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

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 IFNg 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 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 I open-label, multicenter clinical study (NCT02764151) has been initiated.

Oncogenic GLI1 and STAT1/3 activation drives immunosuppressive tryptophan/kynurenine metabolism via synergistic induction of IDO1 in skin cancer cells

“…As positive control demonstrating the repressive effect of the IDO1 product kynurenine, we show that treatment of PBMC cultures with kynurenine significantly inhibited CD4 + and CD8 + T cell proliferation (Fig. S3A, B), in line with its documented repressive effect on T cells [74][75][76].…”

Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells

“…Anti-PD1 therapy is, to date, one of the most effective anticancer immunotherapies. Despite this success, a significant number of patients develop, or will develop, resistance to this therapy [2][3][4][5] . Innate resistance to anti-PD1 therapy is found in 60% of melanoma patients 6 , and 25% develop resistance after an initial phase of objective response 7 .…”

Trial watch: IDO inhibitors in cancer therapy

“…96 In several preclinical tumor models in mice, PF-06840003 strongly reduced intratumoral Kyn levels and inhibited tumor growth in both monotherapy and, with an increased efficacy, in combinatorial regimens with PD-L1 or CTLA4 blockers. 97 Recently, BGB-5777, a potent CNS-penetrating IDO1 inhibitor, enabled a durable survival benefit in a fraction of patients with advanced glioblastoma when combined with nivolumab and radiation therapy. 98,99…”