Development of IDO PET agents for immunotherapy

用于免疫治疗的 IDO PET 制剂的开发

基本信息

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
项目类别：
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

项目摘要

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).

抽象的最近批准了多种实体瘤的几种PD-1/PD-L1途径抑制剂恶性。每10名皮肤黑色素瘤3-4例患者的患者会收缩，并且也许持久的反应，有10例其他癌症患者中，只有不到2个具有任何临床益处。这是一个非常重要的问题，因为检查点免疫疗法很昂贵，在多年以来来。为了解决检查点免疫疗法的低反应率，它与其他还广泛评估治疗方法以提高总体反应率。其中， PD-1抑制剂与吲哚胺2,3-二氧酶（IDO1）抑制作用的组合引起了人们对由于IDO1在免疫疗法中发挥了特殊作用，因此现场。 IDO1是一种酶，其基因表达为由干扰素 - 伽马（IFN）正调控，这是一种仅由免疫细胞产生的免疫细胞因子子集（自然杀手，天然杀伤细胞，CD4和CD8 T细胞，先天淋巴样细胞）。因此，只有携带肿瘤浸润免疫核管（所谓的“发炎”）的肿瘤有望产生IDO1。其次，IDO1分解了免疫细胞激活所需的必需氨基酸色氨酸。 IDO1表达和活动升高不仅会导致色氨酸部署，还会导致产生的积累 Kynurenine代谢产物还将阻止T细胞激活，诱导T细胞凋亡，并促进将幼稚的T细胞分化为CD4+调节性T细胞，从而进一步抑制CD8+效应T细胞。临床 IDO1途径的重要性反映在特定IDO1抑制剂的临床发展中与PD-1抑制剂结合在各种实体瘤中显示出明显更高的抗肿瘤活性在早期的临床研究中，与任何一种药物相比。这种快速的进步和动态性质免疫系统迫切需要在体内重复监测IDO活动。在此提案中，我们的目标是基于IDO1底物和 IDO1抑制剂。与11C-AMT相比，我们的代理人不仅可以容易合成和更长的半衰期具有提高的目标特异性（例如，通过在TRP环5位置阻止羟基合同）。我们期待该赠款提案的结果将使我们能够在体内非侵入性和重复性地监视IDO1活动，这将为未来的多中心临床试验中测试这些问题的基础，使用PD-1 仅抑制剂即可评估是否存在肿瘤浸润的免疫细胞；或与ido1结合各种癌症的抑制剂以监测治疗过程中的IDO1表达曲线，并选择最佳根据每个患者的概况（个性化医学）的时间点和效果剂量。