Pi3K pathway leading to lymphocyte activation, proliferation and pro-inflammatory cytokine secretion in human PBMC in-vitro. A robust increase in CD4 effector T cell proliferation and Granzyme B secreting CD8 T cells was observed with GSK3359609 treatment in in-vitro assays utilizing PBMC from healthy donors, cancer patients or tumor infiltrating lymphocytes (TIL). Modest induction of regulatory T cell proliferation and IL-10 secretion were also observed. Significant increase in IFNγ (p We further explored treatment settings where a combination therapy may condition the tumor immune microenvironment to a more favorable context for ICOS agonist therapy. Treatment with an anti-PD1 antibody resulted in strong upregulation of ICOS expression on tumor infiltrating CD8, CD4 effector and regulatory T cells while decreasing ICOS+ Tregs relative to CD8 and CD4 effectors in the tumor microenvironment. Synergistic anti-tumor activity was observed for the combination of PD-1 with ICOS agonist antibodies in preclinical studies. These studies provide a strong rationale for the ongoing FTIH Phase I study of GSK3359609 administered alone and in combination with pembrolizumab to patients with selected advanced solid tumors. Citation Format: Sapna Yadavilli, Tianqian Zhang, Ashleigh Hahn, Laura M. Seestaller-Wehr, Hong Shi, Yao-Bin Liu, M.Phillip DeYoung, David J. Kilian, Meixia Bi, Michael P. Adam, Shu-Yun Zhang, Sabyasachi Bhattacharya, Yuliya Katlinskaya, Christina Blackwell, Christopher B. Hopson, Niranjan Yanamandra, Roopa Srinivasan, Patrick A. Mayes, Axel Hoos. ICOS agonism induces potent immune activation and anti-tumor response in non-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1637. doi:10.1158/1538-7445.AM2017-1637