Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.

Bruno Gomes
Gregory Driessens
Derek Bartlett
Danying Cai, The Jackson Laboratory
Sandra Cauwenberghs
Stefano Crosignani
Deepak Dalvie
Sofie Denies
Christopher P Dillon
Valeria R Fantin
Jie Guo
Marie-Claire Letellier
Wenlin Li
Karen A Maegley
Reece Marillier
Nichol Miller
Romain Pirson
Virginie Rabolli
Chad Ray
Nicole Streiner
Vince R Torti
Konstantinos Tsaparikos
Benoit J Van den Eynde
Martin Wythes
Li-Chin Yao
Xianxian Zheng
Joseph Tumang
Manfred Kraus

Abstract

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 IFNγ 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 Treg 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 IDO1 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 antibodies blocking the immune checkpoint ligand PD-L1. We demonstrate that anti-PD-L1 therapy results in increased IDO1 metabolic activity thereby providing additional mechanistic rationale for combining PD-(L)1 blockade with IDO1 inhibition in cancer immunotherapies. Supported by these preclinical data and favorable predicted human pharmacokinetic properties of PF-06840003, a Phase-1 open-label, multicenter clinical study (NCT02764151) has been initiated.