Unleashing the Power of ICOS Agonism: Enhancing Immune Responses Against Cancer

The inducible T-cell costimulator, also known as ICOS, is a receptor that is crucial for the survival and differentiation of activated T cells. It is involved in the regulation of memory and regulatory T cell pools, as well as in the modulation of humoral responses. In preclinical studies, enhancing the ICOS pathway has been shown to stimulate anti-tumor activity and improve responses to CTLA4 blockade.

A new, selective anti-human ICOS agonist, GSK3359609, has been developed and tested in both human and mouse models. This antibody activates ICOS signaling through the phosphorylation of Pi3K pathway intermediates, leading to lymphocyte activation, proliferation, and the secretion of pro-inflammatory cytokines. In vitro tests using peripheral blood mononuclear cells (PBMCs) from healthy donors, cancer patients, and tumor infiltrating lymphocytes (TILs) demonstrated a significant increase in CD4 effector T cell proliferation and the secretion of Granzyme B by CD8 T cells. Additionally, there was a modest induction of regulatory T cell proliferation and IL-10 secretion. Notably, there was a significant increase in IFNγ and TNFα secretion in both primary PBMC and TIL assays. Gene expression analysis confirmed the activation of genes associated with T and B cell activation.

In mouse models, an ICOS surrogate antibody was used in immune-competent tumor models, resulting in tumor regressions in 10-40% of mice. This was accompanied by an increase in effector memory T cells in the periphery and enhanced T cell activation and proliferation in lymphoid tissues and tumors. There was also an increase in the expression of PD1, PD-L1, and PD-L2 genes in tumors from ICOS antibody-treated mice, along with an increase in cytotoxic T cell signature and the induction of an IFNγ gene signature.

Further research explored combination therapies that could condition the tumor immune microenvironment for ICOS agonist therapy. Treatment with an anti-PD1 antibody led to an upregulation of ICOS expression on tumor-infiltrating CD8, CD4 effector, and regulatory T cells, while decreasing the relative number of ICOS+ Tregs in the tumor microenvironment. A synergistic anti-tumor effect was observed when combining PD-1 with ICOS agonist antibodies in preclinical studies.

These findings support the ongoing Phase I study of GSK3359609, both as a monotherapy and in combination with pembrolizumab, for patients with selected advanced solid tumors. The study was presented at the American Association for Cancer Research Annual Meeting in 2017.