Characterization Of The Selective Lndoleamine 2,3-Dioxygenase-1 (Ido1) Catalytic Inhibitor Eos200271/Pf-06840003 Supports Ido1 As A Critical Resistance Mechanism To Pd-(L)1 Blockade Therapy

Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFN gamma and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment. This leads to effector T-cell anergy and enhanced T(reg)function through upregulation of FoxP3. As a nexus for the induction of key immunosuppressive mechanisms, IDO1 represents an important immunotherapeutic target in oncology. Here, we report the identification and characterization of the novel selective, orally bioavailable IDOI inhibitor EOS200271./PF-06840003. It reversed IDO1-induced T-cell anergy in vitro. In mice carrying syngeneic tumor grafts, PF-06840003 reduced intratumoral kynurenine levels by over 80% and inhibited tumor growth both in monotherapy and, with an increased efficacy, in combination with anti- bodies blocking the immune checkpoint ligand PD-L1. We demonstrate that anti-PDL1 therapy results in increased IDO1 metabolic activity thereby providing additional mechanistic rationale for combining PD-(L)1 blockade with IDOI inhibition in cancer immunotherapies. Supported by these preclinical data and favorable predicted human pharmacokinetic properties of PF-06840003, a phase I open-label, multicenter clinical study (NCP02764151) has been initiated. (C) 2018 AACR.