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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.
Journal Molecular cancer therapeutics
Vol 17
Issue 12
Date 2018 12
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
PF-06840003 EOS200271|PF 06840003 IDO1 Inhibitor 10 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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown renal carcinoma not applicable PF-06840003 Preclinical Actionable In a preclinical study, PF-06840003 inhibited tumor growth in a syngeneic mouse model of renal carcinoma (PMID: 30232146). 30232146
Unknown unknown colon cancer not applicable PF-06840003 Preclinical Actionable In a preclinical study, PF-06840003 inhibited tumor growth in syngeneic mouse models of colon cancer (PMID: 30232146). 30232146
Unknown unknown melanoma not applicable PF-06840003 Preclinical Actionable In a preclinical study, PF-06840003 inhibited tumor growth in a syngeneic mouse model of melanoma (PMID: 30232146). 30232146
Unknown unknown breast cancer not applicable PF-06840003 Preclinical Actionable In a preclinical study, PF-06840003 inhibited tumor growth in a syngeneic mouse model of breast cancer, however, did not inhibit tumor growth in another mouse model (PMID: 30232146). 30232146
Unknown unknown pancreatic cancer not applicable PF-06840003 Preclinical Actionable In a preclinical study, PF-06840003 inhibited tumor growth in a syngeneic mouse model of pancreatic cancer (PMID: 30232146). 30232146
Unknown unknown breast cancer not applicable Avelumab + PF-06840003 Preclinical - Cell line xenograft Actionable In a preclinical study, PF-06840003 and Bavencio (avelumab) combination treatment inhibited tumor growth in a cell line xenograft model of breast cancer engrafted with human CD34-positive cells (PMID: 30232146). 30232146
Unknown unknown colorectal cancer not applicable Avelumab + PF-06840003 Preclinical Actionable In a preclinical study, PF-06840003 and Bavencio (avelumab) combination treatment inhibited IDO1-mediated immunosuppression and resulted in tumor growth inhibition of 74% while treatment with PF-06840003 alone led to a tumor growth inhibition of 41% in a syngeneic mouse model of colorectal cancer (PMID: 30232146). 30232146