Abstract 1637: ICOS agonism induces potent immune activation and anti-tumor response in non-clinical models
Authors: Yadavilli Sapna , Zhang Tianqian , Hahn Ashleigh , Seestaller-Wehr Laura M. , Shi Hong , Liu Yao-Bin , DeYoung M.Phillip , Kilian David J. , Bi Meixia , Adam Michael P. , Zhang Shu-Yun , Bhattacharya Sabyasachi , Katlinskaya Yuliya , Blackwell Christina , Hopson Christopher B. , Yanamandra Niranjan , Srinivasan Roopa , Mayes Patrick A. , Hoos Axel 
Published: July 2017

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&lt;0.05) and TNFα secretion was observed in both primary PBMC and TIL based assays. Gene expression analysis of GSK3359609 treated human T cells confirmed changes in genes associated with T and B cell activation. In mice, an ICOS surrogate antibody was utilized in immune competent mouse tumor models. Tumor regressions were observed in 10-40% of mice and were associated with a robust increase in effector memory T cells in periphery as well as increases in T cell activation and proliferation in lymphoid tissues and tumor. Robust increases in PD1, PD-L1 and PD-L2 gene expression were observed in the tumors from ICOS antibody treated mice along with an increase in cytotoxic T cell signature and induction of an IFNγ gene signature. Changes in regulatory T cell proliferation were also observed in the blood and tumor of mice treated with the mouse ICOS agonist however changes were consistently less in magnitude than corresponding functional changes in cytotoxic CD8+ and effector CD4 cells.

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