Development of IDO PET agents for immunotherapy

用于免疫治疗的 IDO PET 制剂的开发

• 批准号: 10304847
• 负责人: Zibo Li
• 金额: $ 39.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304847
• 关键词: Address; Amino Acid Transporter; Animal Model; Apoptosis; Applications Grants; Biopsy; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer cell line; Cell Line; Cells; Clinical; Clinical Pathways; Clinical Research; Clinical Trials; Collaborations; Complement; Complex; Cutaneous Melanoma; Cytotoxic T-Lymphocytes; Data; Development; Diagnosis; Dioxygenases; Disease; Economic Burden; Enzymes; Essential Amino Acids; Evaluation; Exposure to; FDA approved; Foundations; Future; Gene Expression; Goals; Half-Life; Healthcare; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Interferon Type II; Knock-out; Kynurenine; Label; Lead; Lymphocyte; Lymphoid Cell; Malignant Neoplasms; Mediating; Metabolic; Methods; Modeling; Modification; Molecular; Monitor; Mothers; Multi-Institutional Clinical Trial; Mus; Nature; North Carolina; Organ; PD-1 inhibitors; PD-1/PD-L1; PDL1 pathway; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physicians; Play; Positioning Attribute; Positron-Emission Tomography; Predictive Value; Prognosis; Property; Protein Biosynthesis; Radiation exposure; Regulatory T-Lymphocyte; Research; Role; Scientist; Selection for Treatments; Solid; Solid Neoplasm; Specificity; Stromal Cells; T-Cell Activation; T-Lymphocyte; Testing; Time; Tracer; Transportation; Tryptophan; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Universities; analog; base; cancer cell; checkpoint therapy; clinical application; clinical development; clinical imaging; clinical translation; cytokine; density; design; dosage; effector T cell; enzyme activity; experience; experimental study; fluorodeoxyglucose; immune activation; improved; in vivo; inhibitor; interest; molecular marker; novel; patient screening; personalized medicine; predicting response; profiles in patients; prognostic; programmed cell death protein 1; radiotracer; response; screening; side effect; success; targeted agent; treatment planning; tumor; tumor microenvironment; uptake

Abstract Several PD-1/PD-L1 pathway inhibitors were recently FDA approved for various solid tumor malignancies. While for every 10 patients with cutaneous melanoma 3-4 patients will have shrinkage and perhaps durable response, less than 2 out of 10 patients with any other cancer will have any clinical benefit. This is an extremely important problem to be solved because the checkpoint immunotherapies are expensive, lifelong treatments with potential side effect and considerable economic burden in health care in the years to come. In order to solve the low response rate of checkpoint immunotherapy, its combination with other treatment methods are also being widely evaluated to improve the overall response rate. Among them, the combination of PD-1 inhibitor with Indoleamine2,3-dioxygenase (IDO1) inhibition draws special interest in the field due to the special role of IDO1 played in immunotherapy. IDO1 is an enzyme whose gene expression is positively regulated by interferon-gamma (IFN), an immune cytokine that is only produced by immune cell subsets (natural killer, natural killer T cells, CD4 and CD8 T cells, innate lymphoid cells). Therefore, only tumors bearing tumor-infiltrating immune cells (the so called ‘inflamed’) are expected to produce IDO1. Second, IDO1 breaks down the essential amino acid tryptophan that is required for immune cell activation. Elevated IDO1 expression and activity will not only cause tryptophan depletion, but the resulting accumulation of kynurenine metabolites will also block T cell activation, induce T cell apoptosis, and promote the differentiation of naïve T cells into CD4+ regulatory T cells that further inhibit CD8+ effector T cells. Clinical importance of the IDO1 pathway is reflected upon the clinical development of specific IDO1 inhibitors who in combination with PD-1 inhibitors have shown significantly higher antitumor activity across various solid tumors in early clinical studies compared with either agent alone. This fast advancement and dynamic nature of immune system prompt the urgent need to monitor IDO activity repetitively in vivo. In this proposal, we aim to synthesize and evaluate novel 18F labeled agents for IDO1 PET imaging based on both IDO1 substrate and IDO1 inhibitors. Compared with 11C-AMT, our agents not only allow easy synthesis and longer half-life, but also has improved target specificity (for example by blocking hydroxynation at 5 position of Trp ring). We anticipate that results from this grant proposal will allow us to monitor IDO1 activity non-invasively and repetitively in vivo, which will provide the foundation for testing these probes in future multicenter clinical trials using PD-1 inhibitors alone to evaluated whether there is tumor-infiltrating immune cells; or in combination with IDO1 inhibitors across various cancers to monitor IDO1 expression profile during the treatment and select the best time point and effect dosage based on each patient’s profile (personalized medicine).

摘要 几种PD-1/PD-L1通路抑制剂最近被FDA批准用于各种实体瘤 恶性肿瘤而每10名皮肤黑色素瘤患者中，就会有3-4名患者出现萎缩， 也许是持久的反应，10个患有任何其他癌症的患者中只有不到2个会有任何临床益处。 这是一个需要解决的极其重要的问题，因为检查点免疫疗法是昂贵的， 终身治疗具有潜在的副作用，在医疗保健方面的经济负担相当大， 来了为了解决检查点免疫治疗的低应答率，将其与其他 还在广泛评估各种治疗方法，以提高总体缓解率。其中以 PD-1抑制剂与吲哚胺2，3-双加氧酶（IDO 1）抑制剂的组合引起了人们的特别兴趣， 由于IDO 1在免疫治疗中的特殊作用，IDO 1是一种酶，其基因表达是 受干扰素-γ（IFN γ）的正调节，IFN γ是一种仅由免疫细胞产生的免疫细胞因子 亚群（自然杀伤、自然杀伤T细胞、CD 4和CD 8 T细胞、先天性淋巴细胞）。因此只有 携带肿瘤浸润免疫细胞的肿瘤（所谓的“炎症”）预期产生IDO 1。 其次，IDO 1分解免疫细胞激活所需的必需氨基酸色氨酸。 IDO 1表达和活性升高不仅会导致色氨酸耗尽，还会导致由此产生的积累 犬尿氨酸代谢物的释放也将阻断T细胞活化，诱导T细胞凋亡，并促进T细胞凋亡。 将幼稚T细胞分化为进一步抑制CD 8+效应T细胞的CD 4+调节性T细胞。临床 IDO 1途径的重要性反映在特定IDO 1抑制剂的临床开发上，这些抑制剂 与PD-1抑制剂的组合在各种实体瘤中显示出显著更高的抗肿瘤活性 在早期的临床研究中，与单独使用任何一种药物相比。这种快速的进步和动态的性质， 免疫系统对IDO活性的影响提示了在体内重复监测IDO活性的迫切需要。在本建议中，我们的目标是 合成和评价用于IDO 1 PET成像新型18F标记试剂， IDO 1抑制剂。与11 C-AMT相比，我们的试剂不仅合成简单、半衰期更长，而且 具有改进的靶特异性（例如通过阻断Trp环5位的羟基化）。我们预计 这将使我们能够在体内非侵入性和重复性地监测IDO 1活性， 这将为在未来使用PD-1的多中心临床试验中测试这些探针提供基础 单独使用抑制剂以评估是否存在肿瘤浸润性免疫细胞;或与IDO 1组合 在各种癌症中使用IDO 1抑制剂，以监测治疗期间的IDO 1表达谱， 根据每个患者的情况确定时间点和有效剂量（个性化用药）。