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Ref Type | Journal Article | ||||||||||||
PMID | (30232146) | ||||||||||||
Authors | Gomes B, Driessens G, Bartlett D, Cai D, Cauwenberghs S, Crosignani S, Dalvie D, Denies S, Dillon CP, Fantin VR, Guo J, Letellier MC, Li W, Maegley K, Marillier R, Miller N, Pirson R, Rabolli V, Ray C, Streiner N, Torti VR, Tsaparikos K, Van den Eynde BJ, Wythes M, Yao LC, Zheng X, Tumang J, Kraus M | ||||||||||||
Title | 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. | ||||||||||||
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Abstract Text | 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 I open-label, multicenter clinical study (NCT02764151) has been initiated. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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PF-06840003 | PF-06840003 | 0 | 0 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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PF-06840003 | EOS200271|PF 06840003 | IDO1 Inhibitor 12 | PF-06840003 is a selective inhibitor of IDO1, which inhibits IDO1-mediated suppression of an immune response, thereby potentially rescuing immune cell proliferation, and subsequently inhibiting tumor growth (PMID: 30232146). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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