Abstract 4600: Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg)

Abstract

Naturally suppressive CD4+ Foxp3+ Treg are essential for immune tolerance. Although Treg-mediated suppression of effector cells is important to control inflammation and prevent autoimmune diseases, the presence of Treg in the tumor microenvironment (TME) has been shown to dampen anti-tumor immune responses. Human Treg express CCR4, the receptor for the chemokines CCL17 and CCL22. These chemokines are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff). Preclinical and clinical data supports a role for CCR4-mediated recruitment and accumulation of Treg in the TME which can be associated with poor prognosis. Further, recent longitudinal studies in patients receiving IO agents demonstrate an influx of Treg in responding patients which may dampen optimal anti-tumor responses. Therefore, CCR4 is an ideal target to selectively block Treg recruitment into the TME. We have developed structurally unique series of small molecule antagonists of CCR4. These antagonists have cellular potencies in multiple assays (e.g. chemotaxis of primary human Treg in 100% serum) in the low double-digit nM range. Representative compounds are selective against other chemokine receptors, GPCRs and ion channels, including the hERG channel, and lack inhibition of common human CYP450 enzymes. Moreover, compounds have excellent in vitro and in vivo ADME properties, consistent with convenient oral dosing. In preclinical syngeneic tumor models, these CCR4 antagonists block Treg migration and support expansion of activated Teff. In contrast to the non-selective approach of depleting anti-CCR4 antibodies, our compounds reduce Treg in the tumor, but not in peripheral tissues such as blood, spleen or skin. In preclinical efficacy studies, CCR4 antagonists potentiate the anti-tumor effects of various checkpoint inhibitors and immune stimulators such as anti-PD-L1 and anti-CD137 antibodies. We observe enhanced tumor growth inhibition and increased tumor regressions when these agents are combined with CCR4 antagonists, without any gross toxicity. Further characterization of these CCR4 antagonists and their anti-tumor effects will be described. Citation Format: Oezcan Talay, Lisa Marshall, Cesar Meleza, Maureen K. Reilly, Omar Robles, Mikhail Zibisky, Abood Okal, Lisa Seitz, Jenny McKinnell, Scott Jacobson, Erin Riegler, Emily Karbaz, David Chian, Angela Wadsworth, Paul Kassner, David Wustrow, Jordan S. Fridman. Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg) [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 4600. doi:10.1158/1538-7445.AM2017-4600

658 A phase 2 study to assess the safety, efficacy of FLX475 combined with pembrolizumab in patients with advanced or metastatic gastric cancer

“…C-C chemokine receptor type 4 (CCR4), the cognate receptor of the secreted proteins C-C motif chemokine ligand 17 (CCL17), and 22 (CCL22), is the predominant chemokine receptor on human T reg and is responsible for migration and accumulation of T reg in the TME. 1,2,3 FLX475 is an orally available and selective small-molecule antagonist of CCR4 which demonstrated potent inhibition of CCL17-and CCL22-induced CCR4-mediated chemotaxis, an increase in the intratumoral T eff /T reg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. 4 Given the proposed mechanism of action, a Phase 2 study investigating the safety, efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer is being conducted.…”

CCR4 Antagonists Inhibit Treg Trafficking into the Tumor Microenvironment

“…Our efforts to design an orally bioavailable small molecule IO therapy have led us to the discovery of FLX475, a potent and selective CCR4 antagonist that blocks T reg migration to the TME in several tumor models . Phase I trials for FLX475 are currently in progress.…”